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Anti-toxoplasma antibodies administered passively to mice may lead to suppression of enhancement (reported for the first time with Protozoan parasites) of subsequent antibody response when these animals are later infected with Toxoplasma gondii. The outcome is dependent on infecting strain of Toxoplasma and the antigen-antibody ratio.
PURPOSE: This study was designed to measure response rates and survival in patients with acquired immunodeficiency syndrome (AIDS) and suspected Toxoplasma encephalitis treated empirically and in AIDS patients treated for biopsy-proven toxoplasmosis. PATIENTS AND METHODS: AIDS patients identified at Bellevue Hospital between August 1985 and May 1986, who had abnormal computed tomographic scans of the brain and who received empiric treatment for toxoplasmosis, constitute the empirically treated cohort. A cohort with biopsy-proven toxoplasmosis was identified from Bellevue Hospital neuropathology records spanning 1981 through 1986. Patient records were reviewed with a standardized data form, and tomograms were evaluated by neuroradiologists unaware of the identity of the scans. Survival analysis was performed by the product limit method. RESULTS: Of 38 empirically treated patients, 26 responded clinically and radiographically within four weeks of initiation of therapy. Four of nine patients who underwent biopsy responded to treatment. There was no difference in these response rates (68% versus 44%, p = 0.24). The median survival of the empirically treated responders, from first diagnosis of AIDS to last follow-up, was 422 days. Among the 30 responders, five patients discontinued therapy and four of them had relapses. No relapses occurred in the 25 patients who continued full-dose therapy indefinitely (p = 0.0004). Sixteen of 30 patients (53%) receiving continuous therapy developed toxicity, which required a change in medication. There was no difference in the survival of patients who continued to receive sulfadiazine and pyrimethamine compared with those in whom clindamycin was substituted for sulfadiazine (median, 311 days versus 422 days, p = 0.25). CONCLUSION: A policy of empiric treatment of suspected Toxoplasma encephalitis is satisfactory, and patients who respond to such therapy and continue to take full therapeutic doses of anti-Toxoplasma drugs have relatively long survivals.
The effects of swimming exercise on the pathogenesis of acute murine toxoplasma infection were studied. Swimming (45 min/day) initiated on the day of inoculation with the avirulent Me49 strain of Toxoplasma gondii did not alter survival of infected mice. At a later stage of infection, daily swimming appeared to promote the recovery of appetite and weight gain. Immune activation was apparent in toxoplasma-infected mice, and swimming blunted splenic enlargement but not the respiratory burst activity of peritoneal exudate cells. Infection caused a significant elevation of serum tumor necrosis factor (TNF) levels which was attenuated by a daily swimming program. These data show that swimming exercise is not deleterious to mice acutely infected with T. gondii Me49 and that the more rapid recovery in exercised mice is associated with reduced serum TNF levels.
A murine model of congenital Toxoplasma encephalitis (CTE) was established in NMRI mice following prenatal infection with a low dose of Toxoplasma gondii (DX strain). Histopathologically, the disease exhibited the key features of human CTE including foci of necrosis, intracerebral calcifications, and ventriculitis. The inflammatory response in the brain of infected animals was predominantly mediated by macrophages and granulocytes with additional participation of astrocytes. These findings indicate that the prenatal Toxoplasma infection closely parallels human CTE, but differs significantly from adult toxoplasmosis.
We report the screening and monitoring results of toxoplasma activity in 602 cases of hematopoietic stem cell transplantation (HSCT) in Chinese. A total of 13 recipients and 12 donors (including one donor-recipient pair) were serologically positive for toxoplasma, giving an incidence of 2.1% and 2.3%, respectively. All patients except those with glucose-6-phosphate dehydrogenase (G6PD) deficiency received sulfamethoxazole-trimethoprim (septrin) prophylaxis post-HSCT. None of the 292 deaths, including eight seropositive (either donor or recipient) cases, were attributable to toxoplasma. Only two of 16 seropositive survivors remained seropositive, while none of 60 seronegative cases (including six with G6PD deficiency) seroconverted. We concluded that in low incidence areas, toxoplasmosis is not a significant complication of HSCT with septrin prophylaxis. Most patients are also expected to remain seronegative after HSCT.
OBJECTIVE: Our goal was to determine the frequency of mother-to-child transmission of Toxoplasma gondii from human immunodeficiency virus-infected mothers who are also chronically infected with T. gondii. STUDY DESIGN: One hundred thirty-eight women were entered into a prospective study of human immunodeficiency virus infection in pregnancy. The women were seen at enrollment, during the third, sixth, and eighth months of pregnancy (except those enrolled later in pregnancy or at delivery), at 2 and 6 months post partum, and at 6-month intervals thereafter through 4 years after delivery. Standardized interviews and physical examinations were performed, and blood was drawn at each visit. Toxoplasma serologic testing was performed on the sample drawn earliest in pregnancy; the Sabin-Feldman dye test for immunoglobulin G antibodies and enzyme-linked immunoassays for immunoglobulins M, A, and E were used. Univariate analysis for categoric variables was performed with chi2 and two-tailed Fisher exact tests, and for continuous variables the Student t test was used. Statistical Analysis System procedures were followed. RESULTS: Twenty-eight of 138 (20.2%) women who had positive test results for human immunodeficiency virus had positive findings of the Sabin-Feldman dye test. Serologic status for T. gondii did not correlate with age, immune status, parity, or drug use. One of 27 children born to women who were seropositive for both human immunodeficiency virus and T. gondii (one child's serologic status for T. gondii was unknown) had Sabin-Feldman dye test antibodies beyond age 6 months (3.7%, 95% confidence interval 0.09% to 18.9%). Among the cohort of human immunodeficiency virus-infected mothers the rate of mother-to-child human immunodeficiency virus transmission did not vary with maternal Toxoplasma status. However, with sample sizes of 28 and 110, respectively, for the mothers who were T. gondii seropositive and seronegative, the power to detect a difference in the human immunodeficiency virus transmission rate between these groups would be relatively small. CONCLUSIONS: Transmission of T. gondii from a chronically infected mother can occur in the setting of a human immunodeficiency virus infection, but this is not a common phenomenon. In a small cohort of human immunodeficiency virus-infected women we did not observe its occurrence among those without severe immunocompromise.
The regulatory role of interferon-gamma receptor (IFN-gammaR)- and tumor necrosis factor receptor (TNFR)-mediated immune reactions for the activation of cerebral endothelial cells, microglia, and astrocytes was evaluated in a model of murine Toxoplasma encephalitis (TE). Brain endothelial cells of wild-type mice reacted in response to Toxoplasma infection with a strong up-regulation of the vascular cell adhesion molecule, the intercellular adhesion molecule (ICAM)-1, and major histocompatibility complex (MHC) class I and II antigens. A similar response was seen in mice genetically deficient for either TNFR1, TNFR2, or both TNFRs, whereas IFN-gammaR-deficient (IFN-gammaR0/0) mice were found to be defective in the up-regulation of these molecules. However, recruitment of leukocytes to the brain and their intracerebral movement were not impaired in IFN-gammaR0/0 mice. In addition, microglia of Toxoplasma gondii-infected IFN-gammaR0/0 mice failed to induce expression of ICAM-1, leukocyte function-associated antigen (LFA)-1, and MHC class I and II antigens, whereas wild-type and TNFR-deficient mice up-regulated these molecules. Moreover, TNF-alpha mRNA production of F4/80(+) microglia/macrophages was impaired in IFN-gammaR0/0 mice, but not in TNFR-deficient mutants. However, induction of interleukin (IL)-1beta, IL-10, IL-12p40, and IL-15 mRNA was independent of IFN-gammaR and TNFR signaling. In conclusion, IFN-gammaR, but not TNFR signaling, is the major pathway for the activation of endothelial cells and microglia in murine TE. These findings differ from observations in other inflammatory central nervous system disorders, indicating specific regulatory mechanisms in this parasitic cerebral infection.
In patients with acquired immuno-deficiency syndrome, the differential diagnosis between primary brain lymphoma and toxoplasma encephalitis is not radiologically always straightforward, especially in the presence of a solitary cerebral lesion. In this context, involvement of the corpus callosum is almost exclusively associated with primary brain lymphoma. We describe here an HIV-infected patient who presented with a single and large cerebral lesion affecting the corpus callosum, suggestive of primary brain lymphoma on MRI-scan but who nonetheless responded clinically and radiologically to an anti-toxoplasma drug trial confirming the diagnosis of toxoplasma encephalitis.
Small vessels showing inflammatory cell infiltrates were invariably observed in the vicinity of intact Toxoplasma tissue cysts within the brains of mice congenitally infected with the protozoan. Lymphocytes were observed in intimate contact with the luminal aspect of the endothelium, penetrating into the thickened basal lamina and in the perivascular area, which also contained macrophages and neutrophilic granulocytes. Rarely, lymphocytes were observed attached to the outer membrane of the host neurone which contained a Toxoplasma tissue cyst and within the inflammatory infiltrate associated with a disintegrating cyst. An hypothesis is presented which combines these morphological observations to explain the events associated with tissue cyst associated recrudescence of latent Toxoplasma infection in mouse brain.
Effective primary prevention of congenital toxoplasmosis requires up to date information on locally relevant risk factors for infection in pregnant women. In Naples, risk factors for toxoplasma infection were compared in recently infected women (as assessed by detection of specific IgM in serum) and susceptible, IgG negative women. Recent infection was strongly associated with frequency of consumption of cured pork and raw meat. Eating cured pork or raw meat at least once a month increased the risk of toxoplasma infection threefold. This simple study design for determining locally relevant sources of toxoplasma infection is the first report of cured pork as a risk factor for infection. Further research is required to determine cyst viability in cured pork products. Our findings suggest that in southern Italy, cured pork and raw meat should be avoided by susceptible pregnant women.
A sample of European starlings, Sturnus vulgaris, culled from a communal roost in a city in Central England, was examined for infection with Toxoplasma. Eleven (8%) of 133 birds were confirmed as infected after horizontal passage of brain homogenate through mice. Serological examination, using the indirect and direct agglutination tests, proved unsatisfactory for screening starlings for Toxoplasma infection. If the proportion of starlings infected with Toxoplasma in this sample is representative of the population as a whole, then this bird could play an important role in the maintenance of the infection in urban environments.
We report a case of cystitis due to Toxoplasma gondii in a patient with AIDS who presented with dysuria and urinary frequency. To our knowledge, this is the first reported case of cystitis due to this organism. Microscopy of bladder specimens revealed inflammatory cystitis, with Toxoplasma cysts disseminated within the mucosa. No other pathogen could be detected by urine culture, cytoscopy, or staining of bladder specimens obtained at autopsy. Diagnosis of cystitis due to Toxoplasma gondii may be difficult because this illness is associated with misleading radiologic and endoscopic findings. Toxoplasmosis is a rare but potentially curable cause of culture-negative cystitis in patients with AIDS.
Toxoplasmosis is an important disease in immunocompromised hosts, particularly in patients with AIDS and in heart transplant recipients. Infection with Toxoplasma is less commonly seen in recipients of other solid organ transplants. We report a case of fulminant disseminated infection with Toxoplasma after liver transplantation. Despite numerous diagnostic studies including open lung biopsy, toxoplasmosis was diagnosed only at the time of autopsy and involved the brain, spinal cord, pituitary gland, lungs, and heart. Toxoplasmosis should be considered in the differential diagnosis of multiorgan failure in the early period after liver transplantation. If mismatched serologies could be identified then clinical suspicion might be higher and prophylactic or empirical therapy could be instituted. The United Network for Organ Sharing (Richmond, VA) should consider including serology for Toxoplasma in the testing of donors.
Active cytomegalovirus (CMV) infection is associated with immunosuppression and predisposes to the development of life-threatening superinfections in immunocompromised patients. In a mouse model of virus-induced immunosuppression, acute murine CMV (MCMV) infection induced reactivation of dormant Toxoplasma gondii infection, producing Toxoplasma pneumonia. Changes in lung lymphocyte numbers and phenotypes appeared to be integral to the pathogenesis of MCMV-induced reactivation of T. gondii pneumonia. Numbers of lung CD4+ cells decreased during acute MCMV infection in mice with dormant T. gondii infection as well as in previously uninfected mice. Dually infected mice subsequently developed reactivation of Toxoplasma pneumonia. The pneumonia was characterized by a large influx of T lymphocytes, predominantly CD8+ cells, into the lungs. These lung lymphocytes markedly suppressed the ability of immune splenocytes to proliferate in response to T. gondii antigens and concanavalin A in vitro. These results suggested that the initial fall in the numbers of lung CD4+ cells observed after MCMV infection may have induced reactivation of T. gondii infection in the lungs. The subsequent pneumonia appeared to be a manifestation of a massive influx of T lymphocytes, especially CD8+ cells, into the lungs.
OBJECTIVE: To study Toxoplasma encephalitis (TE) in advanced HIV infection, including predictive factors, possible prophylactic regimens and impact on survival. DESIGN: Epidemiological analysis of data collected prospectively during the Alpha study, a double-blind, randomized clinical trial, comparing two doses of dideoxyinosine in patients with advanced HIV disease. PATIENTS: First episode of TE occurred in 75 out of 499 patients participating in the trial. METHODS: Kaplan-Meier estimates and semi-parametric Cox's model were used. RESULTS: A low CD4 cell count and a positive Toxoplasma serology were strongly predictive of the occurrence of TE. In patients with CD4 counts < 100 x 10(6)/l and a positive Toxoplasma serology at entry to the study, the 12-month TE incidence was 25.4%. Patients who were receiving at entry any of the following potentially antitoxoplasmic drugs: trimethoprim-sulphamethoxazole, pyrimethamine, dapsone, pyrimethamine-sulphadoxine or sulphadiazine, had a lower TE incidence than those who were not; 6.2 versus 18.8%, respectively (P < 0.001). The rate of survival 12 months after TE was 29.6%. Even after adjusting the major prognostic covariates, TE was predictive of death (P < 0.001; relative risk, 1.8). CONCLUSIONS: The high HIV incidence, morbidity and mortality in high-prevalence areas suggests that primary prophylaxis should be given in patients at high risk for toxoplasmic reactivation.
PURPOSE: Our goal was to determine if there are any T2-weighted MR signal characteristics of Toxoplasma encephalitis that might be useful in diagnosis and/or in gauging the effectiveness of medical therapy. METHOD: We retrospectively analyzed the MR, CT, thallium-201 SPECT brain scans, and medical records of 27 patients with medically proven (26) and biopsy proven (1) Toxoplasma encephalitis, supplemented by autopsy findings in 4 additional patients, 2 of whom had postmortem MR correlation. The neuropathologic literature was also reviewed. RESULTS: Among the 27 patients, we discovered three distinct imaging patterns. Ten (37%) patients had predominantly T2-weighted hyperintense lesions and had been on medical therapy an average of 3 days (excluding one outlier). Ten (37%) patients had T2-weighted isointense lesions and had received medical therapy an average of 61 days. Seven (26%) patients had lesions with mixed signal on T2-weighted images and had been on treatment an average of 6 days. Analysis of autopsy material from the four additional patients revealed the presence of organizing abscesses in three and necrotizing encephalitis in one, while the patient who had a brain biopsy demonstrated both types of pathologic lesions. In both cases having postmortem MRI, organizing abscesses appeared isointense to hypointense on T2-weighted images. CONCLUSION: There is a definite variation in the appearance of lesions of Toxoplasma encephalitis on T2-weighted images that precludes a definitive diagnosis based on signal characteristics alone. Pathologically, our data suggest that T2-weighted hyperintensity correlates with necrotizing encephalitis and T2-weighted isointensity with organizing abscesses. Furthermore, in patients on medical therapy the T2-weighted MR appearance may be a transition from hyperintensity to isointensity as a function of a positive response to antibiotic treatment, indicating that the signal change might be used to gauge the effectiveness of medical therapy.
In order to study the effect of Toxoplasma infection on hormonal levels in pregnant ewes, twenty-eight Scottish Blackface ewes were dosed orally with Toxoplasma gondii oocytes at 91 +/- 1 days of gestation. Fifteen of these ewes were vaccinated with an experimental Toxoplasma iscom vaccine prior to inoculation. Further three ewes were used as non-infected controls. All challenged ewes became infected. Plasma was analysed for the content of 15-ketodihydro-PGF2 alpha, progesterone and oestrone sulphate. The endocrinological changes appeared to reflect the pathological changes in the uterus. Infected animals tended to show an increase in the levels of the prostaglandin metabolite between two and eleven days after challenge, followed by a decrease in progesterone and later also of oestrone sulphate levels. Following the initial phase, the pattern was more variable but related to the outcome of gestation. There was a marked tendency towards more normal endocrinological patterns in the vaccinated animals in comparison to unvaccinated challenged ones.
The sera of 3,463 pregnant women were screened, at the first antenatal visit, for antibodies to rubella, cytomegalovirus (CMV) and Toxoplasma gondii. Rubella antibodies were detected in 97.5%, CMV antibodies in 71% and toxoplasma antibodies in 45% of women. Asymptomatic toxoplasmosis occurred during pregnancy in 3 of 609 (0.5%) and primary CMV infection in 5 of 338 (1.5%) initially seronegative women whose sera were retested at the end of their pregnancies. The observed incidence of toxoplasmosis was similar to that calculated on the basis of the age-related prevalence of antibodies found in this study. On the basis of these observations it is estimated that congenital toxoplasmosis and congenital CMV infection due to primary maternal infection each occurs in up to 2/1,000 infants in this community. Very few of these infants have obvious abnormalities at birth, but follow-up studies elsewhere have shown that many of them suffer significant long-term sequelae. Routine antenatal screening for rubella antibodies is well established and justifiable for this preventable congenital infection. However, routine antenatal screening for CMV antibodies cannot be justified at present, since neither immunization nor treatment is available. Further information is required to determine the cost-effectiveness of routine antenatal screening for toxoplasma antibodies and treatment of proven maternal infection during pregnancy.