[Cerebral toxoplasmosis concomitant with primary toxoplasma infection in AIDS].
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Biomedical subjects
Publications and source records attributed to F Derouin.
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We report seven cases of cerebral or disseminated toxoplasmosis that occurred following bone marrow transplantation (BMT) and review the other 24 cases described in the literature. For all the cases, toxoplasmosis occurred within 6 months of BMT, with the highest incidence in the second and third months. Twenty-four of 26 recipients tested serologically before BMT were positive for Toxoplasma gondii, a finding that supports the view that such cases result from reactivation of latent infection. At the onset of clinical symptoms, IgG antibody titers were unchanged or decreased in 23 of 25 documented cases, and IgM antibodies were detected in two cases. Antemortem diagnosis was made in 16 cases and was based on the response to specific therapy in six cases and/or the demonstration of the parasite in body fluids or tissues in 10 cases. Autopsy was performed in 19 cases and revealed that infection was not restricted to the brain but either involved lung or heart tissue or was disseminated in 14 cases.
The efficacy of clarithromycin in a murine model of acute toxoplasmosis was studied. Clarithromycin was administered alone and concurrently with minocycline, and efficacy was assessed by survival rates and sequential determination of parasite burden in blood, brains, and lungs. Limited protection resulted from administration of each drug alone, whereas a remarkable synergistic effect followed concurrent administration. Survival of mice treated with 200 mg of clarithromycin plus 20 mg of minocycline per kg of body weight daily was 95%; that of mice treated with 50 mg of clarithromycin plus 50 mg of minocycline per kg daily was 93%. The parasite burden in the blood and organ tissues of these mice was markedly reduced compared with that in mice treated with a single agent. In mice treated with 200 mg of clarithromycin plus 50 mg of minocycline per kg per day, survival was 100% during the 30-day experiment; no parasites were found in blood and tissues.
The efficacy of azithromycin administered alone or combined with pyrimethamine or sulfadiazine was examined in a murine model of acute toxoplasmosis. Outbred Swiss mice acutely infected with tachyzoites of the virulent RH strain were treated for 10 days from day +1 postinfection. The efficacy of each regimen was assessed in terms of survival rates and sequential titration of parasites in blood, brain, and lungs by using a tissue culture method. Administration of azithromycin at 300, 150, or 75 mg/kg of body weight per day resulted in prolonged survival relative to that of untreated controls; sequential examination of parasite burden showed early eradiaction of Toxoplasma gondii from the lungs, whereas dissemination to the brain was not prevented. A remarkable synergistic effect was observed when azithromycin (150 mg/kg/day) was administered in combination with pyrimethamine or sulfadiazine at noncurative dosages, i.e., 12.5 and 200 mg/kg/day, respectively. In mice treated with azithromycin plus sulfadiazine and azithromycin plus pyrimethamine, parasite burdens in blood and organs, relapses after cessation of therapy, and mortality were all markedly reduced relative to mice treated with any of the agents alone. These results show that azithromycin, which is remarkably active on pulmonary Toxoplasma infection, significantly potentiates the curative effect of sulfadiazine or pyrimethamine.
1. Toxoplasma gondii is a ubiquitous, obligate intracellular parasite of worldwide distribution. In humans, the parasite exists in two forms: the tachyzoite is the rapidly multiplying stage of the parasite which actively invades host cells and represents the principal pathogenic form at the acute phase of the disease; the bradyzoite is the form which multiplies slowly in host cells, resulting in the formation of cysts which persist in tissues. Several antigenic components have been identified, some of which are characteristic for each parasitic stage; particularly, in tachyzoites, the 30 kDa membrane protein represents up to 5% of the total protein content. 2. Toxoplasma infection in humans is usually asymptomatic because of effective immunity involving antibodies, T cells and cytokines. Activated macrophages, CD4 and CD8 lymphocytes and cytokines, such IFN gamma, play a major role in the control of acute infection and the maintenance of infection at the chronic stage. The alteration of immune functions, as observed in congenitally infected children and in HIV-infected patients, may induce the recrudescence of previously latent toxoplasmosis, in relation to disruption of the cyst form of the parasite. The resulting reactivation is responsible for life-threatening infections which are frequently manifested as toxoplasmic encephalitis. 3. In this review, the parasite and immunological factors participating in the pathogenesis of the lesions associated with acute, chronic and reactivated toxoplasmosis are presented.
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A repetitive original DNA sequence, TGR1E, was cloned and sequenced, then used to develop a polymerase chain reaction (PCR) test for detecting Toxoplasma gondii. Preliminary studies were performed using purified T. gondii DNA or a lysate of purified T. gondii cells [7], with or without a leukocyte lysate. A negative correlation was evidenced between sensitivity of the test and the amount of cellular debris contaminating the DNA to be amplified. Nevertheless, the method was tested on 100 clinical specimens subjected to lysis using the same method. Among the 88 specimens from AIDS patients, four were positive by conventional diagnostic tests and by PCR. Among the 12 specimens tested as part of evaluations for the prevention of congenital toxoplasmosis, PCR failed to detect the positive results yielded by conventional tests on two amniotic fluid specimens. No false positive result was seen with the PCR method.
Acute lethal infections were obtained in mice by intraperitoneal (IP) injection of 10(2) or 10(4) tachyzoites of the virulent RH and C56 strains. Chronic infections were obtained by IP injection or peroral (PO) gavage of 20 cysts of the avirulent C strain. Mice were sacrificed at varying intervals after infection and parasite burdens were quantitated in blood, brain, and lungs using a tissue culture method. Acutely infected mice died within 6 to 10 days postinfection as a function of the strain and inoculum size. With either strain, tachyzoites were first detected in lungs on either Days 2 or 4 postinfection, according to the inoculum size, then in brain and blood at Days 4 or 6; parasitic loads remained constantly at a higher level in lungs than in brain until the date of death. Bradyzoites could only be detected in lungs, from Days 4 or 6 until death. In chronic infections, similar results were obtained for IP and PO infected mice. Both tachyzoites and bradyzoites were first detected in lungs and brain from Day 7 after infection; tachyzoites remained at a higher level in lungs than in brain until Day 10, then subsequently decreased in lungs. At Day 50, tachyzoites were not detectable in lungs, whereas bradyzoites remained at a constant level; in brain, both parasitic stages were detectable at a similar level throughout the follow-up period. These results indicate that infection with a virulent Toxoplasma strain is characterized by an early involvement of lungs, with pneumonia as the principal cause of death.(ABSTRACT TRUNCATED AT 250 WORDS)
The efficacy of dapsone alone or combined with pyrimethamine against Toxoplasma gondii was investigated experimentally. For in vitro studies, a sensitive immunoassay was used for assessment of Toxoplasma growth in tissue cultures; dapsone was found to have a significant inhibitory effect at a concentration of 0.5 micrograms/ml in the cultures, and the 50% inhibitory concentration was estimated to be 0.55 micrograms/ml. When pyrimethamine and dapsone were combined, an important synergistic effect which was associated with morphological alterations of the parasites was observed. In vivo studies were performed in a murine model of acute toxoplasmosis in which a tissue culture method was used to estimate the parasite burden in the blood, lungs, and brains of infected mice. Dapsone alone, which was administered at 100 mg/kg/day for 10 days from day 1 after infection, was unable to prevent parasite dissemination and only delayed the time to death of treated mice compared with the time of death of untreated controls. When dapsone and pyrimethamine (18.5 mg/kg/day) were administered in combination from day 4 after infection, parasites were cleared from blood and organs within 6 days, but relapses were observed 15 days after the cessation of therapy. When treatment was started at day 1 after infection, 100% of mice survived and relapses were not observed, suggesting a good efficacy of this combination for preventive therapy.
Antibody titers to Toxoplasma gondii were studied in 62 AIDS patients with active toxoplasmosis (cerebral in 42, pulmonary in 10 and ocular in 10), confirmed by biopsy or by imaging techniques with a therapeutic test, and in 1,499 HIV-positive patients. The purpose of this study was to evaluate the value of antibody assays for the diagnosis of active infection and the prevalence of toxoplasmosis in HIV-positive individuals. IgG antibodies to Toxoplasma were found in 61 of the 62 AIDS patients, but not in one patient with pulmonary toxoplasmosis, with no significant differences in mean titers obtained by dye test, indirect immunofluorescence and sensitized agglutination. Twenty patients (31.7%) had dye test titers of 400 IU/ml or more; three patients had IgM antibodies. Thirteen (38%) of the 34 patients who had serial antibody assays exhibited a rise in IgG titers with no detectable production of IgM antibodies. Antibodies to Toxoplasma were found in 75% of the 1,499 HIV-positive subjects, a proportion which is not significantly different from that seen in HIV-negative controls; however, HIV-positive subjects were significantly more likely than controls to have high titers (greater than or equal to 500 IU in 18.7% of patients versus 9.2% of controls, p less than 0.001). A follow-up study in 177 HIV-positive patients with antibodies to Toxoplasma showed an annual reactivation rate of 12%; in five of 30 patients, the rise in antibody titers occurred concomitantly with or a few months before clinical toxoplasmosis; 25 patients remained asymptomatic.(ABSTRACT TRUNCATED AT 250 WORDS)
Parasitic and fungal organisms which are likely to cause pulmonary infections in immunosuppressed patients can be detected in broncho-alveolar fluid (BAL fluid). Single and standard methods, such as direct examination of the pellet, eosine-methylene blue fast (RAL 555), cultures in usual mediums of mycology must be systematically applied to this sample and may help detect these organisms without further exploration. If the results are negative, more recent techniques can be used if they present a real asset: an easier reading and mostly an improved sensitivity. Such is the case of immuno-fluorescence assay with monoclonal antibodies for detection of Pneumocystis carinii, and inoculation of MRC5 fibroblast cell line in tissue culture for isolation of Toxoplasma. Fungal pulmonary infections diagnosis has not yet succeeded in benefiting from modern findings: latex tests proposed for the detection of circulating antigens are nor sensitive nor specific, except the "Crypto LA test". Considering the relatively frequent association with other infectious agents, the detection of a parasitic or fungal organism in the BAL fluid should not interrupt investigation of this sample; neither should it lead to hasty conclusions regarding the responsibility of this agent in acute pneumopathy. This role will have to be evaluated according to criteria which are different for each isolated organism.
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The in vivo effects of antimicrobial agents against Toxoplasma gondii were evaluated in mice that were infected intraperitoneally with 10(4) tachyzoites of the RH strain by determination of survival rates and study of the kinetics of growth of T. gondii in infected mice. At various intervals after infection, subcultures of serial dilutions of blood, lung, and brain homogenates were performed in fibroblast tissue cultures for determination of parasitic loads. Pyrimethamine (18.5 mg/kg per day), sulfadiazine (375 mg/kg per day), and clindamycin (300 mg/kg per day) were administered for 10 days from day 1 or day 4 after infection. Untreated control mice died within 9 days and showed early and predominant lung involvement. All mice treated with sulfadiazine administered from day 1 survived and were apparently healthy; parasitic loads decreased early after treatment, but a relapse was observed 5 days after the cessation of therapy. When pyrimethamine was administered from day 1, 7 of 11 mice died within 25 days; by determination of parasitic loads, the effect of pyrimethamine was only demonstrable from day 6, and a relapse was constantly observed after the cessation of therapy. When pyrimethamine and sulfadiazine were administered in combination, 100% of mice survived; when therapy was started at day 1, parasites remained undetectable; in mice treated from day 4, parasites were eradicated by day 8 but infection relapsed 8 days after the cessation of therapy. All mice treated with clindamycin from day 1 or day 4 died within 10 days, but parasitemia was always undetectable. These results indicate that study of the kinetics of parasitic loads in blood and organs may provide additional information on the effect of antimicrobial agents against T. gondii in regard to the evolution of the infection and may represent a reliable basis for the determination of therapeutic regimens in humans.
Since 1983, we have seen 11 cases of toxoplasmic retinochoroiditis in patients with AIDS. Ocular toxoplasmosis appears to be a growing concern in AIDS: 3.3% in 1983, 6.1% in 1988 and 5.9% during the first trimester of 1989. Anti-Toxoplasma gondii antibody titers in the aqueous humour were not conclusive, therefore the diagnosis was based on ophthalmoscopic criteria and on a rapid response to specific therapy. As for brain toxoplasmosis, treatment must be continued indefinitely to prevent relapse. Seven out of 11 patients had cerebral toxoplasmosis, which was diagnosed by computerized tomography (CT) scan. This suggests that a neurological evaluation and a brain CT scan should be performed in all AIDS patients with toxoplasmic retinochoroiditis.
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PURPOSE: To perform a retrospective and descriptive study of Toxoplasma gondii pneumonia in patients infected with the human immunodeficiency virus (HIV). Clinical presentation, diagnostic procedures, results of therapy, and hypotheses on pathophysiology are discussed. PATIENTS AND METHODS: The study consisted of 13 HIV-infected patients who had developed T. gondii pneumonia. Eight had acquired immunodeficiency syndrome (AIDS) prior to T. gondii pneumonia and three of them had non-Hodgkin's lymphoma. Mean CD4 cell count was 32 x 10(6)/L. Serum anti-toxoplasma antibody titers were measured by an indirect hemagglutination assay and/or by an indirect immunofluorescence assay. RESULTS: All patients had fever and bilateral pulmonary infiltrates; two of them presented with septic shock. Mean arterial oxygen tension was 47 +/- 12 mm Hg. The diagnosis was established by bronchoalveolar lavage in 10 of 11 cases, open lung biopsy in one case, and postmortem biopsy in two cases. Serologic evidence of past infection was observed in 11 of 12 cases, while one patient presented with acute disseminated disease and absence of serum anti-toxoplasma antibody response. Extrapulmonary involvement was present in seven patients: liver (four), brain (three), bone marrow (two), heart (two), stomach (one). Ten patients recovered from T. gondii pneumonia. CONCLUSION: T. gondii pneumonia must be considered in AIDS patients with severe diffuse bilateral pneumonia, especially when associated with a very low CD4 cell count or non-Hodgkin's lymphoma. In most of these cases, disseminated disease was associated with reactivation of prior latent infection.
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