ETIOLOGY
Members of the cat
family (Felidae) are the only known definitive hosts for the sexual stages
of T. gondii and thus are the main reservoirs of infection. Cats
become infected with T. gondii by carnivorism (1). After
tissue cysts or oocysts are ingested by the cat, viable organisms are
released and invade epithelial cells of the small intestine where they
undergo an asexual followed by a sexual cycle and then form oocysts, which
are excreted. The unsporulated oocyst takes 1 to 5 days after excretion to
sporulate (become infective). Although cats shed oocysts for only 1 to 2
weeks, large numbers may be shed. Oocysts can survive in the environment
for several months and are remarkably resistant to disinfectants, freezing,
and drying, but are killed by heating to 70°C for 10 minutes.
Human infection may be acquired in several ways: A) ingestion of undercooked
infected meat containing Toxoplasma cysts (2); B)
ingestion of the oocyst from fecally contaminated hands or food (3); C)
organ transplantation or blood transfusion; D) transplacental transmission;
E) accidental inoculation of tachyzoites. The parasites form tissue cysts,
most commonly in skeletal muscle, myocardium, and brain; these cysts may
remain throughout the life of the host.
Toxoplasma gondii is an intracellular organism which infects warm blooded animals and humans.
Toxoplasma is
one of the most important sources of foodborne diseases and congenital
infection. An estimated 1.5 billion people globally are infected,
frequently with unknown lifelong health complications (
86,
150).
Toxoplasma is
“Category B pathogenic agent” according the Center for Disease Control
(CDC), and National Institute of Health (NIH). Following acute phase,
the organisms dwell mainly in muscles and brain in cyst forms for the
lifetime awaiting to be reactivated.
Toxoplasma was discovered a
century ago (1908) by Nicolle and Manceaux in an African rodent.
Despite ever since ongoing investigations, yet there is no safe and
effective therapy for congenital, chronic infection or a vaccine
available to prevent toxoplasmosis.
Toxoplasma is an Apicomplexan protozoan parasite with sexual
stage which takes place after oral infection in the intestinal epithelia
of cats, as organisms replicate and mature to form resistant oocysts
passed in the feces (
68).
Oocysts are formed by gametogony and sporogony. Cats usually become
infected within 6 months of their life and pass unsporulated (immature)
oocysts for about 1-2 weeks. Approximately millions of oocysts are
excreted in the feces of cat 5 to 20 days after initial infection.
Unsporulated oocysts become sporulated and mature in about 1 to 2 days
in the moist soil to become infective forms of sporozoites. Sporozoites
within protective oocyst are highly infectious when ingested and oocysts
can remain viable in warm moist soil for over 1 year.
Humans and animals acquire systemic form of infection in asexual stage
through consumption of contaminated animal products including fresh
untreated milk, raw/undercooked meat and seafood or mature oocysts in
water, fruits and vegetables (
52,
54,
150).
After sporozoites are released in the body they transform into
tachyzoites, and attack every type of nucleated cells. Tachyzoites are
the proliferative form in acute stage and reactivated stage of chronic
infection. Bradyzoites are shaped in the dormant cysts during inactive
or chronic stage of infection which replicate more slowly than the
tachyzoites. Small pseudocysts are formed in tissues mainly during the
early infection about a week after infection. Tissue cysts are formed
within the host cells after acute stage and may contain thousands of
bradyzoites which can persist as viable organisms as long as the host
lives
Presence of the free tachyzoites establishes an active toxoplasmosis susceptible to available anti-
Toxoplasma drugs.
Tissue cysts are formed within the host cells which protect the
bradyzoites against antimicrobial agent. The slow replicating
bradyzoites are protected by the cyst wall against the action of the
most available antimicrobial drugs. Bradyzoites are less susceptible to
destruction by proteolytic enzymes than tachyzoites (
52). Tissue
cysts detection in biopsy specimens in addition to presence of
inflammatory cells in the vicinity of the cysts determine patient with
reactivation of dormant
Toxoplasma infection. Sporozoites are highly infectious when ingested. Oocysts can remain viable in environment for long period of time.
Toxoplasmosis Transmission
Toxoplasmosis is not acquired by casual direct contact from infected person with intact skin or airborne.
The common routes of transmission include:
a.
Foodborne by contaminated water, milk, meat, unwashed fruits and vegetables or utensils.
b. Fetal Maternal (congenital).
c. Cat-man and animals: By handling contaminated soil, water and accidental fecal-oral infection.
d. Contaminated blood and organ transplant transmission.
e. Less common routes are “Sexual Transmission” by contaminated semen, and body fluid.
f. Accidental lab acquired infection by inoculation of contaminated material.
g. Breast feed transmission through contaminated milk with
cysts and tachyzoites or environmental contamination of udders with
oocysts.
Toxoplasma tachyzoites are secreted into milk in various farm
animals. Contaminated milk transmission from farm animals has been
reported by the consumption of unpasteurized milk from livestock as well
as less common farm animals like camels and donkeys’ milk (
41,
53,
187).
Tachyzoites survive in the fresh milk and milk products in
refrigeration for several days and can transmit the infection.
Appropriate heating, freezing, or pasteurization can eliminate the
infective forms for safe consumption.
EPIDEMIOLOGY
Toxoplasmosis is a global disease which burden humans and animals. The
infection is usually asymptomatic and mild, while the prevalence of
exposure increases with age and the lifestyle. There are conflicting
reports regarding the decline of the seroprevalence rates of
Toxoplasma infection in United States. It is estimated 22.5% of the U.S.A. population 12 years and older have been infected with
Toxoplasma (
31)
. However,
the infection report is on the rise in Europe (50% to 75%), Africa,
South America, and Asia where the rate of infection is as high as 90% (
181) possibly due to better diagnostic techniques and awareness.
Toxoplasma infection
is endemic in the farms and rural areas representing poverty and lack
of appropriate hygiene. In the United States, the age-adjusted
Toxoplasmaseroprevalence
among people from 6 to 49 years old was reported to be 10.8% (95%
confidence limits 9.6%, 11.9%), and for child-baring women 15 to 44
years old 11.0% (95% confident limit 9.5%, 12.4%) (
101).
Amongst immunocompetent individuals, the initial infection usually
leads to a latent chronic infection that is effectively controlled by
the host immune system. While, babies and immunosuppressed individuals
are in a higher risk for active toxoplasmosis. The immunosuppressed ones
include transplant recipients (bone marrow and solid organ
transplants), patients with hematologic malignancy (
e.g. Hodgkin's disease), and AIDS patients (
70). The incidence of clinical manifestation of toxoplasmosis is uncommon among patients with CD4+ counts >200 cells/µl.
Toxoplasmaencephalitis
has been reported in 30% of AIDS patients with CD4+ counts of less than
100 cells/µl and who are not receiving effective anti-
Toxoplasma prophylaxis or highly active antiretroviral therapy (HAART) (
73). The incidence of
Toxoplasma-induced
encephalitis and the rate of mortality have significantly declined in
United States and Europe where HAART and prophylactics for opportunistic
infections including
Toxoplasma are used and the guidelines for the use are appropriately implemented.
Humans and animals become infected by ingestion of contaminated food or
hands with oocysts excreted from infected cats or consumption of
undercooked meat containing cysts. Sporulated oocysts are transmitted to
humans through soil during gardening, handling infected cat’s feces,
contaminated fruits and vegetables or unpurified water (
12,
20). Indeed, contaminated water is reported as a major source for infection during pregnancy in rural area (
3). In the United States most farm animals including pig, lamb, goat, chicken and game animals were found infected to harbor
Toxoplasma cysts
CLINICAL MANIFESTATIONS
Immunocompetent Patients
Acute toxoplasmosis is mostly subclinical and unnoticed in immune-intact
humans and animals with flue like symptoms, fever, and cervical
lymphadenopathy. The symptoms may last for a few weeks or up to months.
In some individuals the clinical symptoms can be broad and mimic viral
diseases such as infectious mononucleosis, cytomegalovirus and human
herpes virus-6 with manifestation of sore throat, splenohepatomegaly,
and presence of immature lymphocytes in blood stream. In addition,
patients may develop symptoms of hepatitis, pancreatitis, splenitis,
myocarditis, myositis and pain (
31,
148,
150,
151).
Toxoplasmosis can be suspected in those patients with immunosuppressive
conditions or unexplained syndromes in those who travelled to
unsanitary and rural areas.
Maternal and Fetal Toxoplasmosis
Pregnant women become infected by ingesting oocysts containing
sporozoites contaminated food and water or consuming cysts with
bradyzoites infected undercooked meat. The acute toxoplasmosis can be
subclinical and diagnosed by routine serologic examinations. The primary
infection acquired during pregnancy can be transmitted and infect the
fetus via the placenta. However, normal women (immunocompetent) who were
exposed to infection in past and prior pregnancy with low or stable
anti-
Toxoplasma IgG antibody titers are immune and mostly deliver healthy neonates.
Additionally, transplacental transmission occurs by the reactivation of
the chronic or latent infection caused by stressors due to pregnancy and
other immunsuppressors. In any cases, whether oocysts or cysts are the
origin of the infection, the organisms transform to active stage of
tachyzoites and propagate to reach uterus. Tachyzoites then penetrate
the transplacental blood barrier and invade the fetus to compromise the
embryonic development.
Toxoplasma infection rate of
child-bearing women in Brazil is estimated 50% to 80%, and about 50% of
children have antibodies titers. Also, 5 to 23 infants are found to be
infected per 10,000 at birth in Brazil (
54). Contaminated food and water with
Toxoplasma oocysts are reported as the main source of human infection in North America (
22,
130). The
National Collaborative Chicago-based Congenital Toxoplasmosis (NCCCTS)
reported that 78% of moms with infected infants had primary infection
originated from oocysts while only half of these moms had direct contact
with cats America (
22,
130).
While, educational hygienic programs are beneficial to the community,
by itself cannot protect health and socioeconomic consequences related
to the toxoplasmosis. Therefore, an effective and practical global cat
vaccination program, implementation of serological testing of pregnant
women, newborns, and those in high risk of infection followed by
effective preventive and therapeutic regimens are necessary to eradicate
toxoplasmosis.
Congenital Toxoplasmosis
Congenital disease was first reported in a 3 days old baby girl in New
York, 1938 who developed seizure and eyes lesion and died after one
month of birth (
214). Congenital toxoplasmosis is mostly a subclinical infection in about 85% of the infants whose mothers have been treated for
Toxoplasma during pregnancy (
143).
Theses proportions are influenced by factors such as, the time of
maternal infection, treatment given to the mother, organism load and the
genetics of the host and the strain of
Toxoplasma. The
incidence of fetal infection is estimated 2% if the maternal infection
occur before week 10 and 90% in the last weeks of pregnancy. However,
early maternal infection is reported to cause higher risk of disease and
brain damage. Congenital toxoplasmosis manifests with spontaneous
miscarriage and abortion, fetal growth retardation, encephalomyelitis,
intracranial calcifications, hydrocephalus, neurological, mental
illnesses, retinochoroiditis, visual and auditory inflammatory
disorders, cardiovascular abnormalities (
55,
130,
150,
152,
174), gastrointestinal complications and pain (
57,
114,
148,
149,
150,
158).
The severity of complications depends on the gestation period when the
fetus is infected, and the earlier the infection the more severe the
complications (
55,
174).
Those fetuses infected late in gestation may born normal, but develop
symptoms of CNS and retinochoroiditis later in life and the new lesions
may occur in untreated as well as treated children (
55). Retrospective trials (2000–2011) reviled 18% (2206/12035) prevalence rate of anti-
Toxoplasma antibody
in pregnant women. Thirty eight per 10,000 of these women had acute
infection and 5.8% transplacentally infected their neonates as reported
in Argentina
Other factors involve are genetic tendency affecting immune response including HLA may influence clinical outcomes (
99,
123).
As pregnancy progresses, maternal immune system is modified to tolerate
the growing semi-allogeneic fetus, at the same time to protect mom and
offspring against pathogens. Therefore, pregnancy requires a complex
balance in regulation of the immune system at the fetal maternal
utero-embryonic border ensuring tolerance (Th2) of the fetus (
142,
150).
The HLA-G expression reprograms maternal immune response towards
tolerance. Professional antigen presenting B cells can activate or
silent T cells, to partake in regulation of the immune response. B
cells are involved in humoral immune response leading to pre-eclampsia,
during pregnancy
Spiramycin therapy can prevent maternal transmission of infection in
infants, particularly when administered within 8 weeks of seroconversion
(
199). The
proportion of infected newborns was 61% from untreated-infected mothers
and 23% in the group receiving spiramycin treatment (
36).
Retinochoroiditis clinical cases can occur in up to 80% of the infants
born with congenital toxoplasmosis cases with subclinical symptoms,
particularly during puberty and adolescence (
135,
213), which can be prevented by early diagnosis and treatment of the children (
80,
207). Isolation of
Toxoplasma from the placenta is associated with
Toxoplasma infected
infant. The proportion of infected babies depends on the early
diagnosis and treatment given during pregnancy. Usually 90% of
untreated-infected moms deliver infected babies, in contrast 25% of
treated with spiramycin and 50% of those moms receiving spiramycin and
the combined pyrimethamine plus sulfadiazine in alternating courses
deliver seronegative infants (
36).
Ocular Manifestation of Disease
Retinochoroiditis often occurs in congenital infection in neonates but
it can also happen post parturition as acquired toxoplasmosis in
immunocompetent children or adults (
18,
61,
137).
About 21% of adults in Southern Brazil were found infected. In
immunosuppressed and immunodeficient individuals particularly
AIDS
patients ocular involvement may occur due to relapse of a
previously-acquired infection. Patients, often develop multiple active,
atypical, large atypical and bilateral retinal lesions (
145). Many patients may develop ocular disease soon after
Toxoplasma infection.
From 205 patients (10-96 years old) tested for ocular Toxoplasmosis
between 2004-2010 at Palo Alto Medical Foundation Toxoplasma Reference
Laboratory, 11.7% were detected to have recent infection (
100).
Before the
AIDS pandemic only 50 cases of toxoplasmosis were documented in immunosuppressed patients (
121,
182). Then
the number of diagnosed cases significantly increased to several
thousands of cases afterward. Clinical presentation of toxoplasmosis in
these patients varies, as a prolonged unexplained fever to visceral
manifestations, with neurological and pulmonary lesions
In
HIV and
AIDS patients, the major findings are
Toxoplasma-induced encephalitis, as well as ocular, pulmonary or disseminated disease (
118,
119).
In a French hospital database on
HIV with 60,000 patients, the
incidence changed from 29% in 1992 to 14% in 1995 and 2.6% in 1998. This
decline in the number of patients with toxoplasmosis was due to the
advancement of HAART in 1995 as well as other prophylactic compounds
such as combined
trimethoprim plus
sulfamethoxazole.
Patients with encephalitis may develop symptoms of headache, fever, and
neurological symptoms, including dizziness, confusion, coma, motor
defect, visual abnormalities, and seizures.
Immunosuppressed Patients
Patients with dormant toxoplasmosis who receive allogeneic hematopoietic
stem cell transplants or those with graft versus host disease are at
risk of severe or fatal toxoplasmosis by reactivation of their latent
infection. Toxoplasmosis can be manifested with fever, pneumonia or
brain cysts which should alert the healthcare staff of infection.
Seronegative patients who received a seropositive donor organ are
similarly at risk of toxoplasmosis.
Organ Transplantation, Blood Transfusion and Toxoplasmosis
Organ transplant patients with liver, lung, bone marrow, pancreas and
kidney recipients are at risk for toxoplasmosis. This is as a result of
immunosuppressive treatments and organ from infected donors or
reactivated chronic infection followed with a high morbidity and
mortality rate if not detected in early stages. Toxoplasmosis is
considered as underestimated complication following hematopoietic stem
cell transplantation and blood transfusion (
195).
It is commonly detected in autopsy or remains undetected due to the
general and non-specific symptoms combined with lack of clinical
awareness of healthcare personals (
140). In
Japan, while the incidence rate of toxoplasmosis in transplant patients
is low (1.8%) but the mortality in infected patients reported to be
very high (
195). Toxoplasmosis is frequently difficult to diagnose and potentially fatal in kidney transplant recipients.
Women with renal disease who become pregnant are generally in
a very high risk especially in those with chronic renal insufficiency,
end-stage renal disease, dialysis patients and transplant recipients.
Hypertension is the most common life-threatening problem in these moms.
Transplant recipients are at risk for infections including
Toxoplasma and can infect their fetus
.
Renal disease patients have an increased risk for prematurity
and intrauterine growth restriction. For women who conceive after
starting dialysis, the probability of a surviving infant is reduced to
50% (
89,
90).
Therefore, transplant recipients including allogeneic bone marrow and
peripheral blood stem cell for malignant hematologic diseases and severe
congenital immunodeficiency conditions need to be monitored for
Toxoplasma as well as other opportunistic infections (
90).
Mental Diseases and Toxoplasmosis
Toxoplasma attacks the central nervous system with adverse
affect in brain neuro-structural development and pathological, as well
as psycho-behavioral alteration, leading to mental retardation (
11,
24,
211). More recently, maternal exposure or latent
Toxoplasma infection
has been linked to a potential increased risk for autism and
schizophrenic episodes and this hypothesis has received a great deal of
scientific and media coverage (
62).
Toxoplasma can alter brain dopamine (
59,
203). In a longitudinal trial, women with chronic toxoplasmosis had a high risk of self-harm and accidents (
162). Another cross-sectional study indicated that
Toxoplasma seropositive individuals had elevated risk of nonfatal suicidal violence (
216).
Women with chronic toxoplasmosis have higher proportion to deliver
infants with genetic or developmental disorders. For instance premature
fetuses show slower rates of development in the first trimester as well
as postnatal motor development in infants of moms with latent
toxoplasmosis. In addition, these infants had a significant delayed in
ability to control their head movements (p<0.05), due to decreased
strength of embryonic quality control related to immunosuppression
caused by infection in mothers. These defects may be due to severity of
congenital toxoplasmosis, cognitive and developmental deficits or caused
by the diarrheal malnutrition (
103).
A 20 year retrospective trial with military personnel, university
students, pregnant women and blood donors has shown even asymptomatic
Toxoplasma infection can greatly affect humans (
62). The infected subjects varied from controls in the characteristic behaviors suggesting
Toxoplasma influences
personality and increasing probability of traffic accidents of infected
individuals. Dormant infection in mothers is associated with
immunosuppression, and high prevalence to have children with Down
syndrome or schizophrenia (
62).
Another trail evaluated school children in rural area for seropositive
and seronegative, developmental age, body mass, height, physical
fitness, grades and the risk factors of infection like contact with
house cats and consumption of undercooked meat products. The prevalence
was 41% for children to have anti-
Toxoplasma antibodies
measured by IFAT and ELISA tests. The rate of infection was lower in
boys (36%) than in girls (44%). The developmental age measures with
electrophoretical mobility of nuclei and school performance was
significantly lower for
Toxoplasma infected girls compared to
matched controls. Those boys who ate raw/undercooked meat products were
most likely to be seropositive (
134).
Another observational study (2000-2012) from Nepal, declared congenital
toxoplasmosis as second to malaria with highest parasitic burden of
9255 disability-adjusted life year of 95% (
48).
Toxoplasmosis and Autoimmune Disease
While, etiological factors in the induction of autoimmune disease remain
obscure a possible link with toxoplasmosis may exist.
Immunosuppressants, and monoclonal antibodies such as anti-TNF are
extensively used in the treatment of autoimmune diseases and organ
transplantation may provoke acute toxoplasmosis in these patients. Sera
of 1514 patients with 10 autoimmune diseases in Europe and Latin America
and 437 controls investigated for the prevalence of auto-antibodies and
anti-
Toxoplasma antibodies IgG and IgM in serum (
186). Anti-
Toxoplasma antibody IgG was positive in 42% of patients versus 29% of controls (
p<0.0001). Anti-
Toxoplasma antibody IgM was more prevalent in patients with anti-phospholipid syndrome (
p<0.01), systemic sclerosis (
p<0.05) and inflammatory bowel disease (
p<0.05), than in controls. Anti-
Toxoplasma antibody IgG was associated with ANCA-associated vasculitides (
p<0.01), anti-phospholipid syndrome (
p<0.0001), autoimmune thyroid diseases (
p<0.0001), systemic sclerosis (
p<0.0001), and rheumatoid arthritis (
p<0.0001). The findings support the notion that
Toxoplasma may contribute to the pathogenesis of autoimmune disease (
150,
152,
186).
Chronic inflammatory bowel disease (IBD) is mainly Crohn’s disease and
ulcerative colitis. Chronic inflammatory bowel disease is considered as
an exaggerated immune response to gut microbiota, and toxins from gram
negative lipopolysaccharid (LPS), bypassing the inflamed mucosa (
23,
153,
154).
Additionally, extensive use of immunosuppressive agents in IBD patients
increases the possibility to develop opportunistic diseases and
toxoplasmosis. The greatest risks of infections may relate to the
combined use of immunomodulating agents rather than to individual drugs (
57).
Chronic inflammatory bowel disease patients treated with
corticosteroids, azathioprine, methotrexate, cyclosporine, and
TNF-blocking biological are susceptible to infections. Crohn’s patients
are prone for gut abscess formation followed by infectious complications
as well as toxoplasmosis. This alerts the physicians treating patients
with IBD to be aware of the risk for infectious as well as of strategies
to minimize these infectious complications in these patients (
57,
150).
Severe colonic inflammatory response is observed in pregnancy model for
toxoplasmosis, associated with significant shortening in colonic length,
with infiltration of lymphocytes, and macrophages and microabscess
formations in the cryptic structures in infected dams (
148,
149,
157,
158).
Chemically induction chronic inflammatory bowel disease model for
ulcerative colitis utilizes oral administration of dextran sulfate
sodium (DSS) for 3-16 cycles to induce chronic inflammation in the gut (
153,
154)
with increased gram negative gut microbiota. Colitis significantly
increases colonic LPS (550-fold) in concentrations. Similarly,
Toxoplasma induced ileitis with significant elevated ileal concentrations LPS (3,300-fold)
P<0.01 (
58). Sera from 119 chronic inflammatory bowel disease patients and 98 controls were assessed for anti-
Toxoplasma antibody. Titer of anti-
Toxoplasma was found higher in chronic inflammatory bowel disease patients than controls suggesting possible involvement of
Toxoplasma in the pathogenesis of chronic inflammatory bowel disease, and specifically in Crohn’s disease (
114). Finally,
while inflammation is essential mechanism of defense against pathogens,
excessive and chronic inflammatory response as in
Toxoplasma infection severely damages the tissues and organs similar to as observed in patients with autoimmune diseases (
30,
150).
Toxoplasmainfection causes an exaggerated Th1 systemic inflammatory response which enhances pro-atherogenic effects (
115,
170).
Toxoplasma and Sexual Attraction
Recent investigations reveal mind alteration and sexual attraction in
Toxoplasma infected rats to seek cat’s urine odor, while normal rats fear and flight as innate survival defensive (
91,
106,
150).
Therefore, brain altered and fearless infected rodent is eaten by cats’
species (definitive host) to complete the organism’s sexual lifecycle.
Toxoplasma impairs
the limbic brain neurons responsible for instinct defensive behavior
and judgment activity adjacent to limbic regions of sexual desire when
exposed to cat’s odor (
91).
Toxoplasmosis is sexually transmitted to the partner by contaminated
semen during natural mating. Also, artificial insemination of semen from
infects animals’ results in vertical transmission with 80% embryonic
growth disruption and abortion (
4,
117,
209). In
fact, sexual transmission with infected semen during natural mating as
well as artificial insemination remains as a potential route for
vertical transmission to progeny in humans. Additionally, pregnant women
with latent infection have a higher risk of infants with genetic or
developmental disorders such as premature and slow motor development.
These defects may be linked to malnutrition due to diarrhea and gut
disorders or congenital toxoplasmosis induced developmental deficits (
103,
152).
LABORATORY AND RADIOLOGICAL DIAGNOSTICS
Toxoplasma infection is a serious health risk issue for the
fetus and immunocompromised patients. Therefore, rapid and accurate
diagnostic measures are required for possible preventions and available
therapeutic modalities.
Toxoplasma infection and toxoplasmosis
can be confirmed by the use of various methodologies including
serological tests, polymerase chain reaction (PCR), and histological
exams, as well as isolating the organisms and imaging
analysis. Diagnosis of toxoplasmosis is mainly based on the serological
tests detecting anti-
Toxoplasma-specific antibodies in the patients’ sera samples. Most of the commercial serological kits currently available are based on
Toxoplasma lysate antigens (
137).
Lab tests are less reliable in the immunosuppressed patients which
diagnosis performed in the context of the clinical development.
Serologic Diagnosis for Toxoplasma Antibodies
The detection of
Toxoplasma-specific IgM, IgG, IgA are to
establish the infection in patients exposed to the organisms. Patients
with negative IgG and IgM do not have serological evidence of prior
exposure to the organism and are considered as uninfected; except for
patients with organ transplant which serological tests alone are not
reliable. Patients with positive IgG but negative IgM are possibly
infected for several months or years. Positive or negative IgG and
negative IgM serological tests results obtained in commercial
laboratories are usually reliable (
113,
171).
Positive IgM test may indicate a recent acquired or an activated
infection in the patients. In neonates a positive IgM test 5 days or a
positive IgA after 10 days of birth confirms congenital toxoplasmosis.
Sabin-Feldman dye test, a complement-lysis-based assay with relative sensitivity and specificity to measure anti-
Toxoplasma IgG antibodies is the international “gold standard” for diagnosis of toxoplasmosis (
183).
The Sabin-Feldman dye test is considered to be somehow more reliable
than commercially available ELISA kits in some labs, but the test is
time consuming and requires live organisms treated with each serum
dilution to be analyzed under the microscope (
38).
Available commercial kits require parasite antigen and have interassay variability. The recombinant
Toxoplasma SAG1
antigen expressed in bacteria as inclusion bodies, and refolded in
native form by dialysis has shown promising results. The antigen used in
ELISA can detect IgG in saliva and sera with 100% sensitivity and
specificity (
32). In
addition, the new multiplex, BioPlex® 2200 automated analyzer (Bio-Rad
Laboratories, Hercules, CA) and ToRC IgG/IgM kit can detect anti-
Toxoplasma antibodies
in the same assay and is considered superior to Platelia IgG/IgM ELISA
test (Bio-Rad Laboratories) or Toxo-Screen Direct Agglutination assay
(bioMérieux, Lyon, France) with 91.3% specific and 97.8% sensitive to
detect IgG and IgM, thus yielding more precise diagnosis of acute
Toxoplasma infection (
82).
Isolation of Toxoplasma
Detection of the organisms establishes an acute infection. Isolation can
be done by tissue culture or mouse inoculation. Cell culture is more
widely available, but mouse inoculation is more sensitive. Bradyzoites
in cysts and free tachyzoites in infected tissue biopsies are detected
using immunohistochemical staining, Giemsa and other direct staining
methodologies.
Immunohistochemical Staining (IHC)
IHC is a reliable technique for possible visualization of organisms in
biopsies or sections. The paraffin-embedded sections are cut,
deparaffinized with xylene, rehydrated in alcohol baths, washed in PBS
with 0.1% bovine serum albumin (BSA), then quenched for endogenous
peroxidase activity by incubating in 3% hydrogen peroxide in methanol 30
min, and blocked with rabbit serum (Dako #N1699) for 30 min. The
sections are incubated with poly or monoclonal anti-
Toxoplasma antibody,
diluted 1:500 for 90 min and developed with DAB-Chromogen
(DakoCarpenteria, CA) for about 5 min until signal developed and
subsequently counterstained with hematoxylin then ammonia treated,
dehydrated stepwise through alcohol, and cleared in xylene (
148,
158). IHC detection of organisms proves infection, but negative does not rule out the disease.
Giemsa Staining
Smears or paraffin embedded slide sections stained withGiemsa reveals a fine nuclear detail of
Toxoplasma organisms. It stains nuclei of the
Toxoplasma organisms and permits differentiation among the cells (
149).
Polymerase Chain Reaction (PCR)
Amplification of
Toxoplasma DNA is preferred
technique to diagnose congenital and disseminated toxoplasmosis in
HIV/AIDS patients. PCR is applied to body fluids including blood,
saliva, urine, CSF, bronchoalveolar lavage as well as brain tissue.
Sensitivity may be variable, but specificity remains high. The real-time
PCR assay has been shown to be the best-performing technique to detect
DNA in amniotic fluid with 98% sensitivity and 100% specificity compared
to other conventional PCR and nested PCR, or multiplex-nested-PCR
techniques similarly utilizing B1 gene primers (
198).
Pathology
The visualization of tachyzoites in infected tissue specimens
with IHC stain or Geimsa stained smears of body fluids (amniotic fluid,
CSF, bronchoalveolar fluid) along with infiltration of inflammatory
cells can establish the diagnosis of acute infection.
Radiologic Examinations
CT and MRI scans showing calcifications in the brain or
multiple lesions are major diagnostic modalities suggesting the presence
of
Toxoplasma encephalitis. The other major differential
diagnostic possibility is CNS lymphoma. Brain biopsy may be indicated in
a patient with sporadic lesion (
31,
139).
Fetal Maternal Toxoplasmosis Diagnostics
Toxoplasma infection during pregnancy causes a
serious health risk for the fetus. Thus, quick and accurate diagnostics
are essential for possible preventions and available therapeutics. Fetal
maternal toxoplasmosis is diagnosed using serological assays to detect
types and levels of anti-
Toxoplasma antibodies. Sera exam is
necessary to be repeated during the gestation period and suggested at
the birth. Therefore, pregnant women are routinely tested in Austria,
France, Italy, Portugal, and Uruguay for antibodies detection. In
addition, limited screening program are utilized in Belgium, Germany,
and Switzerland. Fetal and neonatal screening for congenital
toxoplasmosis are performed on more than two million pregnant women each
year in Europe, and North and South America with estimated cost of more
than 500 million dollars annually (
150,
165).
However, United States so far does not require routine screening of
pregnant women for toxoplasmosis. Considering significant variation of
the disease manifestation and cosmopolitan distribution of
Toxoplasma infection, it is recommended that infants with unexplained severe systemic disease to be tested for congenital toxoplasmosis (
9).
Seronegative pregnant women signifying no previous infection are at
risk for infection and recommended to be serologic tested monthly until
birth.
Standard laboratory diagnosis of toxoplasmosis is based on the presence of IgM and IgG anti-
Toxoplasma antibodies, and molecular technology is utilized as alternative tools to increase sensitivity (
96). Typical infection is associated with high anti-
Toxoplasma IgM
antibody followed by a rise in IgG levels in 1 to 3 weeks after
infection. However, atypical infection with IgG sero-conversion occurs
in pregnancy without detectable IgM levels. These cases are very
difficult to diagnose in congenital toxoplasmosis (
72). The pregnant women with low or steady levels of IgG anti-
Toxoplasma antibody
have been previously exposed to the organism and fetus may remain safe.
However, detection of IgM or elevation of IgG anti-
Toxoplasma antibodies
suggest a new acquired or reactivation of chronic/latent infection due
to possible immunosuppression with a risk of infection for the fetus.
Therefore, amniotic fluid exam can be performed to determine health
status of the fetus and possible exposure to the infection.
Toxoplasma-antibodies in infants during the first year of life present congenital toxoplasmosis.
In serious cases of neurological disorders including visual
and auditory impairments, IgM and IgG antibodies combined with CSF
polymerase chain reaction (PCR) is recommended to detect
Toxoplasma DNA.
Of 58 infants (0 to 180 days) born from infected moms, CSF PCR was
positive in 46.5% and 100% negative in uninfected healthy infants. PCR
was positive in 80% of those infants with hydrocephalus, 53% in cerebral
calcifications and 60% of those with eye complications. Therefore,
infants with neurological disorders, IgM and IgA antibodies combined
with CSF PCR, are considered to yield a higher sensitivity for diagnosis
of congenital toxoplasmosis when compared with each test alone (
147).
Anti-
Toxoplasma IgG and IgM with similar specificity
and sensitivity are detected with the Vidas (bioMérieux), Architect
(Abbott), and Liaison (DiaSorin) systems. The LIAISON system is a fully
automated system based on chemiluminescence and antigen bound to
magnetic microparticles. The Vidas system fits the needs of smaller
laboratories with high specificity and a powerful avidity test in
pregnant women and infants sera. A confirmatory serologic test is
recommended to improve the rate of detection of congenital toxoplasmosis
at 1 year of life (
141,
164).
Additional serological tests to detect
Toxoplasma specific
IgG and IgM in blood samples are the indirect fluorescent antibody test
(IFAT), microparticle enzyme immunoassay (MEIA) and enzyme-linked
fluorescent assay (ELFA) used according the manufacturer’s instructions.
The IgM sensitivity is reported 60% with specificity 100% except for
IFAT with 92% and ELISA-IgA of 57% respectively (
10). The molecular diagnostic include Western Blot analysis to detect anti-
Toxoplasma IgM and IgA in infected infants (
49). Cerebral toxoplasmosis is fatal if not treated and difficult to diagnose. Detection of anti-
Toxoplasma IgM in CSF is reported as a reliable marker for cerebral Toxoplasmosis (
96).
PATHOGENESIS
Following ingestion of the tissue cyst or oocyst form by
humans, gastric digestive juices disrupt their outer cyst wall releasing
infective forms, bradyzoites and sporozoites which rapidly invade
intestinal enteroepithelial cells. They transform to active and
replicate form of tachyzoites and infect adjacent cells to reach the
lymphatic and blood stream. Organisms infect all nucleated cells and
further invade brain, eye, heart and skeletal muscle and fat tissues as
well as the placenta and fetal tissue to result congenital infection.
Oral gavage of cysts containing bradyzoites resulted in inconsistent
prototype for dissemination. Luciferase-derived
in vivo signal
imaging indicates significant numbers of tachyzoites are first observed
in chest area and later signal spread to other organs and abdominal
area. In contrast, mice infected via direct ingestion of infected
organs, the signals from organisms are first detected replicating in the
abdominal area (
21).
Tachyzoites trigger a strong immune response responsible for
the clinical symptoms of toxoplasmosis during the acute or reactivation
of the latent infection. In immunocompetent individuals free tachyzoites
provoke a strong immune system and are killed by serial activation of
complement associated antibodies, reactive oxygen and nitrogen radicals,
osmotic fluctuations, and intracellular acidification. Humoral immune
responses, IgG, IgM, and IgA are responsible for lysing extracellular
tachyzoites. However, some tachyzoites attach cells and invade
intracellular milieu and parasitophorous vacuole to avoid the innate and
adaptive immune mechanisms. These tachyzoites transform into
bradyzoites with distinct structure and slower metabolism which
replicate to form the resistant tissue cysts. Tissue cysts primarily
form in muscles, heart, brain, and retina, are responsible for the
chronic infection. In immunocompetent individuals the cell-mediated
immunity response including macrophages, natural killer cells, CD4+ T
cells (Th1) and CD8+ T cells are responsible to control the propagation
of the organisms (
2,
142). Cytokines
such as TNFα, IFNγ, IL-1, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15 mediate
protective immunity. Co-stimulatory molecules such as CD28 and CD40
ligand are critical for the regulation of IL-12 and IFNγ production in
response to the parasite. It is possible that different cytokines
production initiates the extent of the infection in individuals. Hence,
Toxoplasma may specifically impact levels of circulating cytokines, and results in differences in the clinical severity of toxoplasmosis (
163). Tissue-specific immune responses, such as that in the central nervous system are being currently elucidated.
Immunosuppression caused by T-cell mediated immunity
impairment as in administration of anti-CD52 monoclonal antibody, in
AIDS, allogeneic hematopoietic bone marrow and transplantation may lead
to the transformation of bradyzoites to the rapid dividing tachyzoites
and reactivation and dissemination of the toxoplasmosis. Tachyzoites
cause significant pathology in severely immunocompromised individuals
with as high as 100% mortality rate if untreated. While in the presence
of intact innate, humoral and cellular immune responses the acute
infection eventually transition into the life-lasting chronic and
asymptomatic phase waiting for an opportunity to become activated.
TOXOPLASMA GENOTYPES
The organism genetic analysis obtained from humans and animals mainly in North America and Europe has categorized
Toxoplasma into
three genetically distinct clonal lineages (types I, II, III) which may
reveal important biological and clinical differences (
105,
132,
184,
189). For
instance, strains differ in a number of phenotypes, such as virulence,
persistence, oral infectivity, and migration capacity, induction of
cytokine expression, modulation of host gene expression and severity of
disease. Therefore, the outcome of toxoplasmosis in patients becomes
also variable (
132). Type
I strains demonstrate more acute and a greater ability to migrate and
disseminate as well as more virulence than type II strains. Type I and
II strains are significantly more prevalence and associated with disease
in humans. Type III strains are more common in animals but less
frequent observed in cases of human toxoplasmosis (
92).
In Europe, chronically infected pregnant women are predominantly
infected with type II and in South America (Colombia) with types I and
III (
166). Recent
genetic investigations in North America reveals most outbreaks result
from contaminated water and vegetables with oocysts in cats’ feces and
transmitted to humans and animals. The National collaborative
Chicago-based congenital toxoplasmosis reported 78% of the mothers from
epidemic area acquired primary infection from oocyst forms, while only
49% kept house cats (
22,
150).
CURRENT AVAILABLE ANTI-TOXOPLASMA THERAPIES
Toxoplasma infection in healthy immunocompetent
individuals is hardly detected and or treated. The related symptoms are
usually resolved in a few weeks or months. However, treatments are
required in unresolved (after 2 to 4 weeks) or severe cases as well as,
in immunosuppressed and HIV/AID and congenital toxoplasmosis.
Pyrimethamine (Daraprim)
Antimicrobial pyrimethamine, a folic acid antagonist which
inhibits the dihydrofolate reductase (DHFR), is a major enzyme in the
purine pathway in organism (
108). Pyrimethamine
is effective against tachyzoites in acute toxoplasmosis but has no
effect on cysts in chronic stage of disease. In addition it has
cytotoxity effects as shown
in vitro (
43,
56) and in animal studies (
168).
Pyrimethamine should be administered in combination with
other effective drugs as the efficacy is very limited. The possibility
of relapses following discontinuation of the drug in immunosuppressed
patients warrants prolonged duration of treatment following the acute
phase of the infection. Pyrimethamine is metabolized in liver and its
pharmacokinetics is not altered by renal insufficiency. The lack of
correlation between serum concentrations and varying pharmacokinetics
between patients suggest genetic differences in metabolizing the drug
and monitoring serum levels of pyrimethamine can be useful in patients.
Oral administration daily is necessary treatment in acute
infection. Pyrimethamine in immunocompetent adults at a daily dose of 25
mg (0.3 mg/kg) leads to serum concentrations of 0.9 to 1.7 µg/ml. In
HIV patients a dose of 50 to 75 mg/day leads to serum concentrations of 1
to 4.5 µg/ml with peak levels at 3.3 hours (
105). A minimal serum concentration of 3.0 µg/ml may be required to treat
Toxoplasmaencephalitis in HIV infected patients (
212). Serum
concentration 4 h after a daily dose of 1 mg/kg in infants was 1.3
µg/ml which decreased to 0.7 µg/ml if was given every other day (
131)
which remained fairly stable during treatment period. Concentrations of
pyrimethamine achieved in infants' sera with standard dosages had
effective inhibitory effect
in vitro on most virulent strains including the RH strain (
131). CSF concentrations of pyrimethamine range 10 to 25 % of the serum in patients with leukemia or AIDS patients with
Toxoplasma encephalitis (
212). Half-life
of the drug was 40 hours in brain tissue and 28 hours in serum, which
implies that a dose of 50-100 mg every other day is convenient for
prophylactic therapy in AIDS. Pyrimethamine may interact with other
drugs including phenobarbital affecting hepatic enzymes and the drug
metabolism can be altered in liver disease patients.
Anti-
Toxoplasma activity of sulfonamides is by inhibiting dihydrofolate-synthetase enzyme essential in the purine pathway in
Toxoplasma, while have minor cytotoxicty and side effects (
1,
122).
Sulfadiazine is
commonly prescribed while other sulfonamides, sulfapyrazine,
sulfamerazine and sulfadimidine are also effective and can be used as
trisulfapyrimidine combination (sulfadimidine, sulfamerazine and
sulfadiazine).
Spiramycin
A macrolide antibiotic, spiramycin is fairly safe and acts on
Toxoplasma by inhibiting protein synthesis demonstrated
in vitro and
in murine model for toxoplasmosis. It is exclusively used to prevent
maternal-fetal transmission of organisms. However spiramycin monotherapy
is less effective than pyrimethamine or sulfadiazine. Spiramycin is
primarily used in pregnant women to prevent
Toxoplasma fetal maternal transmission in those with active or acquired
Toxoplasma infection
in early gestation period (≤18 weeks). It is mainly to prevent
transmission of infection and not effective after transplacental
transmission of organisms (
76). Spiramycin is used broadly in Europe (
76). Spiramycin has no teratogenic effect and is well-tolerated to be administered for several months.
A clinical trial in pregnant women treated with a daily dose
of 3 g, the maternal serum, cord blood and placenta tissue average
concentrations were 1.9 µg/ml, 0.8 µg/ml and 6.2 µg/g respectively (
74). The fetal-maternal ratio in sera was about 0.5 by the weeks 21-24 of pregnancy and 0.7 at birth (
64).
Administration of Spiramycin to infected pregnant women is associated
with a significant decrease (60%) of the risk for placental and fetal
infection (
43) and maternal-fetal transmission (
47). Spiramycin
is rapidly adsorbed by sera, with elevated levels to persist in tissues
and placenta. It is ineffective against cerebral toxoplasmosis in AIDS
patients (
112). Spiramycin
application is specifically to protect fetus against acquired
toxoplasmosis during pregnancy in a dose of 3 g/day oral route in 2 or 3
divided doses [206].
Clindamycin
The effect of
clindamycin on
Toxoplasma has been established in murine models of acute and chronic toxoplasmosis (
7). Clindamycin
is absorbed following oral administration with peak of 4 and 8 µg/ml
after ingestion of 300 and 600 mg tablets respectively (
116)
and a half-life of about 2.7 hours. It is excreted in urine and bile,
and partially metabolized in active and inactive metabolites.
Approximately 90 % of Clindamycin is bound to plasma proteins and
dispersed in retina, iris and choroid and retina, but CSF and brain
penetration is not proven. The efficacy of clindamycin plus
pyrimethamine has been shown to be comparable to that of pyrimethamine
plus sulfadiazine in AIDS patients with
Toxoplasma encephalitis (
39).
Other Macrolides
The inhibitory activity of roxithromycin, clarithromycin, and azithromycin has been observed
in vitro in high concentrations but the mechanism of action is not well known (
7,
8,
85). Roxithromycin is protective in murine with acute toxoplasmosis and high virulent strain of RH
Toxoplasma but does not protect against cyst forming in the brain (
8,
33).
Atovaquone
Atovaquone (566C80, hydroxy-1,4-naphthoquinone) is FDA approved in Adults toxoplasmosis (
93). It is active
in vitro and
in vivo (
179) and the most active compound against tachyzoites and cysts, yet not approved for fetal–maternal and children toxoplasmosis (
35). Atovaquone is anti-fungal
Pneumocystis pneumonia and anti-
Babesia microti, causative of human blood-borne babesiosis endemic in New England and Northeastern of United States (
94,
95,
159). Atovaquone acts by targeting mitochondrial respiration to block and collapse the membrane in the organisms (
71,
193). Atovaquone
has a half-life of 1.5–3 days and mainly binds to plasma proteins (99%)
and is excreted into feces (94%) without being metabolized (
177). Atovaquone
has been shown to protect against maternal congenital toxoplasmosis and
inflammatory complications in animal model (
149,
158).
Atovaquone (administered orally as a suspension) combined
with either pyrimethamine or sulfadiazine as treatment for acute disease
for patients with
Toxoplasma encephalitis has been shown to be
effective, with 6-week response rates of 75% (21/28 patients) for
atovaquone plus pyrimethamine and 82% (9/11) for atovaquone plus
sulfadiazine. Thus,
atovaquone plus pyrimethamine can be used as an alternative treatment for patients intolerant to sulfonamides, and
atovaquone plus sulfadiazine for patients who are intolerant to pyrimethamine (
34,
107). In addition, combined atovaquone plus pyrimethamine or sulfadiazine are also effective in for
Toxoplasma encephalitis in AIDS patients (
34).
Trimethoprim, Trimetrexate, Piritrexime
Folate Inhibitors with mechanism of action similar to pyrimethamine to inhibit DHFR are reported to be effective
in vitro and in animal models against
Toxoplasma and other opportunistic disease
Pneumocystis pneumonia (
79,
156).
Trimethoprim plus sulfamethoxazole combined regimen (trimethoprim 10
mg/kg/divided in two doses) has reported to have similar efficacy as
pyrimethamine plus sulfadiazine in AIDS patients with
Toxoplasma encephalitis (
27,
108,
191,
201,
202).
Other Drugs
Combined dapsone (100 mg/kg/day) plus pyrimethamine (18.5
mg/kg/day) protected 100% of infected mice with no relapses after
discontinuation of the treatment (
42). Qinghaosu (artemisinin) extracted from a Chinese herb and its derivatives have
in vitro activity against tachyzoites of
Toxoplasma [8] as well as malarial organisms and herpes viruses.
Immunomodulators
The role of
cellular immunity in the defense against
Toxoplasma has
been clearly established. Macrophages play an essential role in early
immune response against infection. Recent findings indicate that IFNβ
production by infected cells is associated with organisms’ death,
independent of IFNγ activation. This action is dependent on endosomal
Toll-like receptors in macrophages and the cytoplasmic receptor retinoic
acid-inducible gene 1 (RIG-I) in fibroblasts (
132). Additionally, IFNγ is effective
in vitro and
in vivo possibly by activating macrophages and stimulating natural killers and humoral response (
128) and interfering in the metabolism of
Toxoplasma. IFNγ was effective in mice with chronic
Toxoplasma encephalitis (
196) and protected against lethal infection (
85). Combined IFNγ plus roxythromycin demonstrated synergistic effects in murine encephalitis (
85).
Recombinant interleukin 2 significantly decreased mortality in mice by
reducing the number of cysts in brain [188]. IL-12 improved survival of T
cell deficient mice during
Toxoplasma infection by enhanced production of IFNγ from natural killer cells (
75). The combined IL-12 plus clindamycin or atovaquone has been shown to be effective in murine toxoplasmosis well (
5).
Combination Drugs
Pyrimethamine plus sulfonamides have synergistic effects to increase pyrimethamine activity 6-8 fold against tachyzoites (
200) as demonstrated in animal models (
168).
In vitro studies reveal, pyrimethamine in 0.02 µg/ml and sulfadiazine 0.1 µg/ml to have synergism (
43)
versus inhibitory IC50 for sulfadiazine monotherapy to be 2.5 µg/ml. A
minimal serum concentration of pyrimethamine 0.75 µg/ml in the presence
of sulfonamides is needed to treat
Toxoplasma encephalitis in HIV infected patients (
212).
In infants serum concentration at 4 h after a daily dose of 1 mg/kg was
1.3 µg/ml which decreased to 0.7 µg/ml when was given every other day (
131).
Combined pyrimethamine plus sulfadiazine with proven
synergistic effect remains as basis treatment for human toxoplasmosis,
but possible side effects including rash creates major obstacle for
application. Pyrimethamine plus sulfadoxine can be used for prolong
treatment and available in oral or parenteral route. In case of rash
desensitization program is practiced (
172). Combined pyrimethamine plus sulfadoxine has been shown with synergistic effect in murine toxoplasmosis (
122),
while 100% of organisms were eradicated when treated immediately and
only 32% when delayed 72 hours after inoculation of
organisms. Pyrimethamine plus sulfadoxine has severe side effects.
Other Combinations
Combined pyrimethamine plus clindamycin has been shown to be effective in AIDS patients with
Toxoplasma encephalitis (
39). Similarly combination of trimethoprim plus sulfamethoxazole (
201,
202),
pyrimethamine plus atovaquone or atovaquone plus sulfadiazine have been
demonstrated to be effective as well in the AIDS population (
34,
107).
Oral administration of trimethoprim plus sulfamethoxazole and
intravenous clindamycin combined with short-term dexamethasone for the
cerebral edema, have been reported effective against cerebral
toxoplasmosis in patient with improved symptoms and reduced antibodies (
96). Combined clarithromycin plus sulfadiazine is reported with high synergistic effect (
6).
THERAPEUTIC INDICATIONS
Acute Toxoplasmosis in Immunocompetent Patient
Immunocompetent patients with severe symptomatic disease
including, lymphadenopathy, myositis, myocarditis, hepatitis, or ocular
involvement require treatments.
Acute Infection During Pregnancy
Spiramycin generally is recommended to manage fetal maternal
infection for the first and early second trimesters. Spiramycin can
reduce the risk of maternal-fetal transmission when treatment started
before infection has reached the embryo. Spiramycin in U.S.A is
available through the Investigational New Drug (IND) process at the Food
and Drug Administration [FDA, Administration (301/796-1600). Spiramycin
is not recommended when fetus is suspected to be infected (see below
recommendations for pyrimethamine plus sulfadiazine and folinic acid).
Application: Spiramycin is recommended for
pregnant women suspected acquired the infection < 18 weeks of
gestation and administered until delivery.
Spiramycin (PO) dose: 1g (3 million units)/8 hr or total: 3g (9 million units)/day
Alternatively pyrimethamine plus sulfadiazine and leucovorin
is given to pregnant women in the late second and third trimesters to
treat positive infected fetus by means of PCR for amniotic fluid or
suspected with abnormal ultrasound after the 18 week of pregnancy
following written consent and under close supervision (
138,
139).
Pyrimethamine plus sulfadiazine passes placental barrier and is
recommended for women with acquired acute infection after 18 weeks of
gestation. Due to the increased risk of maternal-fetal transmission of
the organisms in late pregnancy indicated (
180).
Pyrimethamine 50 mg/day and sulfadiazine 3g/day is administered until
delivery with hematological monitoring. Pyrimethamine plus sulfadiazine
significantly reduce the rate of
Toxoplasma isolation from the
placenta and antibody synthesis of specific IgM and IgG titers in the
neonate. Side effects include fetal injury. Trimethoprim plus
sulfamethoxazole has been recommended as an alternative to treat
congenital toxoplasmosis during pregnancy (
45).
Recommendation: Pyrimethamine is teratogenic and should not be used in pregnancy before week 18.
Recommended for women suspected of having acquired the
infection at ≥ 18 weeks of gestation; those with positive amniotic fluid
PCR test or abnormal ultrasound suggestive of congenital toxoplasmosis,
and who is over 18 weeks of gestation.
Application: Pyrimethamine: 50 mg/12 hr for 2 days followed by 50 mg daily (PO)
Sulfadiazine: 75 mg/kg (first dose) followed by 50 mg/kg every 12 hr (maximum 4 g/day) (PO)
Leucovorin (Folinic acid): 10-20 mg daily (during and for 1 wk after pyrimethamine therapy) (PO)
Congenital Toxoplasmosis
Infants with congenital toxoplasmosis require therapy during
the first year of life in order to treat acute disease or to prevent
secondary complications (
172).
About 75% of infants which were exposed to infection during gestation
period from moms treated with spiramycin develop latent disease.
Postnatal treatments are necessary when fetus diagnosed positive by
means of amniotic fluid, specific and IgM or IgA seropositive for active
infection after birth or
Toxoplasma isolated from
placenta. In contrast only 10% of infants may have negative isolation
when their infected mother was not treated, 25% from mother treated with
spiramycin and 50% from mothers received spiramycin and pyrimethamine
plus sulfadiazine combined with leucovorin as typical drugs in
alternation therapy for 1 year (
36,
139).
Therefore, infants with negative PCR in the amniotic fluid and negative
results for organisms in placenta still require treatment to prevent
congenital toxoplasmosis.
Pyrimethamine plus sulfadiazine is the standard treatment to
prevent ocular symptoms. The Chicago Collaborative Treatment Trial
recommendation requires continuous therapy for the first year of life in
those children with possible infection (
127).
Acute retinochoroiditis has been shown to become subclinical within two
weeks or less following the application of therapy and without visual
loss in most treated patients (
133). Most infants without hydrocephaly have normal IQ ranges versus half of those with hydrocephaly (
127,
176,
197). About
75% of infants treated early after birth for toxoplasmosis,
intracranial calcifications diminished or resolved by age 1 (
160).
While serologic titers appeared in 97.7% of the cases following
discontinuation of the treatment, but this did not lead to an increased
risk of ocular relapse (
50).
A clinical trial in 257 newborns from infected moms treated with
spiramycin and pyrimethamine plus sulfadoxine in France, 24% were
diagnosed with congenital infection. From these, 7% were predicted to be
infected in the first, 24% in second, and 59% in third gestation
period, respectively (
17). Infected infants are required to be treated for 1 year.
Application: Pyrimethamine: 1 mg/kg /12 hr for 2 days, followed by 1 mg/kg/day for 2- 6 months, followed by 1 mg/kg three doses/week
Sulfadiazine: 50 mg/kg/12 hr
Leucovorin (Folinic acid): 10-20 mg three times/ week
Prednisone (CSF protein ≥ 1 g/dL for retinochoroiditis): 0.5 mg/kg/12 hr until CFS protein < 1 g/dL or symptoms resolve.
Treatment of older children with active disease continues 1-2 weeks after resolution of symptoms.
Pyrimethamine: 1-25 mg/kg every 12 hr for 2 days followed by 1-25 mg/kg per day
Sulfadiazine: 75 mg/kg (first dose) followed by 50 mg/kg every 12 hr
Leucovorin (Folinic acid): 10-20 mg three times weekly
Prednisone for retinochoroiditis: 0.5-20 mg/kg/12hr, rapid taper
Ocular Toxoplasmosis
Acute ocular toxoplasmosis requires urgent therapy for 6 to 8
weeks and a minimum of 2 weeks after inflammation is resolved in
ophthalmic and angiographic examination. Commonly, in 2 weeks of
treatment ocular lesions are resolved and further visual loss seized (
125,
133). Pyrimethamine (100
mg for 1 day followed by 25 to 50 mg/day) is used plus sulfadiazine (1g
four times/day), plus leucovorin(folinic acid, 5-25 mg). Pediatric:
pyrimethamine (2 mg/kg first day then 1 mg/kg/day) plus sulfadiazine (50
mg/kg twice/day), plus leucovorin (7.5 mg/day) for 4 to 6 weeks
followed by reevaluation of the patient. Leucovorin is used to protect
the bone marrow from toxic effects of pyrimethamine. In case of
hypersensitivity reaction to sulfa drugs, pyrimethamine
plus clindamycin is recommended. In
contrasttrimethoprim plus sulfamethoxazole combination has been used in
case of pyrimethamine intolerance. Other alternative drugs are
atovaquone plus pyrimethamine and azithromycin (
31,
125,
161).
Steroids (corticosteroid) are recommended as adjuvant for patients with
severe inflammatory responses, retinochoroiditis and macula involvement
or CSF protein ≥ 1 g/100ml (
73).
Infection in Immunocompromised Patient
In immunosuppressed patients, treatment of acute
toxoplasmosis is required to protect against 100% mortality
rate. Therapies and duration depend upon clinical manifestation, oral
administration, severity and duration of the immunosuppression (
190). Maintenance
therapy is modified according to the duration and the intensity of the
immunosuppression. Similar criteria are used as in HIV and AIDS
patients. Usually it is discontinued in transplant recipients after the
immunosuppressive agent is tapered.
Infection in AIDS Patients
The number of cases of toxoplasmosis in
HIV infected patients
has remarkably decreased primarily due to the extensive use of
trimethoprim plus sulfamethoxazole as primary prophylactic regimen for
both
Pneumocystis pneumonia (
156)
and toxoplasmosis, as the use of highly active antiretroviral therapy
(HAART) lead to immune restoration. The recommendations are based on
data from trials conducted before 1996 (
204). Persons with
AIDS who develop active toxoplasmosis including
Toxoplasma encephalitis should be treated until significant immunologic improvement is achieved (
73).
STANDARD OF CARE THERAPY
Acute Therapy
The therapy of choice for
Toxoplasma encephalitis consists of the combined pyrimethamine plus sulfadiazine and leucovorin (folinic acid) (
69,
144). Pyrimethamine
penetrates to bypass brain blood barrier efficiently even in the
absence of inflammation. Leucovorin reduces the possible hematologic
toxicities associated with pyrimethamine therapy (
69). The
dose can be increased up to 50 mg/day in case of cytopenia. The
duration of acute stage therapy is 3-6 weeks. Only if a complete
clinical and radiological response is obtained therapy can be concluded (
111,
210). A complete or partial clinical response to the combined therapy is achieved in 70% to 75% cases of
Toxoplasma encephalitis
in HIV-infected patients with probability of survival after an acute
episode to be 90% to 95% (39). The combined therapy has similar rate for
other sites of infection such as the eyes. A disseminated infection
followed by the septic shock leads to a poor prognosis (
118).
Trimethoprim plus sulfamethoxazole was reported in a small
(77 patients) randomized trial to be effective and better tolerated than
pyrimethamine plus sulfadiazine (
201). No
parenteral formulation of pyrimethamine exists for the patients who
cannot take oral tablets. However, sulfamethoxazole is available in
parenteral form. ICU patients and those with severe
Toxoplasma encephalitis can receive parenteral trimethoprim plus sulfamethoxazole or oral pyrimethamine plus parenteral clindamycin.
Treatment is usually initiated upon assumption of
Toxoplasma encephalitis,
based on clinical symptoms of fever, neurological manifestations,
seizers and the presence of brain lesions detected by CT scan or MRI.
The diagnosis of
Toxoplasma encephalitis is less likely in
Toxoplasma seronegative
patients (e.g. HIV+) with single lesion detected by MRI and/or patients
who are on trimethoprim plus sulfamethoxazole prophylactic for
Pneumocystis pneumonia (
31,
120,
156).
Application: Pyrimethamine 50 mg/12 hr (2 days) followed by 25-50 mg daily
Leucovorin (Folinic acid) 10-50 mg/day (PO) continued 1 week after Pyrimethamine.
Sulfadiazine (PO) 75 mg/kg (first dose) followed by 50 mg/kg/12hr
Trimethoprim plus Sulfamethoxide 5-10 mg/kg/12 hr (PO or IV)
Maintenance Therapy
To prevent relapse maintenance therapy has been well established practice in AIDS patients (
80). The relapse rate is reported approximately 30% despite zidovudine therapy (
40). Maintenance
therapy is based on the combined therapies used at doses reduced by
half. The combined therapy with pyrimethamine plus Sulfadiazine has been
shown to be more effective than the pyrimethamine plus clindamycin
alternative combined therapy to prevent relapse. European study revealed
relapse rate to be 6% patient with sulfadiazine versus 23% patient with
clindamycin (
104). Maintenance
therapy can be discontinued in patients with CD4 counts above 200
cells/µl, and undetectable HIV viral load for 3 to 6 months.
Alternative Therapeutic Regimens
The alternative therapy for patients, who do not tolerate or
fail to respond, is combined pyrimethamine plus clindamycin and
leucovorin (
173). About
70% - 86% of the patients had a favorable response and improved by 1-6
week of therapy. The adverse effects included non-
Toxoplasma related
neurological symptoms due to the pyrimethamine plus clindamycin
combined therapy in 30-50% of patients, which required discontinuation
in 20% cases. The adverse effects of clindamycin are primarily
gastrointestinal due to microbiota alteration with a risk of Clostridium
difficile colitis. The combined therapy can be used in half reduced
dose for the maintenance therapy to prevent side effects but can also
lower efficacy compared the conventional therapeutic doses (
104).
Combined therapies with trimethoprim plus Sulfamethoxazole,
Pyrimethamine plus Atovaquone or Ataovaquone plus Sulfadizine are also
effective in AIDS patients with
Toxoplasma encephalitis.
Combined Pyrimethamine plus Macrolides
Due to the high rate of adverse reaction and intolerance to
above combinations, specifically in AIDS patients other combinations of
pyrimethamine plus clarithromcyin (2g/day) or azithromycin (500 mg/day)
might be effective (
60).
The adverse effects requiring discontinuation in 20% of patients were
increased in serum transaminase levels and hearing loss in two studies.
After successful use of combination therapy during the acute or primary
stage, one half of doses of same agents are recommended for maintenance
or secondary prophylaxis.
Application: Pyrimethamine 50 mg/12 hr (2 days) followed by 25-50 mg daily
Leucovorin (Folinic acid) 10-50 mg/day (PO) plus pyrimethamine and continued 1 week after
Sulfadiazine 75 mg/kg (first dose) then 50 mg/kg/12 hr (PO)
1000 (<60 kg) to 1500 mg (>60 kg) every 6 hr
Or Clindamycin 300-1200 mg/6 hr (PO or IV)
Atovaquone 1500 mg/12 hr (PO)
Trimethoprim plus Sulfamethoxide 5-10 mg/kg/12 hr (PO or IV)
Pyrimethamine/folinic acid
Plus Clarithromycin 500 mg/12 hr (PO)
Or Dapsone 100 mg/d (PO)
Or Azithromycin 900-1200 mg/day(PO)
Adjuvant Therapy
Congenital Toxoplasmosis
Fetal abortion is considered if fetal infection is documented with evidence of fetal abnormalities on ultrasound examination (
16).
In infants with latent infection treated with the combined
pyrimethamine plus sulfonamides and prednisone (1mg/kg/day) oral route
is administered in two divided doses, against inflammatory process, high
cerebrospinal protein content, and severe uveitis. The dose is tapered
when the disease progress subsided.
Ocular Toxoplasmosis
Corticosteroid is administered as adjuvant therapy for
inflammatory condition. Prednisone or methylprednisone (80 mg/day) is
given in adults and children (1.5 mg/kg/day) and dosage tapered. The
primary anti-
Toxoplasma agent will continue minimum 2 weeks after steroids is discontinued (
111,
119).
AIDS
Adjuvant therapy with corticosteroids in
Toxoplasma encephalitis
is routinely administered in AIDS patients with clinical or
radiological signs of brain edema. Solumedrol (240 mg/day) is prescribed
for 3 days, followed by half dose (120 mg/day) for 3 additional days,
and then tapered by half (60 mg/day) until significant clinical
improvement (10 to 20 days). Other regimens such as glycerol or mannitol
have been used in intracranial hypertension to reduce the symptoms (
111,
121).
ENDPOINTS FOR MONITORING THERAPY
Monitoring of Adverse Events
Pyrimethamine administered in high doses may cause seizures.
Children (25kg) receiving 2 mg/kg pyrimethamine or patients with serum
levels of 5 µg/ ml and above are at risk (
131)
and require blood transfusion for detoxification. Pyrimethamine has
antifolinic activity results in bone marrow depression, neutropenia,
thrombocytopenia, and megaloblastic anemia. The side effects are
prevented by oral administration of leucovorin (calcium folinic acid) 5
to 10 mg three times/week for infants and 10 up to 50 mg/day in adults
and HIV infected patients. In fact,
Toxoplasma cannot consume
folates, folic and folinic acid, and requires to metabolize precursor
paraminobenzoic acid. HIV infected patients required to be evaluated for
neutrophil counts two times/week and platelets and hematocrit
once/month (
127).
Neutrophil count below 1000/µl or platelets 90,000/µl necessitate to
escalate folinic acid dosage or withdraw when neutrophils decrease
500/µl to reverse cytopenia. Leucovorin must be administered one week
after pyrimethamine discontinued (
69,
205).
Sulfonamides
Treatment with sulfonamides such as sulfadiazine requires
monitoring the hematological cell count and blood creatinin, amount of
urine output, urea crystal formation, and water consumption (
37). Adequate
hydration and alkalizing the urine can be utilized to prevent the side
effects. In case of nephrolithiasis sulfonamides need to be
discontinued. Trisulfamides can be administered as alternative with
fewer side effects.
Pyrimethamine plus Sulfonamides Combination therapy
The rate of side effects due to the combined pyrimethamine
plus sulfadiazine therapy is approximately 50%, and discontinuation of
one or both drugs is required in 20% to 25% cases (
39,
104).
The most frequent adverse effects include cytopenia, rash and fever.
Alternative use of each drug will detect the drug responsible to be
discontinued.
Clindamycin
The most frequent adverse effects are gastrointestinal
manifestation, possibly due to alteration of microbiota and
pseudomembranous colitis induced by Clostridium difficile. Other adverse
effects seen in
AIDS patients treated with combined clindamycin plus
pyrimethamine, are rash, hepatic function anomalies, neutropenia and
thrombocytopenia (
39,
194).
EXPERIMENTAL THERAPIES
Promising Experimental Compounds
Other compounds, combined rifabutine plus atovaquone for 30
days or rifabutine plus clindamycin for 15 days showed synergism
against
Toxoplasma encephalitis in mice, significantly improved brain inflammation and prolonged survival but did not protect relapses (
178). However,
combined rifabutine plus pyrimethamine and rifabutine plus sulfadiazine
had not significant effect on brain inflammation compared with each
drug alone (
8).
Combined trimetrexate (37 mg/kg/day) plus sulfadiazine (375 mg/kg/day)
prolonged survival (93%) against acute toxoplasmosis in mice. Dapsone
plus sulfamethazine (100 mg/kg/day) with additive effects was active
in vivo against organism.
Experimental Diclazuil, Atovaquone Monotherapy and Combination Therapy
Diclazuril [4-chlorophenyl
[2,6-dichloro-4-(4,5-dihydro-3H-3,5-dioxo-1,2,4-triazin-2-yl)pheny l
acetonitrile] is commonly used in poultry and livestock against
coccidiosis. Diclazuril specifically affects apicoplast, a rudimentary
organelle from
Toxoplasma, and not present in humans and
animals. Diclazuril is a nontoxic agent with rapid absorption following
oral administration to reach a constant level in plasma and
cerebrospinal fluid. Recent studies have shown diclazuril to be well
tolerated and effective in murine model for maternal and
congenital toxoplasmosis (
148,
149,
157). Diclazuril has no teratogenic effect at the administered doses.
While atovaquone protects against some aspects of
gastrointestinal complications in experimental congenital toxoplasmosis
in murine (
158),
diclazuril was superior to atovaquone in improving anemia, colonic
length and hepatic complications against maternal toxoplasmosis (
157). In
addition, diclazuril plus atovaquone combination therapy exerted a
unique synergistic effect against more severe fetal maternal
toxoplasmosis and superior action to diclazuril or atovaquone
monotherapy (
148,
149). Diclazuril
and diclazuril plus atovaquone warrant clinical trials in maternal
congenital as well as in ocular and chronic toxoplasmosis. Finally,
Diclazuril is anticipated to be used as a novel protective and
preventive measure to eliminate the cycle of
Toxoplasma infection in the definitive host, feline.
VACCINES
An effective vaccine to protect cats against sexual stage and
oocysts production and asexual stages and cysts production in animals
and humans is desirable to eradicate the disease. Thus far, there is no
safe and effective vaccine available against
Toxoplasma infection. The only commercialized vaccine is an attenuated-live
Toxoplasma (Toxovax®)for veterinary use with limited success (
25). This
live vaccine protects sheep from abortion due to infection but is not
always effective. The other products have been candidate for vaccines
include, rhoptry proteins, the major virulence factors and various DNA
form
Toxoplasma yet to provide a limited or no
protection. Irradiated tachyzoites given orally to 1 week pregnant rats
did not provide protection in pups and dams against challenge
inoculation of the organisms analyzed by quantitative PCR. However,
immunization protected the birth rate and litter size (
26).
PREVENTIVE MEASURES
Common sense and basic hygienic measurements and hands wash are required as the first step to prevent transmission of the
Toxoplasma infection.
Fruits and vegetables should be thoroughly cleaned or peeled prior
consumption. Meat products and sea food need to be cooked appropriately
or kept frozen at sub 0o degree temperature. Milk products need to be
pasteurized and sanitary or treated water used for drinking. Vulnerable
individual, mainly pregnant women, children and immunocompromised
subjects should avoid direct contact with cat feces. Cats need to be
kept indoors and fed cooked or commercial food. Protective gloves should
be worn before handling contaminated material including sandboxes,
garden soil, or raw meat and hands washed after handling and prior
consumption.
PROPHYLACTIC THERAPEUTIC AGENTS
Congenital Toxoplasmosis
Management of seroconverters is determined by the risk of maternal-fetal transplacental transmission of
Toxoplasma. The average risk of 40% is reduced by about one-half after spiramycin treatment (
139).
Spiramycin has been used in fetal-maternal toxoplasmosis treatment and
prevention in Canada, Latin America and Europe for decades while still
is considered as an “experimental therapy” in United States. Spiramycin
monotherapy is effective in early pregnancy as a preventive measure but
not after fetal exposure to the infection. In a prospective cohort
clinical trial in Brazil 58% of neonates from mothers treated with
spiramycin and over 73% of those from untreated had congenital infection
(
10). Over 50 percent of patients which were treated with spiramycin retained
Toxoplasma DNA in peripheral blood and remained infected (
83).
The date of maternal infection is of important relevance to
transmission. Immunocompetent moms normally have no risk if had exposed
before conception. However, infection during pregnancy period has a high
risk of transmission and congenital toxoplasmosis as the later the
infection date during pregnancy, the higher the risk of transmission (
47).
Among women with seroconversion, the incidence of maternal-fetal
transmission increases as the pregnancy progresses. Spiramycin is most
effective if given as prophylactic and before infection has reached the
embryo. In pregnant women treated with spiramycin, the incidence of
fetal transmission increases from 2%, if maternal infection happen
during 3 to 10 weeks of gestation, to over 30% when after 31 weeks (
87). The
incidence reaches 90% in infections during the last two weeks of
pregnancy. In addition, the earlier the maternal infection occurs during
pregnancy, the higher the risk of brain injury in the fetus. It is
indicated that maternal infection after week 26 may become more
subclinical.
Prophylactic spiramycin is administered as 3g per day, oral
route, and should be given immediately after detection of infection
during pregnancy to reduce the possible transmission to the embryo (
47,
65,
66,
208) or to reduce the severity of the disease in possibly infected infant (
67). A
negative PCR in amniotic fluid requires spiramycin administration to
prevent or delay maternal fetal transmission. Administration of
azithromycin in 500 mg/day for 3 times/ week for 1 to 4 weeks showed
Concentrations in placental tissue were 10 fold higher in placenta than
in amniotic fluid or maternal or cord blood (
194).
Ocular Toxoplasmosis
Repeated exacerbations of ocular toxoplasmosis raise the
requirement for a prolonged prophylactic. The pyrimethamine plus
sulfadoxine combination, 1 tablet for 20 kg every 10 days for 6-12
months or longer as needed can be prescribed and the clinical and
hematological changes closely monitored (
167).
AIDS
The prevalence of encephalitic toxoplasmosis in HIV patients
is reported 30-40% in Europe, with mortality rate of 20% which has
promoted specific preventive measures to control reactivation of
Toxoplasma in seropositive patients (
97,
204).
In contrast the prevalence of primary infection in seronegative
patients is as low as 2%. However, these patients should be monitored
regularly for
Toxoplasma titers (1-2/year) [15].
Toxoplasma seropositive patients ought to be assessed for possible risk of
Toxoplasma encephalitis, and prophylactic therapies (
14,
73,
78,
110).
Toxoplasma Encephalitis in Seropositive Patients
Toxoplasma encephalitis occurs almost exclusively due to reactivation of latent tissue cysts (
31). Primary
infection less often is associated with acute cerebral or disseminated
disease. The severity of the immune defect is a major factor. According
CDC the stage B or C, clinical manifestations, and CD4+ cell count less
than 100/µl are independent factors associated with an increased risk
of
Toxoplasmaencephalitis (
31). The probability to develop
Toxoplasma encephalitis in one year rises 24% in patients with CDC stage C manifestations and 20% in patients with CD4+ below 50/µl (
46). Furthermore, the IgG anti
Toxoplasma antibody titer determined by ELISA at baseline is a preferred prognostic marker for risk of
Toxoplasma encephalitis (
46). The risk increases by 3 fold in patients with titers >150 IU/ml (
36,
101) for IgG by Western blot and is associated with an increased risk of
Toxoplasma encephalitis (
110).
Primary Prophylactic Therapies
Patients who are given trimethoprim plus sulfamethoxazole for
Pneumocystis prophylactic have a very low incidence of
Toxoplasma encephalitis (
28,
84,
124,
169,
185), as trimethoprim plus sulfametoxazole is known prophylactic drug of choice (
204) A
prospective randomized trial in France to determine the most convenient
dose of trimethoprim plus sulfametoxazole was single strength dose per
day compared to double strength tablet per day. Some experts suggest an
every-other day administration (
175). The pyrimethamine plus dapsone combination is effective in preventing
Toxoplasmaencephalitis (
77). However the rate of cross-intolerance between dapsone and trimethoprim plus sulfamethoxazole is approximately 40% (
102). In
an international double blind placebo controlled study no significant
difference was detect between pyrimethamine, 50 mg thrice weekly or
placebo for primary prophylaxis of
Toxoplasma encephalitis (
109). Rash
was the major adverse effect in pyrimethamine arm. In another trial
increased mortality was reported in the arm with pyrimethamine compared
to payrimethamine plus folinic acid (
98). HIV positive patients who are receiving prophylactic trimethoprim plus sulfametoxazole for
Pneumocystis have minimum risk of
Toxoplasma encephalitis.
The patients may not tolerate well trimethoprim plus sulfamethoxazole.
Overall individuals should be assessed for clinical stage of HIV
infection, the CD4 cell count, and the
Toxoplasma antibody titers.
Toxoplasma Prophylaxis and Highly Active Antiretroviral Therapy
The world widespread administration of highly active
antiretroviral therapy (HAART) since 1996 has significantly improved the
risk of opportunistics including toxoplasmosis in HIV positive
patients. HAART therapy significantly elevated CD4+ cell counts followed
by restoration of the immune system and has reduced the rate of
toxoplasmosis to about 5%. Thus, USPHS consensus panels recommend that
primary prophylaxis to be discontinued for toxoplasmosis in patients
with viral control and CD4+ greater that 200/µl for over 6 months. The
possibility for discontinuing secondary prophylaxis has also been
suggested (
81,
204).
Prophylaxis for Other Immunosuppressed Hosts
Organ transplants recipients are in a great risk of toxoplasmosis (
88,
121,
192,
215). Immunosuppressants
especially corticosteroids significantly increase the risk of
toxoplasmosis. Cyclosporine is reported to have some antiparasitic
activity
in vitro and animal experiments and recommended as preferred treatment in patients at risk for toxoplasmosis (
129), others report fatal toxoplasmosis in conjunction with cyclosporine therapy (
13). Mycophenolate mofetil (cellcept) commonly used in kidney transplant has strong therapeutic anti-fungal (
Pneumocystis) and antimicrobial effect (
155), but little information available regarding the anti-
Toxoplasma efficacy of mycophenolate.
Those organ recipients, who are seronegative for
Toxoplasma and transplanted organ from seropositive for
Toxoplasma donor, are recommended to receive pyrimethamine 50 mg/day to markedly reduce the risk of toxoplasmosis (
88,
121,
215). Trimethoprim
plus sulfamethoxazole is a possible alternative which has not been
extensively assessed. In bone-marrow recipients, the risk of
toxoplasmosis is the highest in seropositive patients who receive
bone-marrow from a donor who is seronegative for
Toxoplasma (
44,
63,
126,
146).
The pyrimethamine plus sulfadoxine or trimethoprim plus
sulfamethoxazole combinations have been recommended for children. In
these transplant patients, the duration of chemoprophylaxis depends upon
the duration of the immunosuppressive therapy. Limited information is
available for other causes of immunosuppression (
19).
It has been suggested that patients with immune cell defects or those
on long term corticosteroid therapy, should be considered for
prophylaxis of toxoplasmosis when the CD4 cell count reaches less than
100/µl. Pyrimethamine or trimethoprim plus sulfamethoxazole should be
recommended for the duration of the immune defect persists.
Additional Information
Consultation assistance is available for the diagnosis and management of patients suspected with toxoplasmosis:
Chicago, U.S.A National Collaborative Treatment Trial Study (NCCTS), telephone number (773) 834-4152.
The Toxoplasma Serology Laboratory (Dr Jack
Remington), the Palo Alto Medical Foundation, Palo Alto, CA. Website:
http://www.pamf.org/serology/; Phone number: 650 853 4828]
Centers for Disease Control and Prevention, Atlanta, GA, 1-800-CDC-INFO, weekday 8am-8pm EST. cdc.gov/parasite/toxoplasmosis.
Spiramycin (Rhone-Poulenc Pharmaceuticals) is not FDA
approved, and available via individual investigator IND for treatment of
pregnant women with toxoplasmosis. Information on the Spiramycin
program is available by the Division of Special Pathogens and
Immunologic Drug products at FDA at (301) 827-2335.
FDA Adverse Events Report
The Safe Medical Devices Act of 1990 (SMDA) requires
hospitals and other user facilities to report deaths and serious
illnesses and injuries associated with the use of medical devices.
Erroneous result or any adverse event from an anti-
Toxoplasma commercial test kit resulting in death or serious illness must be reported.
Voluntary report is encouraged directly to MedWatch, the
FDA's voluntary reporting program. Telephone at (800) FDA-1088, by FAX
at (800) FDA-0178,
Mail to: MedWatch, Food and Drug Administration, Rockville, MD 20857
http://www.antimicrobe.org/new/b130.asp
