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Although Toxoplasma gondii infects a large proportion of the world's human population, it is an uncommon cause of disease. Certain individuals, however, are at high risk for severe or life-threatening disease because of this parasite. These include congenitally infected fetuses and newborns and immunologically impaired individuals. Congenital toxoplasmosis is the result of maternal infection acquired during gestation, an infection that is most often clinically inapparent. In immunodeficient patients toxoplasmosis most often occurs in persons with significant defects in T-cell and/or B-cell–mediated immunity, such as those receiving corticosteroids, anti–tumor necrosis factor (TNF) therapies, certain monoclonal antibodies, or cytotoxic drugs, and in those with hematologic malignancies, organ transplants, or acquired immunodeficiency syndrome (AIDS). In the vast majority of otherwise immunocompetent individuals, primary or chronic (latent) infection with T. gondii is asymptomatic; after the acute infection a small percentage suffer chorioretinitis, lymphadenitis, mononucleosis-like syndrome, flulike symptoms, or, even more rarely, hepatitis, pneumonia, brain abscesses, myocarditis, and polymyositis.
T. gondii was first observed in the North African rodent Ctenodactylus gundi by Nicolle and Manceaux in 1908 and was recognized as a cause of human disease in an 11-month-old congenitally infected child by Janku in 1923. It was reported as a cause of encephalitis by Wolf, Cowen, and Paige, who in 1939 observed it in a newborn who presented with seizures, intracranial calcifications, hydrocephalus, and chorioretinitis.
Although relatively few cases of severe toxoplasmosis in adults were reported during the ensuing years, the remarkable report in 1968 by Vietzke and his colleagues, from the National Cancer Institute of the National Institutes of Health, highlighted T. gondii as a cause of life-threatening infection in patients with malignancy, predominantly in those with hematologic malignancies. Brain involvement with focal areas of encephalitis was the primary finding at autopsy in these patients. Since that time, several hundred cases in non-AIDS immunodeficient patients have been recorded in the literature. In 1983 the first report of toxoplasmosis in AIDS patients appeared. Toxoplasmic encephalitis (TE) subsequently was recognized as the major cause of space-occupying lesions in the brains of these patients, almost all of whom had serologic evidence of prior exposure to the parasite. Between 2003–12 more than 6000 estimated cases of toxoplasmosis occurred in the United States, based on International Classification of Disease(s)–9 coding of privately insured patients: 38% with eye disease, 5% with meningoencephalitis, and 45% with unspecified toxoplasmosis. Despite the significant advances that have been achieved in the recent past, major challenges remain in the areas of prevention and management of the acute infection in pregnancy, the fetus, and the newborn ; in understanding the correlation between parasite strains and geographic origin versus disease outcomes ; immune responses in humans ; contribution of the chronic infection to human behavior and psychiatric and other disorders ; and in the understanding and treatment of toxoplasmic chorioretinitis and infection in immunocompromised individuals.
Etiology
T. gondii is a coccidian parasite of felids, with humans and other warm-blooded animals serving as intermediate hosts. It belongs to the subphylum Apicomplexa, class Sporozoa, and can exist in many forms: macrogametes and microgametes, the oocyst (which releases sporozoites), the tissue cyst (which contains and may release bradyzoites), and the tachyzoite ( Fig. 278.1 ).
Population genetic analysis has demonstrated that, at least within Europe and North America, most organisms isolated from both domesticated animals and humans can be grouped into one of three clonal genotypes—types I to III—that may identify clinically relevant biologic differences. Clear differences have been observed in the frequency of parasite genotypes when T. gondii isolates from animals were compared with those of humans. Type III strains are common in animals but observed significantly less often in cases of human toxoplasmosis; most cases in humans in Europe and North America are caused by type II strains. Type II strains are significantly more often associated with reactivation of chronic infections and accounted for 65% of strains isolated from AIDS patients. Both type I and type II strains have been associated with human congenital toxoplasmosis. Multiple genotypes have been associated with ocular disease; in Germany an unusual nonreactive serotype was associated with ocular disease and with more frequent recurrences. Atypical and recombinant strains have been identified with increasing frequency in regions other than the United States and Europe and from animals other than humans and domestic animals; some of these strains appear to be associated with more severe disease, suggesting greater virulence, even in immunocompetent individuals. The most exhaustive studies have now identified six major population clades, although detailed sequence analysis indicates there is a varied amount of genetic exchange within and between these clades. Hence, although the “three-dominant-strain” paradigm is holding for humans in Europe and North America, the situation appears much more complex in other regions and in other animal hosts.
Organism Stages
Oocyst
Cats eventually shed oocysts after they ingest any of the forms of the parasite, at which time an enteroepithelial cycle begins. This sexual form of reproduction begins when the parasites penetrate the epithelial cells of the small intestine and initiate development of asexual and sexual (gametogony) forms of the parasite. Oocyst wall formation begins around the fertilized gamete, and when still immature, oocysts are discharged into the intestinal lumen by rupture of intestinal epithelial cells. Unsporulated oocysts are subspherical to spherical and measure 10 × 12 µm in diameter (see Fig. 278.1A ). Oocysts are formed in the small intestine only in felids and are excreted in the feces for periods varying from 7 to 20 days. More than 100 million oocysts may be shed in the feces in a single day. Sporulation, required for oocysts to become infectious, occurs outside the cat within 1 to 5 days, depending on temperature and the availability of oxygen. Sporulated oocysts contain two sporocysts (see Fig. 278.1A ), each of which contains four sporozoites. Maturation is more rapid at warm temperatures (2–3 days at 24°C compared with 14–21 days at 11°C). Oocysts may remain viable for as long as 18 months in moist soil; this results in an environmental reservoir from which incidental hosts may be infected. Recent clues to some of the features that make oocysts so robust have come from proteomic and transcriptomic analyses. Among other findings, these studies have revealed an abundance of small tyrosine-rich proteins in the oocyst wall. Cross-linking of the tyrosines in these proteins could confer a natural “sun-screen” for the sporozoites within because they are strong absorbers of ultraviolet light.
Tachyzoite
The tachyzoite form (see Fig. 278.1B ) is oval to crescentic and measures 2 to 3 µm wide and 5 to 7 µm long; it requires an intracellular habitat to multiply despite having all of the usual eukaryotic machinery necessary for reproduction. Tachyzoites are responsible for triggering immune responses leading to clinical manifestations seen in both primary and reactivated infection; presence of tachyzoites is the hallmark of active infection requiring treatment. They reside and multiply within vacuoles in their host's cells, can infect virtually all phagocytic and nonphagocytic cell types, and multiply approximately every 6 to 8 hours to form rosettes. Continuous multiplication leads to cell disruption and release of organisms that go on to invade nearby cells or are transported to other areas of the body by blood and lymph. Tachyzoites appear to actively and rapidly migrate across epithelial cells and may traffic to distant sites while extracellular. Recent evidence suggests they might also use the infected host cell as a “Trojan horse” to traffic and gain access to tissues that might not otherwise be easily accessed.
At the anterior end of the tachyzoite there is a cone-shaped structure termed the conoid . It is protruded during the parasite's entry into host cells. Rhoptries , numbering 4 to 12, are club-shaped organelles that terminate within the conoid. The rhoptries, together with surrounding small, rod-shaped organelles (micronemes), have important secretory functions for parasitic invasion. Dense granules are organelles distributed throughout the cytoplasm. Their contents are released into a vacuole, termed the parasitophorous vacuole , that is formed around the parasite during entry into the cell and also into the external environment as excreted-secreted antigens. Some dense granule proteins transit across the membrane surrounding the parasitophorous vacuole, eventually reaching the host nucleus, as described further.
The rhoptries and micronemes produce a collection of proteins that are crucial for the invasion process. These appear to mediate the attachment to the host cell, including the moving junction, a ringlike point of contact between the parasite and host cell surface that migrates down the length of the parasite during invasion. Like the dense granules, the rhoptries also introduce proteins into the host cell that are critical in manipulating the cell, presumably to the advantage of the parasite. These rhoptry and dense granule proteins can be very different (polymorphic) between different strains of T. gondii and appear responsible for many of the differences in virulence seen for types I, II, and III in mice, as described earlier.
A fourth organelle that is restricted to Toxoplasma and its Apicomplexa cousins is the apicoplast. This is akin to chloroplasts of plants, with a similar evolutionary origin involving endosymbiotic algae, but photosynthetic functions have been completely lost. It has its own DNA, RNA, and protein translation, the latter of which is prokaryotic in nature, making for a very attractive target for drug therapies. Indeed, one of the currently used drugs for treatment of human infection, clindamycin, targets the ribosomes of the apicoplast. A major role of this organelle is fatty-acid biosynthesis. Recent work with Plasmodium, which also has this organelle , has demonstrated that the apicoplast is crucial to the synthesis of isoprenoids, making further work on attacking this Achilles heel an attractive prospect.
Tachyzoites cannot survive desiccation, freezing and thawing, or extended exposure to gastric digestive juices. They are propagated in the laboratory in the peritoneum of mice and in cultured cells. Tachyzoites can be visualized in sections stained with hematoxylin and eosin (H&E) but are better visualized with Wright-Giemsa and immunoperoxidase stains. They are used as the killing target in the gold standard test for detection of Toxoplasma IgG.
Tissue Cyst
Once the tachyzoite has invaded the target cell, it can undergo stage conversion into the bradyzoite form. Tachyzoites and bradyzoites are structurally and phenotypically different. Tachyzoites multiply rapidly and synchronously, forming rosettes and lysing the cell, whereas the more slowly replicating bradyzoites form tissue cysts. Molecules are expressed in a stage-specific manner and are responsible for certain of the phenotypic differences between tachyzoites and bradyzoites. Interferon-γ (IFN-γ), nitric oxide (NO), heat shock proteins, and pH and temperature manipulations can trigger conversion of tachyzoites to bradyzoites in vitro and perhaps in vivo as well.
Tissue cysts grow and remain within the host cell cytoplasm, wherein the intracystic bradyzoites continue to divide. Tissue cysts vary in size from younger ones that contain only a few bradyzoites to older tissue cysts that may contain several thousand bradyzoites and may reach more than 100 µm in size (see Fig. 278.1D ). They appear spherical in the brain and conform to the shape of muscle fibers in heart and skeletal muscles. The central nervous system (CNS); eye; and skeletal, smooth, and heart muscles appear to be the most common sites of latent infection. Because of their persistence in tissues in asymptomatic individuals, demonstration of tissue cysts in histologic sections does not necessarily mean that the infection was recently acquired or that it is clinically relevant. Tissue cysts stain well with periodic acid–Schiff, Wright-Giemsa, Gomori methenamine silver, and immunoperoxidase stains. Tissue cysts in meat are rendered nonviable by γ-irradiation (0.4 kGy), heating meat throughout to 67°C, or freezing to –20°C for 24 hours and then thawing, but not by gentle heating in a microwave.
Although the tachyzoite form appears to be indiscriminate in the type of host cell parasitized, it has been suggested that, in brain tissue, there is a predilection for tissue cyst formation to occur predominantly within neurons. However, it has been shown that tissue cysts can form within astrocytes cultured in vitro. In an electron microscopic study of the pathologic changes in brains of infected mice, tissue cysts were observed to remain intracellular throughout the period of study (22 months). There is compelling evidence to suggest that bradyzoites can exit from intact tissue cysts and invade contiguous cells, where they convert to the tachyzoite form. This is the likely explanation for the appearance of “daughter” cysts or clumps of cysts in the brain. Recent evidence suggests that neurons are capable of destroying the invaded parasite and/or that rhoptry proteins are injected into cells they do not infect. These results have implications for how the parasite commandeers host functions.
Transmission and Epidemiology
T. gondii infection is a worldwide zoonosis. The organism infects herbivorous, omnivorous, and carnivorous animals, including birds. Infection in humans most commonly occurs through the ingestion of raw or undercooked meat that contains tissue cysts, through the ingestion of water or food contaminated with oocysts, or congenitally through transplacental transmission from a mother who acquired her infection during gestation ( Fig. 278.2 ). Less common are transmission by transplantation of an infected organ or transfusion of contaminated blood cells. Transmission has also occurred by accidental sticks with contaminated needles or through exposing open lesions or mucosal surfaces to the parasite. Because the sexual cycle of the parasite takes place in the small bowel of members of the cat family, cats play a significant role as powerful amplifiers of the infection in nature (see “ Oocyst ”). Epidemiologic surveys have revealed that in most areas of the world, the presence of cats is of primary importance for the transmission of the parasite. Excretion of oocysts has been reported to occur in approximately 1% of cats in diverse areas of the world. Wild felines, and especially bobcats in the United States, may be among the most important sources of oocysts.
Although ingestion of raw or undercooked meat that contains viable T. gondii tissue cysts will result in infection, the relative frequency with which this occurs in relation to the frequency of infection caused by ingestion of oocysts is unclear. For instance, in countries such as France, where eating undercooked meat is common and the prevalence of the infection is high, meat may be an important cause of the infection. (It was in Paris that the meat-to-human hypothesis of spread of T. gondii was proved. ) In contrast are countries such as those in Central and South America, where the prevalence of the infection in humans is high but the ingestion of undercooked meat is relatively less common. In these areas, oocysts may be the more important source of human infection. Until a newly described method for distinguishing bradyzoite- versus oocyst-initiated infection is validated in these regions, their respective contributions to human infection will largely remain a matter of speculation.
Ingestion of tissue cysts in infected meat (primarily pork and lamb) is a major source of the infection in humans in the United States. T. gondii infection is common in many animals used for food, especially sheep and pigs, with a lower prevalence in cattle, horses, and water buffaloes. Organisms may survive in tissue cysts in these animals for years and can be found in nearly all edible portions of an animal. A seminal study on the prevalence of T. gondii in samples of meat used for human consumption (obtained from grocery stores) was performed in the United States in the 1960s. The parasite was isolated from 32% of pork chops and 4% of lamb chops; there were no isolations from beef, and indeed, cattle appear to be generally not an important intermediate host for this parasite. A recent polymerase chain reaction (PCR)-based study in England found 33% (19/57) of pork and 67% (6/9) of lamb samples positive for T. gondii DNA.
Serologic surveys conducted in the past 20 years in the United States indicate that the prevalence of T. gondii in pigs is declining, with an overall prevalence of 2.6% in a recent National Animal Health Monitoring Survey, presumably due to changing management practices and consolidation of pig production into large-scale operations. However, there are still many isolated small swine farms, including those that raise organic pigs, and the prevalence of T. gondii in these animals can be greater than 90%. Of note, meat for human consumption is not routinely inspected for T. gondii infection in the United States or elsewhere in the world. Seroprevalence of T. gondii infection in a study of lambs in the mid-Atlantic region was recently reported to be 27%. Although T. gondii infection of sheep is widely prevalent, in the United States meat from adult sheep is not usually used for human consumption. Reports of suspect transmission by unpasteurized goat's milk have appeared. In addition to differences in how meat is cooked, the tendency for beef, compared with lamb and pork, to harbor few, if any, cysts may partly explain the differences in seroprevalence in the United States versus Europe; beef accounts for a much greater fraction of meat consumed in the United States compared with Europe, where lamb and pork are more popular.
Acute infection appears to exhibit seasonality patterns in studies reported from Europe and the United States. In a study from the Palo Alto Medical Foundation– Toxoplasma Serology Laboratory (PAMF-TSL; www.pamf.org/serology/ ; 650-853-4828) of 112 consecutive cases of acute toxoplasmic lymphadenitis (TL) in the United States, the distribution of cases was not uniform across the 12 calendar months. The highest peak of cases was in December, followed by a peak in September. Similar months were identified in patients with acute toxoplasmosis in rural areas in France.
T. gondii infection is prevalent in game animals, especially black bears (80% infected) and white-tailed deer, as well as in raccoons (60% infected). Thus wild animal meat can serve as a source of the infection for hunters and their families, especially when care is not taken while eviscerating and handling the game or when meat and other organs from these animals is served undercooked or uncooked.
Although T. gondii tissue cysts may be found in edible tissues of chickens, poultry products are probably not important in the transmission of T. gondii to humans in urban areas because they are usually frozen for storage and thoroughly cooked to avoid diseases that could be caused by contamination by other organisms.
The ingestion of vegetables and other food products contaminated with oocysts probably accounts for infection in seropositive vegetarians. Although isolation of tachyzoites from secretions of people with the acute infection has been claimed, human-to-human transmission of infection by this route has not been established. Outbreaks within families and other groups are common, but there is no evidence of natural human-to-human transmission other than from mother to fetus.
Several epidemiologic studies have identified water as a potential source for T. gondii infection both in humans and animals. In vitro studies have demonstrated that oocysts can sporulate in seawater within 1 to 3 days, can survive in seawater for up to 6 months, and can survive in water treated with sodium hypochlorite or ozone, but not ultraviolet radiation. Population mapping studies of acutely infected individuals as well as case-control studies linked drinking unfiltered water (presumably contaminated with oocysts) to an outbreak of toxoplasmosis in a municipality in the Western Canadian province of British Columbia and to high endemic rates of toxoplasmosis in Rio de Janeiro State, Brazil. In another Brazilian outbreak, T. gondii organisms were detected in water by a variety of methods from an implicated reservoir. Coastal freshwater runoff was observed to be a risk factor for T. gondii infection among southern sea otters along the California coast.
In humans the incidence of T. gondii antibodies increases with increasing age; the incidence does not vary significantly between sexes. The incidence tends to be less in cold regions, in hot and arid areas, and at high elevations. Slaughterhouse workers may have an increased risk for infection. The prevalence of antibody titers to T. gondii varies considerably among different geographic areas and also among individuals within a given population. These differences depend on a variety of factors, including culinary habits and cleanliness of surroundings. A decrease in antibody prevalence over the past few decades has been observed in many countries. In the United States the seroprevalence in US military recruits decreased by one-third between 1965 and 1989; the crude seropositivity rate among recruits from 49 states was 9.5% in 1989 compared with 14.4% in 1965. As another example, in the 1970s, 24% of women in the childbearing age group in Palo Alto, California were seropositive, whereas the rate in 2008 was 10%. Seroprevalence rates in the United States among such women range from 3% to greater than 35%, whereas rates greater than 50% are present in women of childbearing age in much of Western Europe, Africa, and South and Central America. The recent (2011–14) overall age-adjusted seroprevalence of T. gondii infection in persons 6 years or older in the United States was reported to be 10.4%, with a seroprevalence among women age 15 to 44 years at 7.5%. This represented a continuous decline in seroprevalence compared with a similar survey from 15 to 20 years earlier. In multivariable analysis, Toxoplasma seroprevalence increased with age and was higher in males; persons living below the poverty level; persons with a high school or less education; and non-Hispanic black, Mexican American, and foreign-born non-Hispanic white persons compared with US-born non-Hispanic white persons.
Although the prevalence of the infection appears to be declining in certain areas of the world, such as Europe and the United States, this has not been the case, or there has been a documented increase, in other geographic locales. A meta-analysis of blood donors worldwide found an overall seroprevalence of 33%, with a wide range among countries.
T. gondii may survive in citrated blood at 4°C for as long as 50 days, and infection has been transmitted through transfusion of whole blood or white blood cells. Leukocyte transfusions may pose a special risk. The transmission of infection by organ transplantation has been documented and may result from the transplantation of an organ (e.g., heart) from a seropositive donor to a seronegative recipient. In bone marrow transplant (BMT) recipients, toxoplasmosis almost always is a result of recrudescence of a latent infection rather than from the transplant.
The incidence of TE among HIV-infected individuals directly correlates with the prevalence of T. gondii antibodies among the general HIV-infected population, the degree of immunosuppression (best measured by the CD4 cell count), the use of effective prophylactic treatment regimens against development of TE, and the immunologic response to antiretroviral therapy (ART). AIDS-associated TE and toxoplasmosis involving other organs are almost always due to reactivation of a chronic (latent) infection that results from the progressive immune dysfunction that develops in these patients. It is estimated that 20% to 47% of AIDS patients who are infected with T. gondii but are not taking anti- Toxoplasma prophylaxis or antiretroviral drugs will ultimately develop TE. This makes TE a major concern in areas where the use of antiretrovirals is still a treatment relatively few HIV-positive individuals receive.
A substantial decline in the incidence of TE and toxoplasmosis-associated hospitalizations and deaths has been seen in HIV-infected patients who adhere to effective anti- Toxoplasma prophylactic regimens and to ART.
In the United States T. gondii seropositivity among HIV-infected patients has been reported to range from 10% to 45% and directly correlates with the seropositivity in the general non–HIV-infected population. In contrast, the seroprevalence from a similar period was approximately 50% to 78% in certain areas of Western Europe and Africa. In a study in France, 1215 (72.2%) of 1683 HIV-infected patients had serologic evidence of exposure to T. gondii . During the study period (1988–95), the overall incidence of toxoplasmosis in this population was estimated to be 1.53 per 100 patient-years, with an increase from 0.68 per 100 patient-years in 1988 to 2.1 per 100 patient-years in 1992, and a subsequent decline to 0.19 per 100 patient-years in 1995 that was likely related to the widespread use of anti- Toxoplasma prophylaxis. Toxoplasmosis is rare in the HIV-infected pediatric population: 0.06 cases per 100 patient-years were reported among more than 3000 patients participating in clinical trials in the pre-ART era but during a time when Pneumocystis jirovecii pneumonia (PCP) prophylaxis was recommended.
Of interest is the low reported incidence of TE in Africa, despite T. gondii seroprevalence rates of 32% to 78%. Lack of autopsy data and a lack of neuroimaging studies likely contribute to the low reported incidence. It has also been suggested that because of poor access to medical care, many HIV-infected patients in Africa succumb to infection with organisms such as Mycobacterium tuberculosis before they develop the opportunistic infections associated with the advanced stage of HIV infection, including toxoplasmosis. However, in one autopsy series from the Ivory Coast, of 175 patients with AIDS-defining abnormalities, the prevalence of TE was 21%, and in a recent report of 547 HIV-infected patients from Ghana, TE accounted for 29% of admissions and 28% of deaths.
T. gondii infection may be acquired after the acquisition of HIV infection. Seroconversion rates between 2% and 5.5% have been reported in patients followed for periods up to 28 months.
Even before the emergence of AIDS, TE had been recognized as a cause of incapacitating disease and death among HIV-negative immunosuppressed patients, especially in those whose underlying disease or therapy caused a deficiency in cell-mediated immunity. Patients with hematologic malignancies are at a particularly higher risk to develop recrudescence of the infection. Among organ transplantation patients, those with heart, lung, kidney, and BMTs develop toxoplasmosis at a higher rate.
Pathogenesis and Immunity
T. gondii multiplies intracellularly at the site of invasion, with the gastrointestinal [GI] tract as the major route for and the initial site of infection in nature; bradyzoites released from tissue cysts or sporozoites released from oocysts invade, differentiate to tachyzoites, and then rapidly multiply within intestinal epithelial cells. Organisms may spread first to the mesenteric lymph nodes and then to distant organs by invasion of lymphatics and blood. T. gondii tachyzoites infect virtually all cell types, and cell invasion occurs as an active process. Survival of tachyzoites is due to the formation of a parasitophorous vacuole that lacks host proteins necessary for fusion with lysosomes, and consequently acidification does not occur. Active invasion of macrophages by tachyzoites does not trigger oxidative killing mechanisms. With the appearance of humoral and cellular immunity, only those parasites protected by an intracellular habitat or within tissue cysts survive. An effective immune response significantly reduces the number of tachyzoites in all tissues, and after the initial acute stages, tachyzoites are rarely demonstrable histologically in tissues of infected immunocompetent humans. Tachyzoites are killed by reactive oxygen intermediates, acidification, osmotic fluctuations, reactive nitrogen intermediates, intracellular tryptophan depletion, and specific antibody combined with complement. In rodents two classes of immune-stimulated guanosine triphosphate (GTP)ases play a crucial role in destruction of tachyzoites within the parasitophorous vacuole: the p47 immunity-related GTPases (IRGs) and the larger GTP-binding proteins (GBPs).
Tissue cyst formation takes place in multiple organs and tissues during the first week of infection. Despite the ability to isolate T. gondii from normal brains of chronically infected humans, the tissue cyst form is rarely observed in histologic preparations; it has been isolated from both brain and skeletal muscle in 10% of 52 T. gondii– seropositive patients who, at autopsy, had no clinical or pathologic evidence of the infection. The tissue cyst form is responsible for residual (chronic or latent) infection and persists primarily in the brain, skeletal and heart muscle, and the eye.
In immunocompetent individuals the initial infection and the resultant seeding of different organs leads to a chronic or latent infection with little, if any, clinical significance. This chronic stage of the infection corresponds to the asymptomatic persistence of the tissue cyst form in multiple tissues. It is believed that periodically bradyzoites are released from tissue cysts or that cysts “rupture”; cyst disruption in this setting appears to be a clinically silent process effectively contained by the immune system and in the CNS likely results in small inflammatory nodules, with a limited degree of neuronal cell death and architectural damage. However, several investigators have suggested that chronic infection may not be completely asymptomatic and may result in important behavioral changes and neuropsychiatric disorders, although other studies do not have similar findings, and definitive research to support such associations has not yet been reported.
Toxoplasmosis in severely immunodeficient individuals may be caused by primary infection or be the result of recrudescence of a latent infection. It is widely held that reactivation is the result of disruption of the tissue cyst form, followed by differentiation to and uncontrolled proliferation of tachyzoites and tissue destruction. In individuals with deficient cell-mediated immunity, rapid, uncontrolled proliferation of T. gondii results in progressively enlarging necrotic lesions. It has been postulated that damage to any organ in these patients, including the brain, eye, heart, lung, skeletal muscle, GI tract, and pancreas, can result directly from tissue cyst disruption in the parenchyma of the organ itself or from tissue cyst disruption elsewhere in the body, followed by subsequent spread to that organ. Hematogenous spread is supported by the observation of the development of simultaneous lesions in the brain and the presence of parasitemia in 14% to 38% of AIDS patients with TE.
Infection with T. gondii induces both humoral and cell-mediated immune responses. A well-orchestrated and effective systemic immune response, combining both innate and adaptive mechanisms, is responsible for the early disappearance of T. gondii from peripheral blood during the acute infection and limits the parasite burden in other organs. Immunity in the immunocompetent host is lifelong. Exogenous reinfection, which has been demonstrated in laboratory animals, likely also occurs in humans but does not appear to result in clinically apparent disease, although in one case report a chronically infected pregnant woman was infected with a highly virulent strain that resulted in infection of the fetus.
Because T. gondii is a natural parasite of rodents, inbred mice have been used extensively as an animal model for studies of both immunity and immunopathology in this protozoan infection and have yielded a remarkably detailed picture of its host interaction. When tachyzoites invade, they inject the contents of their rhoptries into the host cell cytosol. This delivers not only some of the machinery needed for invasion (contained within the rhoptry necks and known as RON proteins) but also a collection of “effectors” that intercept or co-opt host immune pathways, presumably to the parasite's advantage. These effectors include the rhoptry protein ROP16, which functions as a mimic of host Janus kinases (JAKs), phosphorylating critical tyrosines on host STATs (signal transducers and activators of transcription). Depending on the particular flavor of ROP16 that a given strain carries, the host immune response can be driven in differing directions, either more or less inflammatory, and this can have a profound effect on the host's response and ultimate outcome of the infection. In the case of another set of injected ROPs—ROP5, ROP17, and ROP18—the target is murine IRGs, a key part of a mouse cell's defense machinery. Normally, IRGs attack the membrane of the vacuole in which a pathogen resides, disrupting it and leading to death of the organisms within. ROP5, ROP17, and ROP18, however, collaborate to phosphorylate and thereby inactivate IRGs, although again, the effectiveness of this depends on the specific alleles of ROP5 and ROP18 that a given strain of Toxoplasma carries. Last, dense granules can also introduce polymorphic effectors into the host cell; one such effector, granule 15 (GRA15), has been shown to be crucial to the activation of one of the most central transcription factors in mammalian immune response, nuclear factor kappa B.
Another, GRA6, activates nuclear factor of activated T cells (NFAT) activity. Some GRA proteins transit across the parasitophorous vacuole membrane (PVM) that separates the growing parasites from the host cytosol, eventually reaching the host nucleus. These include GRA16, GRA24 and TgIST ( T. gondii inhibitor of STAT1 transcriptional activity), all of which have profound effects on how the host cell responds to infection. In the case of TgIST, for example, the secreted protein suppresses the immune response by blocking the activity of a key host factor STAT1. These proteins transit across the PVM by an as yet uncharacterized machinery, although one component was recently described (myc regulation 1 [MYR1]). It is important to recognize that these findings do not necessarily represent the mechanisms underlying the immune response to T. gondii in humans. For example, although the effect of ROP16 on STATs may well have a parallel in human cells, IRGs are not part of the human immune response, and so ROP5, ROP17, and ROP18, if they are impacting the outcome of human infection, must be doing so by acting on other targets, such as activating transcription factor-6β. Similarly, Toll-like receptors TLR11 and TLR12 play a major role in the induction of interleukin-12 (IL-12) and host resistance in the mouse, but neither receptor exists in humans, indicating that innate recognition of the parasite in humans must involve distinct mechanisms. This might involve another branch of the innate immune system, NLRs (nucleotide oligomerization domain [NOD]-like receptors), that detect molecular signatures or patterns specific to various pathogens. Recent work has suggested that susceptibility to Toxoplasma infection in humans is associated with a polymorphism in a human NLR known as NALP1 (NACHT-LRR-PYD domains–containing protein 1). The overall question of how Toxoplasma is sensed by the innate arm of the human immune system and how different strains of the parasite do this with differing degrees of success is just beginning to be explored. Of interest, in direct contrast to murine innate cells, human monocytes and dendritic cells do not produce cytokines in response to soluble tachyzoite antigens due to the absence of TLR11 and TLR12. Instead, in human cells phagocytosis of live parasites appears to be a major stimulus for proinflammatory cytokine production.
In murine models T cells, macrophages, and type 1 cytokines (IFN-γ, IL-12) are crucial for control of T. gondii infection. Adoptive transfer and depletion experiments not only confirmed that T cells are essential for control of T. gondii infection but also demonstrated an interplay between CD4 + and CD8 + T cells in both the induction of resistance and the maintenance of latency. Expansion of both natural killer (NK) and γδ T cells early in infection provides innate resistance while the adaptive response mediated through αβ CD4 and CD8 T cells develops. These different subsets of T cells and NK cells are likely to protect the host by secreting cytokines, such as IFN-γ, IL-2, and TNF-α, and apparently not by lysing T. gondii –infected cells. Dendritic cells and inflammatory monocytes also play an important role in control of acute infection and the early production of IL-12, with dendritic cells critically dependent on the Fms-like tyrosine kinase 3 (Flt3) ligand for this response. NK-cell–derived IFN-γ appears critical to the differentiation of IL-12–producing dendritic cells. Early studies suggested that neutrophils were an important component of the early response, but more recent studies suggest that they are not and may, in fact, contribute to the pathology.
The costimulatory molecules CD28 and CD40 ligand are pivotal for the regulation of IL-12 and IFN-γ production in response to the parasite. T. gondii infection of antigen-presenting cells, such as dendritic cells and macrophages, causes upregulation of the counterreceptors for CD28 and CD40L, CD80/CD86, and CD40. Binding of CD80/CD86 to CD28 enhances production of IFN-γ by CD4 + T cells. In addition, binding of CD40L to CD40 triggers IL-12 secretion, which in turn enhances production of IFN-γ. The relevance of CD40L in the immune response to T. gondii is supported by reports of TE and disseminated toxoplasmosis in children with congenital defects in CD40L signaling (hyper-IgM syndrome). Moreover, recent studies have demonstrated that expression of CD40L is defective on CD4 + T cells from HIV-infected patients. This deficiency may play a role in defective IL-12/IFN-γ production associated with HIV infection.
Cytokines play a critical role in defense against the infection and are important in the pathogenesis of toxoplasmosis and TE. IL-12 enhances survival of T-cell–deficient mice during T. gondii infection, by stimulating the production of IFN-γ by NK cells, and is thought to also regulate the expression of the latter cytokine by T cells in immunocompetent mice. IFN-γ has been shown to play a significant role in the prevention or development of TE in mice. The administration to chronically infected mice of a monoclonal antibody against IFN-γ resulted in a dramatic worsening in the degree of encephalitis. In mice with active TE, treatment with IFN-γ significantly reduced the inflammatory response and numbers of tachyzoites.
Differences in IL-12 levels elicited during infection by different strains of the parasite may be responsible for some of the strain-specific differences in virulence in mice. These differences appear to be related to the activation (phosphorylation) of the transcription factor STAT3, which in turn is dependent on the particular allele of ROP16 injected by a given strain, as detailed earlier.
TNF-α is another cytokine pivotal for control of T. gondii infection. TNF-α is required for triggering of IFN-γ−mediated activation of macrophages for T. gondii killing activity and for nitric oxide (NO, an inhibitor of T. gondii replication) production by macrophages. The administration of TNF-α neutralizing antibody to infected mice caused the death of the mice and an increase in the number of T. gondii tissue cysts in the brains of survivors.
IL-10 has been shown to deactivate macrophages and result in reduced in vitro killing of T. gondii. Nevertheless, infected IL-10–deficient mice rapidly succumb to proinflammatory tissue damage, indicating an important protective role for this cytokine. Similarly, IL-4 and IL-6, which are usually considered downregulatory cytokines, have been shown to be important in resistance against TE in the murine model. IL-7 has also been shown to have a protective role against T. gondii in mice. During the early stages of the infection, IL-12, IL-1, and TNF act in concert with IL-15 to stimulate NK cells to produce IFN-γ.
IL-17 and IL-23 have also been implicated in the generation of a potent immune response but are not thought be essential for host resistance.
Several hypotheses have been proposed to explain the role of IFN-γ in host resistance to T. gondii. Involvement of reactive nitrogen intermediates (including NO) is suggested by the observation that l -NG-monomethyl- l -arginine acetate ( l -NMMA), a competitive analogue of l -arginine, simultaneously inhibits NO synthesis and intracellular tachyzoite killing by cytokine-activated peritoneal macrophages and microglial cells. In addition, mice in which NO synthesis is impaired as a result of genetic disruptions of the IFN- γ or IFN-1 genes succumb to the acute infection. Similar enhanced susceptibility was observed in mice treated with the reactive nitrogen intermediate inhibitor aminoguanidine and in NO synthase–deficient mice. The protective role of NO appears to be tissue specific rather than systemic. Because control of the acute infection in vivo was unaffected by NO synthase deficiency, the major role of reactive nitrogen intermediates appears to be to maintain control of established infections in this mouse model.
The IFN-γ–inducible p47 GTPases IRGM3 (IGTP) and IRGM1 (LRG47) have been shown to be required for host control of T. gondii infection in the mouse, and recent studies have linked IRGM3 with the autophagic destruction of Toxoplasma -containing vacuoles in IFN-γ–activated macrophages.
In a recent cytokine study using a high-throughput and multiplex assay, C-X-C motif chemokine ligand 9 (CXCL9) and CXCL10 levels were higher ( P < .05) and resistin levels were lower ( P <.05) in pregnant women with TL compared with those without TL. Among patients with TL, levels of vascular cell adhesion molecule 1 (VCAM-1) and C-C motif chemokine ligand 2 (CCL2) were lower ( P < .05) in pregnant women than in nonpregnant women. These findings likely illustrate human immune responses and parasite subversion efforts to strike a balance among immune protection, pathology, and evasion.
Immunoglobulin G (IgG), IgM, IgA, and IgE antibodies are produced in response to the infection. Extracellular tachyzoites are lysed by specific antibody when combined with complement; this is the basis for the detection of Toxoplasma IgG in what is considered to be the gold standard test for this Ig. In mice, humoral immunity results in limited protection against less virulent strains of T. gondii but not against virulent strains.
Both astrocytes and microglia likely play important roles in the immune response against T. gondii within the CNS. In the early stages of TE in both humans and mice there is a remarkable and widespread astrocytosis restricted to areas in which the parasite is detected. Whereas T. gondii can invade, survive, and multiply within astrocytes, they are killed by activated microglia.
Genetic Susceptibility
The observations in mice that genetic factors in the host contribute to the development and severity of TE and the fact that not all HIV-infected patients with positive T. gondii serologic findings develop TE suggested the possibility that genetic factors may also play a role in the predisposition of AIDS patients for this disease. The major histocompatibility complex (MHC) class II gene DQ3 (HLA-DQ3) has been significantly associated with the development of TE in North American white AIDS patients, whereas the HLA-DQ1 genotype was marginally protective. The HLA-DQ3 genotype was also significantly associated with the development of hydrocephalus in children with congenital toxoplasmosis. In the latter study a mouse model transgenic for human class II MHC found higher organism burden with the HLA-DQ3 than HLA-DQ1 genotype. In a South American white population a study using a higher-resolution typing method identified HLA-DQB*0402 and HLA-DRB1*08 genes , which were in linkage disequilibrium, as risk factors for TE, whereas alleles of HLA-DQB3 were not. Certain HLA-DQA1 and HLA-DQB1 alleles were associated with congenital infection in one recent Brazilian study. Another Brazilian study identified an association between the presence of certain KIR receptors and their class I HLA ligands with the development of ocular lesions in Toxoplasma -seropositive individuals. Thus further studies are needed to better define the contribution of various HLA alleles to susceptibility to TE. In single studies polymorphisms in other genes, including those for IL-6, IL-10, TLR9, NLR family, pyrin domain–containing protein 1 (NALP1, also known as NLRP1), and purinergic receptor P2X(7) (P2RX7) have been associated with congenital toxoplasmosis or retinochoroiditis.
Of interest, although humans with genetic defects in IFN-γ and IL-12 signaling are highly susceptible to mycobacterial and other bacterial infections, there are no reports of toxoplasmosis in these patients, again suggesting important differences in how T. gondii is controlled in humans versus mice.
Pathology
Our knowledge of the pathology of infection in humans has come largely from autopsy studies in severely infected infants and immunodeficient patients. Data from immunocompetent adults are limited almost entirely to results obtained from lymph node biopsy specimens and occasionally from myocardial or skeletal muscle tissue specimens. In addition to the direct demonstration of parasites in tissue and associated pathology, recent studies have revealed that the impact of the parasite may extend to many more cells than are actively infected; that is, mouse studies have shown evidence of injected rhoptry proteins in upward of 50-fold more neurons in a chronically infected brain than actually harbor parasites at that time. The impact of these “injected-uninfected” cells on pathogenesis and other interactions with the host has yet to be determined.
Lymph Node
The histopathologic changes in TL in immunocompetent individuals are frequently distinctive and often diagnostic ( Fig. 278.3A ). There is a typical triad of findings: a reactive follicular hyperplasia, irregular clusters of epithelioid histiocytes encroaching on and blurring the margins of the germinal centers, and focal distention of sinuses with monocytoid cells (see Fig. 278.3A ). Langerhans giant cells, granulomas, microabscesses, and foci of necrosis are not typically seen. Rarely, tachyzoites or tissue cysts are demonstrable. T. gondii DNA has infrequently been amplified from lymph node tissue.
Central Nervous System
Damage to the CNS by T. gondii is characterized by multiple foci of enlarging necrosis and microglial nodules. Necrosis is the most prominent feature of the disease because of vascular involvement by the lesions. In cases of congenital toxoplasmosis, necrosis of the brain is most intense in the cortex and basal ganglia and at times in the periventricular areas. The necrotic areas may calcify and lead to striking radiographic findings suggestive but not pathognomonic of toxoplasmosis. Hydrocephalus may result from obstruction of the aqueduct of Sylvius or foramen of Monro. Tachyzoites and tissue cysts may be seen in and adjacent to necrotic foci, near or in glial nodules, in perivascular regions, and in cerebral tissue uninvolved by inflammatory change. The necrotic brain tissue autolyzes and is gradually shed into the ventricles. The protein content of such ventricular fluid may be in the range of grams per deciliter and has been shown to contain significant amounts of T. gondii antigens.
The presence of multiple brain abscesses is the most characteristic feature of TE in severely immunodeficient patients and is particularly characteristic in patients with AIDS. Brain abscesses in AIDS patients are characterized by three histologic zones. The central area is avascular. Surrounding this is an intermediate hyperemic area with a prominent inflammatory infiltrate and perivascular cuffing by lymphocytes, plasma cells, and macrophages. Many tachyzoites and, at times, tissue cysts as well, appear at the margins of necrotic areas. An outer peripheral zone contains T. gondii tissue cysts. In the areas around the abscesses, edema, vasculitis, hemorrhage, and cerebral infarction secondary to vascular involvement may also be present. Important associated features in TE are the presence of arteritis, perivascular cuffing, and astrocytosis. Because these findings may also be present in patients with viral encephalitis, immunoperoxidase staining is important for differentiating these pathologic processes. Widespread, poorly demarcated, and confluent areas of necrosis with minimal inflammatory response are seen in some patients. Identification of tachyzoites is pathognomonic of active infection, but their visualization may be difficult in H&E-stained sections. The use of immunoperoxidase staining markedly improves the identification of both tissue cyst and tachyzoite forms and highlights the presence of T. gondii antigens (see Fig. 278.3B ). T. gondii DNA can be amplified from cerebrospinal fluid (CSF) or brain biopsy specimens of patients with TE. Of note, PCR-positive results in brain biopsy specimens need to be interpreted with caution. These results may be positive in patients chronically infected with the parasite whose CNS pathology can be explained by a diagnosis other than TE.
At autopsy in AIDS patients with TE, there is almost universal involvement of the cerebral hemispheres and a remarkable predilection for the basal ganglia. In a consecutive autopsy study of 204 patients who died of AIDS, 46 (23%) had morphologic evidence of cerebral toxoplasmosis. In 38 (83%) of the 46 cases, histologic evidence of toxoplasmosis was restricted to the CNS. The cerebral hemispheres were affected in 91% of cases and the rostral basal ganglia in 78%.
A “diffuse form” of TE has been described with histopathologic findings of widespread microglial nodules without abscess formation in the gray matter of the cerebrum, cerebellum, and brainstem. In these patients involvement by T. gondii was confirmed by immunoperoxidase stains that demonstrated tissue cysts and tachyzoites. In diffuse TE the clinical course progresses rapidly to death. It has been postulated that in such cases the lack of characteristic findings on computed tomography (CT) or magnetic resonance imaging (MRI) studies is due to insufficient time for abscesses to form before death occurs.
Leptomeningitis is infrequent and, when present, occurs over adjacent areas of encephalitis. Spinal cord necrotizing lesions are seen at autopsy in approximately 6% of patients with TE. The differential diagnosis of TE lesions includes CNS lymphoma, progressive multifocal leukoencephalopathy, pyogenic brain abscesses, and infection caused by organisms such as Nocardia spp., Aspergillus spp. and other molds, Trypanosoma cruzi , Cryptococcus neoformans, M. tuberculosis, Balamuthia spp., and cytomegalovirus (CMV). More than one agent may be present.
Lung
Pulmonary toxoplasmosis in the immunodeficient patient may appear in the form of interstitial pneumonitis, necrotizing pneumonitis, consolidation, pleural effusion, empyema, or all of these. The pneumonitis is associated with the development of fibrinous or fibrinopurulent exudate. Tachyzoites may be found in alveolocytes, alveolar macrophages, or pleural fluid, or extracellularly within alveolar exudate. T. gondii DNA may be demonstrated in bronchoalveolar lavage (BAL) fluid by the PCR.
Eye
Chorioretinitis in AIDS patients is characterized by segmental panophthalmitis and areas of coagulative necrosis associated with tissue cysts and tachyzoites. Numerous organisms in the absence of remarkable inflammation may be seen around thrombosed retinal vessels adjacent to necrotic areas. Multiple and bilateral lesions may occur. Amplification of parasite DNA in both aqueous humor and vitreous fluid has confirmed or supported the diagnosis of toxoplasmic chorioretinitis in patients with atypical retinal findings for ocular toxoplasmosis or who are immunocompromised.
Eye infection in immunocompetent patients produces acute chorioretinitis characterized by severe inflammation and necrosis. Granulomatous inflammation of the choroid is secondary to the necrotizing retinitis. There may be exudation into the vitreous or invasion of the vitreous by a budding mass of capillaries. Although rare, tachyzoites and tissue cysts may be demonstrated in the retina. The pathogenesis of recurrent chorioretinitis is controversial. One school proposes that rupture of tissue cysts releases viable organisms that induce necrosis and inflammation, whereas another school contends that chorioretinitis results from a hypersensitivity reaction triggered by unknown causes. A study demonstrating efficacy of trimethoprim-sulfamethoxazole (TMP-SMX) in preventing recurrences of chorioretinitis is consistent with the hypothesis that active organism replication is necessary for recurrence.
Recent studies have revealed a much higher incidence of ocular disease, which is often severe, among infected immunocompetent persons in South America than in North America or Europe. This difference seems most likely to be due to differences in the strains of Toxoplasma that predominate in these different regions. This is consistent with observations within the United States, where specific strains appeared to be associated with severe disease, although these studies involved relatively few patients and cannot be considered definitive.
Skeletal and Heart Muscle
Myositis caused by T. gondii has been reported in as high as 4% of HIV-infected patients who present with neuromuscular symptoms, and the same percentage has been observed in autopsy series of AIDS patients in whom a systematic histologic evaluation of the skeletal muscle was performed. Successful isolation from skeletal muscle biopsies has been reported. Microscopy has revealed necrotic muscle fibers with a variable inflammatory reaction. Skeletal muscle involvement has also been reported in the non-AIDS immunodeficient patient.
Toxoplasmic myocarditis is frequently noted at autopsy in AIDS patients but is usually clinically inapparent, with CNS manifestations predominating. Focal necrosis with edema and an inflammatory infiltrate is typical, although abscesses may also be noted. Similar histologic findings are seen in the non-AIDS immunodeficient population, and in both groups cardiac myocytes may be packed with tachyzoites (to produce pseudocysts) in the absence of an inflammatory response.
Biopsy-proven toxoplasmic myocarditis and polymyositis in the setting of acute toxoplasmosis have been reported in otherwise immunocompetent individuals and in patients on corticosteroids (see Fig. 278.3C and D ).
Other Organ Systems
Extensive involvement of the GI tract in AIDS patients may occur with tremendous variation in the inflammatory response. Hemorrhagic gastritis and colitis have been described. Other organs reported to be involved during toxoplasmosis include the liver, pancreas, seminiferous tubules, prostate, adrenal glands, kidneys, and bone marrow.
Clinical Manifestations
Toxoplasmosis describes the clinical or pathologic disease caused by T. gondii and is distinct from T. gondii infection, which is asymptomatic in the vast majority of immunocompetent patients.
Toxoplasmosis is conveniently classified into five clinical categories: (1) acquired in the immunocompetent patient, (2) acquired or reactivated in the immunodeficient patient, (3) ocular, (4) in pregnancy, and (5) congenital. In any category the clinical presentations are not specific for toxoplasmosis, and a wide differential diagnosis must be considered for each clinical syndrome. Furthermore, methods of diagnosis and interpretation of test results may differ according to the patient's specific clinical category. For instance, whereas serologic test results consistent with an infection acquired in the distant past for a nonimmunocompromised pregnant woman in her first half of pregnancy are interpreted as no risk for congenital toxoplasmosis, the same results for a patient about to undergo an allogeneic hematopoietic stem cell transplantation (HSCT) are interpreted as high risk for life-threatening toxoplasmosis in the posttransplantation period.
Toxoplasmosis in the Immunocompetent Patient
In the United States and Europe only 10% to 20% of cases of T. gondii infection in immunocompetent adults and children are symptomatic. Recent reports suggest that this proportion may be higher in other areas of the world, such as Brazil and other countries in Latin America. In addition, it appears that disease severity can also be greater in countries outside Europe and the United States. For instance, community outbreaks of acute toxoplasmosis with an unusually severe clinical presentation have been recently reported from Suriname and French Guiana. In two reports immunocompetent patients presented with severe disseminated disease, including pneumonia and hepatitis, that resulted in four deaths, including one newborn and one fetus, among 22 patients. Based on genotype analysis with microsatellite markers, “atypical” strains (i.e., not one of the three major strains seen in Europe and North America) were responsible for these outbreaks. The remarkable differences in clinical presentation of toxoplasmosis among patients from various regions of the world have significant implications when generating a differential diagnosis in travelers who become ill and are returning from highly endemic areas (e.g., Latin America).
When clinical manifestations are present, toxoplasmosis most often manifests as painless cervical lymphadenopathy, but any or all lymph node groups may be enlarged. On palpation the nodes are usually discrete and nontender, rarely more than 3 cm in diameter, may vary in firmness, and do not suppurate. However, the nodes may be occasionally tender or matted. Fever, malaise, night sweats, myalgias, sore throat, arthralgias, maculopapular rash, hepatosplenomegaly, or small numbers of atypical lymphocytes (<10%) may be present. The clinical picture may resemble infectious mononucleosis or CMV infection, but toxoplasmosis probably causes no more than 1% of “mononucleosis” syndromes. Retroperitoneal or mesenteric lymphadenopathy may produce abdominal pain accompanied by diarrhea. Neurocognitive abnormalities appear to be common during the acute infection among immunocompetent patients.
Toxoplasmic chorioretinitis as a manifestation of acute acquired infection is more common than previously recognized. Chorioretinitis in the setting of acute acquired toxoplasmosis can occur either sporadically or in the context of an epidemic of acute toxoplasmosis. For further discussion of this clinical entity, see “Ocular Toxoplasmosis in Immunocompetent Patients.”
In most cases the clinical course of toxoplasmosis in the immunocompetent patient is benign and self-limited. Symptoms, if present, usually resolve within a few months and rarely persist beyond 12 months. Lymphadenopathy may wax and wane for months and in unusual cases for 1 year or longer. Rarely, an apparently healthy person develops clinically overt disease, for instance, fever of unknown origin or potentially fatal disseminated disease, with myocarditis, pneumonitis, hepatitis, or encephalitis. In children nephrotic syndrome has been reported in association with acute toxoplasmosis. These more aggressive forms of the disease have been more commonly reported from South America. None of the clinical presentations of acquired toxoplasmosis is distinctive; the differential diagnosis of TL includes bacterial lymphadenitis, lymphoma, infectious mononucleosis, CMV or human herpesvirus 6 (HHV-6) “mononucleosis,” cat-scratch disease, sarcoidosis, tuberculosis, tularemia, metastatic carcinoma, endemic fungi (e.g., coccidioidomycosis), and leukemia. Acute acquired toxoplasmosis associated with multiorgan involvement has been reported to mimic other causes of pneumonitis, hepatitis, myocarditis, polymyositis, or fever of unknown origin in apparently immunocompetent patients.
T. gondii has been estimated to cause 3% to 7% of clinically significant lymphadenopathy. The major diagnostic confusion with toxoplasmic lymphadenopathy occurs with Hodgkin disease and the lymphomas. The diagnosis of recently acquired toxoplasmic lymphadenopathy is easily made serologically, but unfortunately, physicians often do not consider this diagnosis in patients with lymphadenopathy. Serologic test titers diagnostic of acute T. gondii infection are often obtained after histologic examination of a biopsied node has suggested the possibility of toxoplasmosis.
Myocarditis as a manifestation of acute toxoplasmosis has been reported in relatively few patients. It may occur clinically as an isolated disease process or as part of a variety of manifestations of disseminated infection. Manifestations include arrhythmias, pericarditis, and heart failure.
Myositis resembling polymyositis as a manifestation of acute toxoplasmosis has also been reported infrequently. Dermatomyositis has been associated with toxoplasmosis, although a cause-and-effect relationship has not been proved.
The clinical features of toxoplasmic myocarditis and polymyositis are illustrated by a case in which both were present in the same individual. A 43-year-old woman presented with cardiogenic pulmonary edema, followed by progressive sinus bradycardia and subsequent complete heart block; viral myocarditis was considered the most likely diagnosis. During the ensuing months, she developed proximal muscle weakness while being treated with corticosteroids; an endomyocardial biopsy (see Fig. 278.3C ) and a quadriceps muscle biopsy (see Fig. 278.3D ) revealed T. gondii . Her symptoms improved on pyrimethamine-sulfadiazine. One year after her initial presentation with myocarditis, retinal lesions characteristic of toxoplasmic chorioretinitis were observed in her right eye. Serologic test results and follow-up were consistent with recently acquired toxoplasmosis.
Several epidemiologic studies have suggested an association between infection with T. gondii and schizophrenia and other mental illnesses, but a definitive etiologic role of the parasite in such disorders has not been established. Population-based studies that include following large cohorts of patients following gestation will be necessary to clarify this potential association.
Toxoplasmosis in the Immunodeficient Patient
In immunocompromised patients toxoplasmosis can present with a wide spectrum of clinical manifestations. Disseminated disease has a 100% case-fatality rate if untreated. Early diagnosis requires a high index of suspicion because routine laboratory tests aimed at detecting bacterial, viral, or fungal infections will not alert clinical laboratory personnel or the clinician to the presence of T. gondii as the etiologic agent. T-cell– and/or B-cell–mediated immunity defects appear to confer the highest risk for toxoplasmosis as observed in patients with hematologic malignancies (especially Hodgkin disease and other lymphomas), organ transplant recipients, or those with AIDS and those receiving immunosuppressive therapy with high doses of corticosteroids or immunomodulators, such as anti–TNF-α agents, for instance rituximab, natalizumab, or alemtuzumab. In immunodeficient patients encephalitis, pneumonitis, and myocarditis reflect active replication and infection in the most commonly involved organs. Pneumonitis is a common and underrecognized manifestation of toxoplasmosis in these patients. Fever of unknown origin may be the sole manifestation of toxoplasmosis in the early stages of the disease. Disseminated infection with multiorgan involvement is not unusual; clinical manifestations may not necessarily reflect the extent and severity of the disseminated infection. Mortality approaches 100% if the infection is not treated or is treated only late in its course. Whereas serious toxoplasmosis in these patients often reflects recrudescence of a latent infection acquired in the distant past (as observed in the setting of AIDS or HSCT), it may also result from recently acquired acute infection (as observed in solid-organ transplants through the transplanted organ) or, more rarely, through the oral route. Although clinical manifestations are similar in patients with different causes for their immunosuppression, additional considerations are provided here for the organ transplant recipient and patient with AIDS.
Toxoplasmosis in the Solid-Organ Transplant Patient
Patients with solid-organ transplants will develop toxoplasmosis most commonly as a result of acquiring T. gondii infection through the transplanted organ, when the allograft of a seropositive donor (D + ) is given to a seronegative recipient (R − ), resulting in a D + /R − mismatch ( Table 278.1 ). Toxoplasmosis can also be the result of reactivation of a previously acquired infection in the recipient, regardless of the serologic status of the donor (D − /R + or D + /R + ; see Table 278.1 ). Fever is often the first manifestation in transplant recipients, followed by signs referable to the brain and lungs.
TABLE 278.1
Source of Toxoplasmosis in the Organ Transplant Patient
| Transplant of an Infected Organ to a Seronegative Recipient (D + R − ) |
|
| Reactivation of Latent Infection in a Seropositive Recipient (D − R + and D + R + ) |
|
D, Donor; R, recipient.
Knowledge of the overall prevalence of Toxoplasma antibodies in a population does not accurately predict the percentage of D + /R − T. gondii mismatches. Rather, this will depend on the prevalence of T. gondii antibodies in the age groups of the donor and recipient populations. For example, in a given geographic area, the prevalence of antibodies in young heart donors may be 3% to 10%, whereas in the older population of individuals, who would more likely be recipients, it may be 15% to 30%. Testing for Toxoplasma IgG antibodies should be performed in every solid-organ transplant candidate before transplantation and on serum from every organ donor.
Since April 6, 2017, organ procurement organizations in the United States have made it mandatory to test all potential organ donors for toxoplasmosis. This allows identification of those recipients at greatest risk of developing toxoplasmosis either because they were seronegative before transplantation and received an organ from a seropositive individual or because they were seropositive before transplantation and thus are at risk for reactivation of their latent (chronic) Toxoplasma infection. Toxoplasma serologies obtained in the posttransplantation period, unfortunately, are frequently not helpful, even in the presence of serious toxoplasmosis. T. gondii antibodies that were demonstrable before transplantation might become negative, rise, or show no change posttransplantation despite life-threatening toxoplasmosis. Transfusion may further compound the difficulties encountered in serodiagnosis during the posttransplantation period.
The incidence of toxoplasmosis among various organ transplant recipients managed at 11 tertiary care hospitals in Spain between 2000 and 2009 was 0.14% (22/15,800). The incidence was significantly greater in heart compared with kidney and liver recipients. The only independent risk factor identified in multivariate analysis was negative serostatus before transplant. Overall mortality was 14%, although two of the three deaths occurred in untreated patients who were diagnosed at autopsy.
At autopsy, histopathologic evidence of multiorgan involvement has been observed, most commonly of the brain, heart, and lungs but also including the eyes, liver, pancreas, adrenal, and kidney.
Heart Transplantation
In a review of infections in cardiac transplant recipients at Stanford Medical Center from 1980–96, results of serologic testing for Toxoplasma were available for 582 donors (35 [6%] had T. gondii –specific IgG antibodies) and 607 recipients (98 [16%] were positive). Results of serologic testing for Toxoplasma were available for 575 D/R pairs; of these, 454 (79%) were D − /R − , 84 (14.6%) D − /R + , 32 (5.6%) D + /R − , and 5 (0.8%) D + /R + . Of the 32 D + /R − patients, 16 were receiving TMP-SMX and/or pyrimethamine prophylaxis, and none developed toxoplasmosis; however, 4 (25%) of the 16 D + /R − patients who were not taking either TMP-SMX or pyrimethamine developed toxoplasmosis, and all died of the infection. None of the 98 patients who were seropositive for T. gondii preoperatively developed clinical evidence of reactivation of the infection. The importance of prophylaxis is further evidenced from an earlier study at Papworth Hospital in England. Fatal or severe toxoplasmosis developed in 57% (4/7) of D + R − mismatched heart transplant patients not receiving prophylaxis. Use of pyrimethamine, 25 mg/day for 6 weeks, reduced the transmission rate to 14% (5/37). In those patients who received pyrimethamine and were infected by the donor heart, only 1 (20%) developed symptoms of the infection in contrast to 4 of 4 (100%) who did not receive pyrimethamine prophylaxis. Subsequently, prophylaxis with TMP-SMX (80/400 mg twice daily orally for 1 year posttransplantation and when on oral prednisolone) was used in heart and lung transplant patients. Of those who were alive at 3 months posttransplantation, 28 (8.75%) were T. gondii mismatches; none had evidence of having acquired Toxoplasma infection. These investigators observed that use of prophylaxis might prolong the period before observation of seroconversion of donor-acquired infection in heart transplant patients for as long as 14 months posttransplantation. Anti- Toxoplasma prophylaxis may not always work, and toxoplasmosis should still be entertained in D + /R − patients who present with unexplained syndromes even when there is a history of taking their prophylactic drugs.
Toxoplasmosis in heart transplant recipients may simulate organ rejection. In such cases toxoplasmosis has frequently been diagnosed by endomyocardial biopsy.
It is important to recognize that many heart transplant recipients with T. gondii antibodies before transplantation may show increases in T. gondii –specific antibodies (IgG and IgM). These patients have not necessarily developed a clinical illness that can be attributed to toxoplasmosis.
Kidney Transplantation
In a review of 31 cases of toxoplasmosis in renal transplant patients the majority occurred within the first 3 months after transplantation; 3 cases occurred more than 1 year after transplantation, and 9 occurred during or immediately after a rejection episode. The greatest risk was in D + /R − mismatches. Fever, CNS symptoms and signs, and pneumonia were the main clinical features. Chest radiographs showed bilateral pneumonia in most cases. The most common organs involved in the 15 cases diagnosed at autopsy were brain, heart, and lungs. T. gondii was not demonstrable in the kidneys. Whereas the overall mortality rate was 64%, 10 of 11 treated patients survived, emphasizing the importance of early diagnosis and treatment. Fatal cases of disseminated toxoplasmosis in kidney transplant recipients have been, unfortunately, unexpectedly diagnosed postmortem. Acute toxoplasmosis in two recipients of renal allografts from the same donor has occurred. Chorioretinitis has been reported as the presenting manifestation of toxoplasmosis in a kidney transplant patient.
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