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Toxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma gondii parasite infects most genera of warm-blooded animals, including humans, but the primary host is the felid (cat) family. Animals are infected by eating infected meat, by ingestion of feces of a cat that has itself recently been infected, or by transmission from mother to fetus. Cats are the primary source of infection to human hosts, although contact with raw meat, especially pork, is a more significant source of human infections in some countries. Fecal contamination of hands is a significant risk factors.
The overall seroprevalence of T gondii in the United States is approximately 15%, and rates of T gondii exposure in HIV patients are similar to those of the general public.In patients with AIDS who have positive Tgondii antibodies, the risk of developing toxoplasmosis is roughly 30% unless prophylactic or antiretroviral medications are commenced. Among immunocompetent patients, clinically evident toxoplasmosis is more likely to occur after the fifth decade of life. Congenital toxoplasmosis is thought to depend on the trimester during which the maternal infection is acquired, with 10-25% of infections occurring in the first trimester, 30% in the second trimester, and 50% in the third trimester.
The seroprevalence of T gondii antibodies varies geographically with some countries such as France and some developing nations reporting antibody positivity rates to T gondii infection as high as 80%.The development of toxoplasmosis among immunocompetent patients does not seem to vary from region to region; however, the prevalence of immunocompromised patients is higher in some nations as a function of both HIV/AIDS infection and also organ transplantation and immunomodulatory medication prescribing.
The incidence of toxoplasmosis (including CNS disease) in patients with AIDS has declined dramatically in the recent past likely due to the evolution of highly active antiretroviral therapy (HAART) and the routine use of prophylaxis against Pneumocystis jiroveci and T gondii. The incidence of CNS toxoplasmosis decreased from 5.4 per 1000 person-years between 1990 and 1992 to 2.2 per 1000 in 1996 to 1998.The routine use of cotrimoxazole prophylaxis both in the United States and internationally has also likely significantly decreased the incidence of CNS toxoplasmosis.
Depending on the location and severity of toxoplasmic chorioretinitis, infection can result in permanent retinal scarring and loss of visual acuity. Recurrent episodes are common, resulting in multiple areas of retinal scarring and functional loss. Toxoplasmic encephalitis and brain abscess can result in permanent neurologic sequelae depending on the location of the lesion and the extent of local damage and inflammation.
While there do exist differences in the seroprevalence of infection among different ethnic groups, these differences likely reflect the regionality of infection rather than a particular susceptibility to infection.
Although toxoplasmosis is well studied in women of childbearing age because of its detrimental effects on the fetus, no difference in prevalence between the sexes is reported.
No difference in seroprevalence based on age has been noted; however, with the exception of T gondii chorioretinitis, older individuals are more likely to manifest clinically evident reactivation of Tgondii infection. Congenitally acquired Tgondii chorioretinitis is more likely to recur in those older than 40 years.
PATHOPHYSIOLOGY,SIGNS AND SYNTOMS
INFECTION IN THE IMMUNOCOMPETENT HOST
Eighty to ninety percent of T gondii infections in immunocompetent hosts are asymptomatic.Generally, when acute infection is symptomatic, symptoms include symmetric lymphadenopathy, fever, and a nonspecific rash. The vast majority of cases are benign and resolve within weeks. However, severe manifestations of infection, including chorioretinitis, can occur in immunocompetent hosts.
Chorioretinitis or ocular toxoplasmosis is a relatively common manifestation of T gondii infection. Ocular toxoplasmosis occurs when cysts deposited in or near the retina become active, producing tachyzoites. Focal necrotizing retinitis is the characteristic lesion, but retinal scars from prior reactivation are typically present. Presentation usually involves eye pain and decreased visual acuity. Adults who acquired disease in infancy usually present with bilateral eye involvement. Adults with acute infection generally present with unilateral ocular involvement.
Approximately 10-20% of pregnant women infected with T gondii become symptomatic. The most common signs of infection are lymphadenopathy and fever. If the mother was infected prior to pregnancy, there is virtually no risk of fetal infection, as long as she remains immunocompetent; however, if the infection is acquired during the pregnancy, there is risk of infection to the fetus. The rate of transplacental infection has been estimated to be 50% for untreated mothers and 25% for treated mothers.
The rate of fetal infection varies with trimester with 10-25% of infections occurring in the first trimester, 30% in the second trimester, and 50% in the third trimester. Infection during the first or second trimesters appears to be most severe. The clinical features of congenitally acquired T gondii infection include chorioretinitis, blindness, seizures, microcephaly, anemia, and encephalitis. Infections acquired during the third trimester are usually subclinical; however, clinical disease may still occur later in life. Seventy-five percent of infants congenitally infected with T gondii manifest no symptoms, 14% had evidence of chorioretinitis and 9% demonstrate signs of CNS involvement.
INFECTION IN IMMUNOCOMPROMISED PATIENTS
Most cases of toxoplasmosis in immunocompromised patients are a consequence of latent infection and reactivation. In patients with AIDS, T gondii tissue cysts can reactivate with CD4 counts less than 200 cells/μ L, and, with counts less than 100 cells/μ L, clinical disease becomes more likely.Patients with CD4 counts less than 100 cell/μ L and who are T gondii IgG antibody positive have a 30% risk of eventually developing reactivation disease without adequate prophylaxis or restoration of immune function.
Although toxoplasmosis in immunocompromised patients may manifest as chorioretinitis, reactivation disease in these individuals is typically in the central nervous system with brain involvement being common.
Toxoplasmic encephalitis and brain abscess presents most commonly as headache, but focal neurologic deficits and seizures are as common. With significant disease, patients may also demonstrate the signs and symptoms of elevated intracranial pressure. Cerebral toxoplasmosis is generally identified on CT scan as multiple ring-enhancing lesions; however, solitary lesions may be seen, and negative CT or MRI scans should not rule out the diagnosis of CNS toxoplasmosis.
Aside from CNS toxoplasmosis, toxoplasmic pneumonitis, myocarditis, as well as disseminated toxoplasmosis are also commonly identified in immunocompromised patients. Toxoplasmic pneumonitis typically presents with symptoms typical for an infectious pulmonary process, including fever, dyspnea, and cough. Chest radiography is often nonspecific, but findings may have an appearance similar to that of Pneumocystis jiroveci pneumonia. Diagnosis is established via bronchoalveolar lavage (BAL). Most patients with extra-CNS manifestations of toxoplasmosis will also be noted to have CNS lesions when appropriate radiographic studies have been performed.
Toxoplasmosis can be difficult to distinguish from that of primary central nervous system lymphoma, and as a result, the diagnosis is made by a trial of therapy (pyrimethamine, sulfadiazine + leucovorin), or a brain biopsy if the drugs produce no effect.
Detection of Toxoplasma gondii in human blood samples may also be achieved by using the polymerase chain reaction (PCR) Inactive cysts may exist in a host which would evade detection.
Toxoplasmosis cannot be detected with immunostaining. Lymph nodes affected by toxoplasma have characteristic changes, including poorly demarcated reactive germinal centers, clusters of monocytoid B cells and scattered epithelioid histiocytes.
Life cycle of Toxoplasma gondii.
Transmission may occur through:
- Ingestion of raw or partly cooked meat, especially pork, lamb, or venison containing Toxoplasma cysts. Infection prevalence in countries where undercooked meat is traditionally eaten has been related to this transmission method. Oocysts may also be ingested during hand-to-mouth contact after handling undercooked meat, or from using knives, utensils, or cutting boards contaminated by raw meat
- Ingestion of contaminated cat feces. This can occur through hand-to-mouth contact following gardening, cleaning a cat's litter box, contact with children's sandpits, or touching a leach, and can survive in the environment for over a year. It is, however, susceptible to high temperatures—above 66 degrees Celsius (150 degrees Fahrenheit), and is thus killed by thorough cooking, and would be killed by 24 hours in a typical domestic freezer.
Cats excrete the pathogen in their feces for a number of weeks after contracting the disease, generally by eating an infected rodent. Even then, cat faeces are not generally contagious for the first day or two after excretion, after which the cyst 'ripens' and becomes potentially pathogenic.
Congenital toxoplasmosis is a special form in which an unborn child is infected via the placenta. A positive antibody titer indicates previous exposure and immunity and largely ensures the unborn baby's safety. A simple blood draw at the first pre-natal doctor visit can determine whether or not the woman has had previous exposure and therefore whether or not she is at risk. If a woman receives her first exposure to toxoplasmosis while pregnant, the baby is at particular risk. A woman with no previous exposure should avoid handling raw meat, exposure to cat feces, and gardening (cat feces are common in garden soil). Most cats are not actively shedding oocysts and so are not a danger, but the risk may be reduced further by having the litterbox emptied daily (oocysts require longer than a single day to become infective), and by having someone else empty the litterbox. However, while risks can be minimized, they cannot be eliminated. For pregnant women with negative antibody titer, indicating no previous exposure to T. gondii, as frequent as monthly serology testing is advisable as treatment during pregnancy for those women exposed to T. gondii for the first time decreases dramatically the risk of passing the parasite to the fetus.
Despite these risks, pregnant women are not routinely screened for toxoplasmosis in most countries (Portugal,France, Austria,Uruguay, and Italy being the exceptions) for reasons of cost-effectiveness and the high number of false positives generated. As invasive prenatal testing incurs some risk to the fetus (18.5 pregnancy losses per toxoplasmosis case prevented), postnatal or neonatal screening is preferred. The exceptions are cases where fetal abnormalities are noted, and thus screening can be targeted.
Some regional screening programmes operate in Germany, Switzerland and Belgium.
Treatment is very important for recently infected pregnant women, to prevent infection of the fetus. Since a baby's immune system does not develop fully for the first year of life, and the resilient cysts that form throughout the body are very difficult to eradicate with anti-protozoans, an infection can be very serious in the young.
Treatment is often only recommended for people with serious health problems or with HIV with CD4 count under 200, because the disease is most serious when one's immune system is weak. Bactrim is the drug of choice to prevent Toxoplasma, but is not the drug to treat.
Medications that are prescribed for acute toxoplasmosis are:
- Pyrimethamine an antimalarial medication.
- Sulfadiazine an antibiotic used in combination with pyrimethamine to treat toxoplasmosis.
Combination therapy is usually given with folinic acid supplements to reduce incidence of thrombocytopaenia.
- clindamycin — an antibiotic used most often for people with HIV/AIDS.
- spiramycin — an antibiotic used most often for pregnant women to prevent the infection of their child.
(Other antibiotics such as minocycline have seen some use as a salvage therapy).
In people with latent toxoplasmosis, the cysts are immune to these treatments, as the antibiotics do not reach the bradyzoites in sufficient concentration.
Medications that are prescribed for latent toxoplasmosis are:
- atovaquone an antibiotic that has been used to kill Toxoplasma cysts inside AIDS patients.
- clindamycin an antibiotic which, in combination with atovaquone, seemed to optimally kill cysts in mice.
BIOLOGICAL MODIFICATIONS OF THE HOST
It has been found that the parasite has the ability to change the behaviour of its host: infected rats and mice are less fearful of cats—in fact, some of the infected rats seek out cat-urine-marked areas. This effect is advantageous to the parasite, which is able to proliferate if a cat eats the infected rat and thereby becomes a carrier. The mechanism for this change is not completely understood, but there is evidence that toxoplasmosis infection raises dopamine levels and concentrates in the amygdala in infected mice.
The findings of behavioural alteration in rats and mice have led some scientists to speculate that Toxoplasma may have similar effects in humans. Toxoplasma is one of a number of parasites that may alter their host's behaviour as a part of their life cycle.
The evidence for behavioral effects on humans is controversial. No prospective research has been done on the topic, e.g., testing people before and after infection to ensure that the proposed behavior arises only afterwards. Although some researchers have found potentially important associations with Toxoplasma, the causal relationship, if any, is unknown, i.e., it is possible that these associations merely reflect factors that predispose certain types of people to infection. However, many of the neurobehavioral symptoms that are postulated to be due to toxoplasmosis correlate to the general function of dopamine in the human brain, and the fact that toxoplasma encodes the dopamine synthesizing enzyme tyrosine hydroxylase makes it likely that neurobehavioral symptoms can result from infection.
These types of studies are suggestive but cannot confirm a causal relationship (because of the possibility, for example, that schizophrenia increases the likelihood of Toxoplasma infection rather than the other way.
Although latent infection with Toxoplasma gondii is among
the most prevalent of human infections, it has been generally
assumed that, except for congenital transmission, it is
asymptomatic. The demonstration that latent Toxoplasma
infections can alter behavior in rodents has led to a reconsideration
of this assumption. When infected human adults
were compared with uninfected adults on personality questionnaires
or on a panel of behavioral tests, several differences
were found. Other studies have demonstrated reduced
psychomotor performance in affected individuals. Possible
mechanisms by which T. gondii may affect human behavior
include its effect on dopamine and on testosterone.
One possible access route to the brain may lead to colonization of the nasal frontal lobe, which could cause behavioral changes listed.
In the rodent model, the effects of T. gondii are best explained in evolutionary terms by the manipulation hypothesis, ie, the parasite changes the behavior of the rodent in such a way as to increase the chances of the parasite's getting into a feline and completing its life cycle. Humans are dead-end hosts for T. gondii, because the chances that a human being will be eaten by a feline are infinitesimally small. Among our primate ancestors, however, this was not always the case,16 as suggested also by contemporary studies of the frequency with which monkeys and apes are eaten by large felines in Africa. For example, a study performed in the Ivory Coast confirmed that primates account for a large proportion of leopards' diet and revealed the predation pressure exerted by large felines on 8 different monkey and 1 chimpanzee species.17 In addition, parasites are not aware that they have entered dead-end hosts, so they are likely to exert whatever effects they do in any host. In this regard, it is interesting to consider the increase in traffic victims among T. gondii–infected humans as a contemporary example of manipulation activity of a parasite. It is also possible that the effects of the parasite are not due to the manipulation in an evolutionary sense but merely due to neuropathological or neuroimmunological effects of the parasite's presence.
If latent T. gondii infections are exerting effects on human personality characteristics and behavior, what is the possible mechanism? It is known that T. gondii increases dopamine in rodents19 and also that treating the rodents with a selective dopamine uptake inhibitor differentially alters the behavior of the infected and uninfected rodents.20 Also the observed low level of novelty seeking in humans infected with Toxoplasma or cytomegalovirus is supposedly associated with high dopamine levels in the ventral midbrain.7,8 The mechanism of the dopamine increase by T. gondii is not known but may involve the inflammatory release of dopamine by increasing cytokines such as interleukin-2.21,22 The dopamine imbalance between the mesolimbic and mesocortical regions in the brain is suspected to play a role in the development of schizophrenia,23,24 which could explain the observed association between schizophrenia and toxoplasmosis (see related articles in this issue of Schizophrenia Bulletin).
It is also possible that differences in the level of testosterone may be responsible for the observed behavioral differences between Toxoplasma-infected and Toxoplasma-free subjects. A lower second- to fourth-digit length ratio,25 greater body height in men,25 longer duration of pregnancy,26 and higher sex ratio (ie, more male births)27 suggest that Toxoplasma-infected subjects have a higher level of testosterone. High levels of steroid hormones have been associated with lower cellular immunity.28,29 Thus, the most parsimonious explanation of the observed high testosterone–toxoplasmosis association is a higher risk of Toxoplasma infection in subjects with higher levels of testosterone and therefore a weaker immunity. Alternatively, in an evolutionary sense, the behavioral changes induced by T. gondii could be side effects of the organism's increase in testosterone in order to impair the cellular immunity of the host and thus increase the chances of surviving in the host organism.
The results obtained during the past 15 years strongly suggest that latent toxoplasmosis influences the behavior not only of rodent hosts but also of humans. The neurophysiological mechanisms and practical effects of these behavioral changes, however, are still to be elucidated.
TOXOPLASMA'S ROLE IN SCHIZOPHRENIA
The possibility that toxoplasmosis is one cause of schizophrenia has been studied by scientists since 1953.These studies attracted little attention from U.S. researchers until they were publicized through the work of prominent psychiatrist and advocate E. Fuller Torrey. In 2003, Torrey published a review of this literature, reporting that almost all the studies had found that schizophrenics have elevated rates of Toxoplasma infection.A 2006 paper has even suggested that prevalence of toxoplasmosis has large-scale effects on national culture. These types of studies are suggestive but cannot confirm a causal relationship (because of the possibility, for example, that schizophrenia increases the likelihood of Toxoplasma infection rather than the other way around).
- Acute Toxoplasma infection sometimes leads to psychotic symptoms not unlike schizophrenia.
- Several studies have found significantly higher levels of Toxoplasma antibodies in schizophrenia patients compared to the general population.
- Toxoplasma infection causes damage to astrocytes in the brain, and such damage is also seen in schizophrenia.