Clinical Spectrum, Radiological Findings, and Outcomes of Severe Toxoplasmosis in Immunocompetent Hosts: A Systematic Review

Background: Accumulating evidence suggests that toxoplasmosis in immunocompetent hosts can be severe and life-threatening. Methods: We performed a systematic review of severe toxoplasmosis cases in immunocompetent patients to gain insight into the epidemiology, clinical characteristics, radiological findings, and outcomes of these cases. We classified severe toxoplasmosis as cases with the symptomatic involvement of target organs (the lungs, central nervous system (CNS), and heart), disseminated disease, prolonged disease (>3 months), or a fatal outcome. Our primary analysis focused on cases published from 1985–2022 to avoid confounding with cases in AIDS patients. Results: We identified 82 pertinent articles (1985–2022) with a total of 117 eligible cases; the top five countries for these cases were French Guiana (20%), France (15%), Colombia (9%), India (9%), and Brazil (7%). Overall, 44% (51/117) of cases had pulmonary involvement, 39% (46/117) CNS, 31% (36/117) cardiac, 24% (28/117) disseminated disease, 2% (2/117) had prolonged disease, and 8% (9/117) of patients died. More than one organ was involved in 26% (31/117) of cases. Eighty-four percent (98/117) of cases occurred in the context of a recent acute primary Toxoplasma infection; for the remaining, the exact timing of infection was unclear. Genotyping data were very sparse. Among those reporting genotyping data, 96% (22/23) were caused by atypical non-type II strains; one case was caused by a type-II strain. Only half of the cases reported risk factors. The most common risk factors were eating raw/undercooked meat or eating game meat (47% (28/60)), drinking untreated water (37% (22/60)), or living in a toxoplasmosis high-prevalence area (38% (23/60)). For the 51 pulmonary cases, the main clinical presentation was pneumonia or pleural effusions in 94% (48/51) and respiratory failure in 47% (24/51). For the 46 CNS cases, the main clinical presentation was encephalitis in 54% (25/46), meningitis in 13% (6/46), focal neurologic findings in 24% (11/46), cranial nerve palsies in 17% (8/46), Guillain–Barre syndrome or Miller Fisher syndrome in 7% (3/46), and Brown–Sequard syndrome in 2% (1/46) of cases; more than one clinical manifestation could also be present. Among the 41 CNS cases reporting the CNS imaging findings, 68% (28/41) had focal supratentorial lesions and 7% (3/41) had focal infratentorial lesions. Brain abscess-like/mass-like lesions were seen in 51% (21/41) of cases. For the 36 cardiac cases, the main clinical presentation was myocarditis in 75% (27/36), pericarditis in 50% (18/36), heart failure and/or cardiogenic shock in 19% (7/36), and cardiac arrhythmias in 22% (8/36); more than one manifestation could also be present. Illness was critical in 49% (44/90) of cases intensive care unit care was needed in 54% (29/54) of cases among those reporting this information, and 9 patients died. Conclusion: The diagnosis of severe toxoplasmosis in immunocompetent hosts can be challenging. Toxoplasmosis should be considered in the differential diagnosis of immunocompetent patients presenting with severe illness of unclear etiology with pulmonary, cardiac, CNS, or multiorgan involvement/failure, or prolonged febrile illness, even in the absence of common exposure risk factors or common manifestations of toxoplasmosis (e.g., fever, mononucleosis-like illness, lymphadenopathy, and chorioretinitis). Fatal outcomes can also rarely occur in immunocompetent patients. Prompt initiation of anti-Toxoplasma treatment can be lifesaving.


Background
Toxoplasmosis is a protozoal disease with worldwide distribution caused by the parasite Toxoplasma gondii (T. gondii) [1][2][3]. T. gondii infections cause significant morbidity and mortality worldwide with a wide spectrum of clinical manifestations both in immunocompromised and immunocompetent hosts. Severe fulminant and even life-threatening toxoplasmosis has been widely reported in congenitally infected offspring, immunocompromised patients with profound immune deficiencies, AIDS patients, transplant patients [4][5][6], and patients receiving chemotherapy, immunosuppressive medications, or novel biologic immunomodulatory agents [7,8]. In immunocompromised patients, severe toxoplasmosis is usually the result of the reactivation of latent infection in the host or the donor transplant organ. Acute primary infections acquired via the oral route can also occur in immunocompromised patients. In immunocompetent hosts, acute primary toxoplasmosis has been primarily viewed either as asymptomatic or minimally symptomatic with fever and mononucleosis-like symptoms, with/or without lymphadenopathy. However, acute primary infections in pregnant women can have devastating sequelae and can lead to congenital toxoplasmosis with severe neurologic or ocular manifestations and even death [9].
An accumulating body of evidence suggests that toxoplasmosis in immunocompetent hosts can cause severe and life-threatening infections. Acute Toxoplasma infections in immunocompetent hosts in certain tropical areas, with the atypical more virulent T. gondii strains and/or with a high parasite load, have been reported to cause severe disease, including disseminated disease and death [10][11][12]. Most cases of disseminated toxoplasmosis in immunocompetent hosts were originally reported from French Guyana and included pneumonia, myocarditis, encephalitis, hepatitis and myositis, and some of those also had fatal outcomes [10][11][12]. Unusual clinical presentations in immunocompetent hosts have also been reported after eating raw meat or wild game meat in diverse country settings [13,14]. High attack rates and severe clinical manifestations have also been reported in the setting of community outbreaks from the ingestion of T. gondii-contaminated municipal water [15].
We performed a systematic review of severe toxoplasmosis cases reported in the literature in immunocompetent hosts to gain insight into the epidemiology, clinical characteristics, radiological manifestations, and outcomes of these cases. Prior reviews had included a limited number of cases, were published more than 1-3 decades ago, and had focused only on specific organ systems or on cases from the Amazonian region only. [16][17][18][19]. We focused on severe toxoplasmosis cases in immunocompetent hosts with the symptomatic involvement of target organs (the lungs, central nervous system (CNS), and heart), disseminated disease, prolonged illness >3 months, or fatal outcomes.
We wanted to increase the awareness among clinicians that in immunocompetent patients, toxoplasmosis should be considered in the differential diagnosis when patients present with severe pneumonia, acute respiratory failure, myocarditis, pericarditis, heart failure, arrhythmias, encephalitis, focal neurologic findings, rapidly progressing fulminant disease with multiorgan failure, and/or prolonged febrile illnesses of unknown origin, even in the absence of common exposure risk factors or common manifestations of toxoplasmosis (e.g., fever, mononucleosis-like illness, lymphadenopathy, and chorioretinitis). It is important to recognize that fatal outcomes can occur in immunocompetent hosts. Early diagnosis and prompt initiation of anti-Toxoplasma treatment can be life-saving.

Methods
We performed a systematic review of articles published in PubMed using three different search strategies (Appendix A). The reference list of eligible papers and pivotal prior review papers were also screened. The last search was performed on 22 August 2022. Details about our screening process are shown in the PRISMA flow chart (Figure 1). Article screening for eligibility at the title/abstract level was performed by one investigator (DCI); potentially eligible papers were retrieved in full text and further screened for eligibility for inclusion by 3 independent investigators (DCI, JL, and DT). Data extraction was performed by JL/DCI and DT/DCI. Discrepancies were solved by consensus (DCI/JGM/JL/DT). We followed the PRISMA guidelines for reporting of systematic reviews (Appendix A-PRISMA checklist). Individual study-level data are available from the authors upon request.

Inclusion Criteria
Eligible for inclusion were cases that fulfilled all the following criteria: (a) Severe disease, defined as cases with symptomatic involvement of the three target organs, namely the lungs, CNS, or heart; disseminated disease; prolonged illness of >3 months duration, or fatal outcome; (b) proper ascertainment of the diagnosis of toxoplasmosis, with toxoplasmosis being the most likely etiology of the reported severe clinical manifestations; and (c) an immunocompetent host. The diagnosis of toxoplasmosis was considered properly ascertained if supported by serologic, molecular, histopathologic or direct examination of body fluids methods, and/or mice sub-inoculation results. The clinical response to anti-Toxoplasma therapy was also used to support the diagnosis. Cases were considered pertaining to immunocompetent hosts if the patient was HIV negative, without underlying immunodeficiency (e.g., malignancy, chronic immunosuppressive medications, etc.) For the few cases not reporting HIV test results, information from long-term follow-up was also used to ascertain the immunocompetent status of the host (e.g., no findings or signs/symptoms of underlying immunodeficiency during long-term follow-up).
Articles of all study designs were considered eligible. When more than one publication from the same investigators was identified-with overlapping patient cases-we kept only the latest article with the largest number of cases reported. For articles published in languages other than English, French, or Spanish, we used Google translation to extract pertinent information.
In our primary analysis, we focused only on cases published between 1985 and 2022 to minimize confounding from cases in AIDS (acquired immunodeficiency syndrome) patients. Early AIDS cases were sporadically reported several years before 1980; the Center for Disease Control released the first definition for AIDS in 1982, the human immunodeficiency virus (HIV) genome was first isolated and described in 1983 [20,21], and the Food and Drug Administration (FDA) approved the first commercial HIV-ELISA test in 1985 [22].
In a secondary analysis, we separately reported the summary findings from the articles published before 1985 to be comprehensive. From these papers, we extracted only limited information (e.g., the title, year, country, and main clinical manifestations of severe toxoplasmosis), acknowledging that some early AIDS cases unavoidably could have been included in those cases.

Diagnostic Methods
Serology was used for the diagnosis of toxoplasmosis in 95% (111/117) of cases, molecular methods in 19% (22/117), and histopathology (from tissue biopsies or autopsy) in 21% (24/117) of cases. The response to anti-Toxoplasma therapy also supported the diagnosis of toxoplasmosis in 80% (88/110) of cases, while for the remaining, this was unclear (not reported). More than one diagnostic method was used for 84% (98/117) of cases (Table 1).

Type of Infection
For 84% (98/117) of cases, severe toxoplasmosis occurred in the context of a recent acute primary Toxoplasma infection; for the remaining, the exact timing of infection was unclear (Table 1).
Genotyping data were sparse. Among those reporting genotyping data, 96% (22/23) were caused by atypical non-type II strains and one case was caused by a type-II strain ( Table 1 and Appendix C-Table A3). This type II strain-associated infection was a case of spinal toxoplasmosis in a 31-year-old patient from France who presented with Brown-Sequard syndrome [33].

Risk Factors
Only half (60/117) of the cases reported risk factors for toxoplasmosis. The most common risk factors were eating raw or undercooked meat or game meat (47% (28/60)), drinking untreated water (37% (22/60)), or living in a high-prevalence toxoplasmosis region (38% (23/60)). In 32% (19/60) of cases, multiple risk factors were reported ( Table 1). Examples of cases associated with the consumption of infected game meat included cases after eating venison [28], wild boar meat [33], maipouri meat from French Guiana [34], or after travel across the Greenland glacier during which undercooked meat was consumed [3]. Examples of cases associated with the drinking of untreated water included cases in hunters/forest policemen (a case from China [35], a case from the US after recent camping in Tennessee [29], and six cases from Colombia [36]), and an outbreak of cases from drinking contaminated community water (e.g., six cases in a community outbreak along the Maroni river [10]). Examples of cases in high-prevalence regions included 23 severe cases reported from French Guiana [10][11][12]34,[37][38][39][40]. Several severe cases were also reported in military personnel, including (a) a case of acute myocarditis in a 20-year-old military fireman in France [41]; (b) a case of pneumonia in a 37-year-old in a military operation in the Peruvian Amazon [42]; (c) a military outbreak with six cases in military personnel deployed in rural areas in Colombia [36]; (d) a case of pneumonia with respiratory failure and disseminated disease in a 35-year old in a military operation in the forests of French Guyana (likely from drinking chemically disinfected river water) [38]; (e) a case of diffuse encephalitis with fatal outcome in a 35-year-old in a military operation in the Amazonian forest (in the context of an outbreak in additional military personnel) [39]; and (f) a case of pneumonia in a 32-year-old missionary in the jungle of Venezuela [43]. Some of the severe cases also occurred in the context of family outbreaks, with other family members reporting less severe disease than the index cases (e.g., cases in Venezuela [43] or the US [44]).

Ascertainment of Immunocompetent Status
Almost all cases published after 1985 were HIV-negative patients. There were 16 cases (14%) that did not report HIV test results; however, in those cases, underlying immunodeficiency was excluded based on information from a long-term follow-up. All ambiguous cases were excluded.

Anti-Toxoplasma Therapy
The types of anti-Toxoplasma treatments and the duration of treatment varied significantly across studies. The majority of cases were treated with pyrimethamine + sulfadiazine (55% (64/117)) or trimethoprim/sulfamethoxazole (14% (16/117)); however, non-standard anti-Toxoplasma therapies or monotherapies (e.g., spiramycin, azithromycin, erythromycin, or clindamycin) were also given in some cases (Appendix C- Table A7).   anti-NMDA-encephalitis: Anti N methyl D aspartate receptor encephalitis. * The pulmonary imaging findings can mimic pulmonary edema/congestive heart failure, atypical pneumonia, PJP pneumonia, and lymphangitis. £ The CNS imaging findings can mimic CNS lymphoma, bacterial or fungal brain abscess, CNS tuberculosis/tuberculomas, rapid progressive neurodegenerative disease, Alzheimer's disease, diffuse Lewy body disease, Creutzfeldt-Jakob (CJD) disease, and metabolic encephalopathy. € There is a predilection for the basal ganglia [57,58], but lesions in all brain parts, including in the spinal cord (more rarely), have been reported. The intensity of contrast enhancement correlates with the leukocyte count and is more intense in immunocompetent patients [18]. ± The cardiac imaging findings can mimic myocarditis, pericarditis from infectious, postinfectious, metabolic oncologic causes, or acute myocardial infarction.

Outcomes
In total, 80% (88/110) of cases of severe toxoplasmosis in immunocompetent patients in whom the diagnosis was promptly considered and treatment was promptly initiated had favorable outcomes, with the improvement or resolution of symptoms and radiographic and laboratory abnormalities at the time of last follow-up (for 7/117 cases the outcome was not reported). In 12% (13/110) of cases, symptoms had improved or resolved without anti-Toxoplasma treatment or before anti-Toxoplasma treatment was initiated. Fatal outcomes were reported for 8% (9/110) of cases [10,11,35,39,54,57,[59][60][61]; among those were four cases with disseminated disease and multiorgan failure, four had encephalitis, and one had a brain mass-like lesion. Eight fatal cases occurred in adults and one in a child [60] ( Table 2).
The cases that improved or resolved without anti-Toxoplasma treatment or before anti-Toxoplasma treatment support the hypothesis for an immunologic mechanism for these manifestations (Table 2). These 13 cases included (a) a case of a 28-year-old from Indonesia with myopericarditis who initially improved with anti-inflammatory medications but subsequently relapsed [47]; anti-Toxoplasma therapy eventually led to complete resolution; (b) a case of a 59-year-old from the US with a history of eating game meat, with acute myocarditis and cardiogenic shock and multiorgan involvement that resolved without anti-Toxoplasma therapy (the diagnosis was made late, after the development of eye findings) [28]; (c,d) two cases from Colombia, [62] one of a 44-year-old with disseminated multiorgan disease, pneumonia respiratory failure, and myopericarditis and one of a 67-year old with pneumonia and acute respiratory failure (in both cases, the diagnosis was made late, after the development of eye findings); (e,f,g) three cases from France with acute myopericarditis that resolved with anti-inflammatory treatment only, without subsequent relapse [63][64][65][66]; (h) a case of a 76-year-old from Spain with ADEM during an acute Toxoplasma infection that resolved with steroids only [67]; (i) a pediatric case from Greece with myocarditis and polymyositis that resolved with steroids only [68]; (j) a case of a 30-year-old from Spain with acute CNS toxoplasmosis (Miller-Fisher syndrome) [69]; (k) a case of a 61-year-old from Spain with CNS toxoplasmosis and seizures [70]; (l) a case of pneumonia in a missionary in the Venezuela jungle-presumably from an Amazonian T.gondii strain-that eventually self-resolved after a prolonged febrile illness for 7 months (prior to anti-Toxoplasma treatment) [43]; and (m) a case of a 48-year-old from the US with myocarditis, polymyositis, and disseminated disease [31] ( Table 2).
The nine fatal cases included (a) a case of acute CNS toxoplasmosis in a 14-year-old boy from India with brain mass-like lesions in the brainstem who died despite anti-Toxoplasma treatment for 2 weeks [60]; (b) a case of a 41-year-old male from India with acute CNS toxoplasmosis with multiple focal hypointense cerebral lesions, in whom the diagnosis of toxoplasmosis was made late and the patient died [57]; (c) a case of a 44-yearold male from Colombia, with multiorgan failure, pneumonia, respiratory failure, and CNS toxoplasmosis [54]; (d) a case of a 41-year old male from China with disseminated toxoplasmosis and multiorgan failure [35]; (e) a case of a 56-yearold from French Guiana with pneumonia and altered levels of consciousness [10]; (f) a case of an 18-year-old from French Guiana with disseminated disease, pneumonia, acute respiratory failure, and myopericarditis [11]; (g) a case of a 23-year-old male from Oman, with acute CNS toxoplasmosis, who presented with encephalitis and posterior fossa mass, who died after the neurosurgical procedure that established the diagnosis of toxoplasmosis [59]; (h) a case of 35-year-old military personnel on a military operation in Amazonian forest who died from diffuse encephalitis (this case occurred in the context of a military outbreak in additional military personnel from the same operation) [39]; and (i) a case of a 69-year-old from Croatia with rapidly progressing dementia due to multiple brain lesions in the basal ganglia. [61] In all the fatal cases, the duration of symptoms was <2 weeks prior to admission except for the last case by Habek et al. [61] who had a 2-month history of cognitive decline prior to admission with hyperintense brain lesions in both thalami and putamina who died from Gram-negative sepsis; the diagnosis of toxoplasmosis in this patient was made postmortem at the autopsy [61].

Time to Resolution
Data on the time to resolution of symptoms were very sparse. Among those reporting this information, symptoms were resolved in <4 weeks in 64% (23/36) of cases (Table 2).

Discussion
This is the largest comprehensive systematic review of all severe toxoplasmosis cases with pulmonary, cardiac, CNS, disseminated disease, or fatal outcomes in immunocompetent patients to date. We identified 117 cases of severe toxoplasmosis in immunocompetent hosts published between 1985 and 2022 and reported from 33 countries. Forty-four percent of cases had pulmonary involvement, and half of those developed respiratory failure. Thirty-nine percent of cases had CNS involvement, with~70% of those having focal supratentorial lesions and~50% brain-abscess/mass-like lesions. Furthermore, 31% of cases had cardiac involvement with~75% of those having myocarditis, 50% pericarditis,~20% heart failure or cardiogenic shock, and~20% cardiac arrhythmias. More than one target organ system was involved in approximately one-third of cases; disseminated disease was reported in one-quarter of cases. Critical illness and the need for ICU admission were reported for almost half of the cases reporting this information. Nine patients died.
Approximately 75% of cases had an acute onset of symptoms <3 weeks prior to admission, and for >90% of cases, the onset of symptoms was <3 months from admission. Classic exposure risk factors or classic clinical manifestations of toxoplasmosis (e.g., fever, malaise, lymphadenopathy, and chorioretinitis) were not always present. Almost all cases occurred in the context of a recently acquired acute primary toxoplasmosis infection. Genotyping data were very sparse, and the majority of the genotyped cases were from non-type-II strains. Nevertheless, a severe case from a type II strain was also reported. Only half of the cases reported risk factors for toxoplasmosis. Outbreaks among military personnel and hunters and family outbreaks were also reported. Not all members in these outbreaks experienced the same disease severity as the index cases. The reporting of these cases from so many diverse countries supports the hypothesis that severe toxoplasmosis in immunocompetent hosts is more widely encountered than previously thought and not limited to the Amazonian region.
Most immunocompetent patients (~80%) with acute severe toxoplasmosis had an excellent response to anti-Toxoplasma treatment if the diagnosis was promptly considered and anti-Toxoplasma therapy was initiated early. Few cases (~12%) improved or resolved without or before anti-Toxoplasma treatment. However, 8% of cases (n = 9) had a fatal outcome; in four of those, the diagnosis of toxoplasmosis was made only postmortem. Prompt diagnosis and treatment can be lifesaving in immunocompetent hosts.
Our team recently identified another case of severe toxoplasmosis in a young immunocompetent patient presenting with severe community-acquired pneumonia and progressive respiratory failure after the ingestion of infected venison procured in the southern United States. The initial diagnosis of disseminated toxoplasmosis was made by plasma metagenomics cell-free DNA (Karius test) and further confirmed by serologies, PCR in bronchoalveolar lavage (BAL) and blood, and liver biopsy histopathology [71]. Initial empiric treatment with trimethoprim/sulfamethoxazole was lifesaving [71].

Clinical Suspicion of Toxoplasmic Pneumonia
Pulmonary toxoplasmosis in immunocompetent hosts should be suspected in patients with dyspnea, shortness of breath, cough, respiratory distress, hypoxia, respiratory failure, and the need for intubation in the absence of alternative explanation and in the absence of a response to empiric therapies.

Clinical Suspicion of Toxoplasmic Cardiac Involvement
Cardiac toxoplasmosis should be suspected in patients with dyspnea, acute chest pain mimicking acute myocardial infarction, palpitations, myocarditis, pericarditis, heart failure, or cardiogenic shock. The classic presentation of toxoplasmic myocarditis with heart failure shortly after an acute Toxoplasma infection likely represents an autoimmune mechanism rather than direct tissue damage. These cases usually have favorable outcomes and can also occasionally self-resolve even before the initiation of anti-Toxoplasma therapy [29,65]. Cases with more prolonged courses and frequent relapses have also been reported (usually in the absence of targeted anti-Toxoplasma therapy), implicating direct cardiac tissue damage from T. gondii in those cases [65,72]. The optimal management of toxoplasmic pericarditis/myopericarditis remains unclear, but the majority of the cases were managed with typical anti-Toxoplasma therapy with a favorable outcome.

Clinical Suspicion of Toxoplasmic CNS Involvement
CNS toxoplasmosis in immunocompetent hosts should be suspected in patients with mental status changes, confusion, agitation, delirium, personality changes, rapidly progressive dementia [61], myoclonus, and seizures with or without fever. Focal neurologic deficits may be absent. Symptoms of CNS toxoplasmosis in some patients were initially thought to be due to brain tumor, and the diagnosis of toxoplasmosis was made only after the brain lesion was surgically removed [60]. The three major clinical patterns of CNS toxoplasmosis are [73] (a) diffuse encephalopathy (with or without seizures), (b) meningoencephalitis, and (c) mass lesions (single or multiple). Cases with ADEM [74], hydrocephalus and ventriculitis [75], central facial nerve palsies [76], Guillain-Barre syndrome (GBS) [37,77], or acute polyradiculoneuropathies have also been reported. The cerebrospinal fluid (CSF) findings can show CSF pleocytosis and elevated CSF protein (up to 100 mg/dl). However, CNS toxoplasmosis should also be considered even in the absence of CSF pleocytosis, or just with mild pleocytosis [58], particularly so in the presence of elevated CSF protein [61]. Low CSF glucose has also been occasionally reported [78]. Low-level peripheral serum eosinophilia (~15%) may be seen, although rare cases with significant peripheral eosinophilia (~50%) have also been reported [51]. The majority of CNS toxoplasmosis cases responded to anti-Toxoplasma treatment. Rare cases with seizures were reported to have self-resolved without anti-Toxoplasma therapy [70]. There were also rare cases with fatal outcomes.
In some cases, the toxoplasmosis diagnosis was suspected only after the development of ocular findings or lymphadenopathy; however, these two findings were present in onlỹ 30% and 74% of cases reporting this information.

Risk Factors for Severe Toxoplasmosis
Factors associated with severe acute toxoplasmosis in immunocompetent hosts include the virulence of the T. gondii strain, the parasite load (inoculum effect), the parasite stage (oocysts vs. tissue cysts), host genetic characteristics, and/or the delay in initiation of anti-Toxoplasma therapy [11,42,55]. Poor host adaptation to atypical virulent T. gondii strains (e.g., Amazonian strains) may also explain differences in the severity of clinical manifestations [79][80][81][82][83]. Although the pathophysiologic mechanism for the increased virulence of the Amazonian strains has not been completely understood, the more virulent Amazonian strain [84] may cause more severe disease via enhanced invasiveness, interference with Th1 host immune responses [34], and dissemination to multiple organs, with lung involvement common in those cases.
Variations in the severity of the disease in common source family outbreaks [44,55] or military outbreaks among military personnel [38,39]-where the implicated T. gondii strains were apparently the same-support the role of the parasite load in the differential observed disease severity. A massive parasite load can overwhelm the immune response and lead to severe toxoplasmosis [55]. The transient decrease in CD4 counts [3,17,38,55,56] observed early in the course of certain cases of severe toxoplasmosis likely contributed to the observed severity. Of note, in all these cases, the initially low CD4 counts normalized after the initiation of anti-Toxoplasma therapy. Otherwise, there is no known drug resistance reported for T. gondii [85].
A detailed exposure history should always be obtained. However, the absence of classic risk factors should not exclude the diagnosis of toxoplasmosis if there is compatible clinical presentation, particularly if patients do not respond to empiric therapies. T. gondii is a ubiquitous parasite, and 50% of patients with acute toxoplasmosis do not report risk factors based on surveys of pregnant women who gave birth to infants with congenital toxoplasmosis [86,87]. Moreover, the fact that the severe toxoplasmosis cases reported in this systematic review came from 33 different countries further supports our hypothesis that the problem is more widespread than originally thought.

Diagnostic Methods
Serological tools, histopathologic examination of tissue biopsies, molecular diagnostics from blood, CSF, other body fluids or tissue biopsies, metagenomic cell-free DNA from blood and/or CSF, and direct examination for tachyzoites of body fluids (BAL, CSF, and ocular fluids) may help to establish the diagnosis of toxoplasmosis and should be promptly sent. Although serologies are the diagnostic methods of choice, physicians should be aware that in very recent acute Toxoplasma infections, only molecular diagnostics (from blood, other body fluids, or tissues) may be positive initially, as antibody immune responses may be delayed.

Prior Reviews
Prior reviews were either non-systematic reviews, had focused only on single organ systems (e.g., toxoplasmic pneumonia or CNS disease), focused only on Amazonian cases, or were published more than 1-3 decades ago [12,[16][17][18]50,61]. Pomeroy et al. [16] (1992) reviewed 13 cases of severe pulmonary toxoplasmosis in immunocompetent hosts, published between 1942 and 1987. Leal et al. [17] (2007) reported six cases of pulmonary toxoplasmosis in immunocompetent hosts and Di Gassi et al. [50] (2014) reported three such cases. Graham et al. [18] (2021) reviewed seven cases of CNS toxoplasmosis in immunocompetent hosts, including four patients with fatal outcomes due to delayed presentation to the hospital, difficulty diagnosing the infection, and lack of anti-Toxoplasma treatment. Habek et al. [61] (2009) reviewed eight such cases. Bossi et al. [12] (2002) reviewed three cases of acute disseminated toxoplasmosis from French Guiana, acquired either from eating raw or undercooked game meat or the ingestion of oocyst-contaminated water in the forest. Jungle wild cats may play a major role in the T. gondii cycle in the Amazonian region. Zhou et al. (2021) [19] had reviewed six cases of cardiac toxoplasmosis in immunocompetent patients.
Our work is the most comprehensive and up-to-date systematic review on this topic. We applied rigorous criteria for the validation of the immunocompetent status of the host and the ascertainment that toxoplasmosis was the most likely explanation for the described clinical symptomatology. Our primary analysis was focused only on cases published on or after 1985 to exclude possible confounding from AIDS cases that were not properly diagnosed early during the AIDS pandemic.
Some study limitations should be acknowledged. It is possible that some cases of toxoplasmosis with prolonged illness might have been missed; however, we believe that the yield of our search for severe cases with pulmonary, CNS, or cardiac involvement, disseminated disease, or fatal outcomes was very high. Furthermore, some cases of severe toxoplasmosis in the setting of outbreaks could have been missed, although our search strategy would have captured severe outbreak cases that their respective papers mentioned in their title or abstract. Moreover, the list of cases published before 1985, included only in our secondary summary analysis, unavoidably, might have also contained some AIDS cases.

Conclusions
The diagnosis of severe toxoplasmosis in immunocompetent hosts is challenging, due to the low clinical suspicion among healthcare providers. However, cases of severe toxoplasmosis in immunocompetent hosts have been reported from many diverse countries, supporting the hypothesis that this condition is more widely encountered than previously thought and not limited to the Amazonian region. Toxoplasmosis should be considered in the differential diagnosis of immunocompetent patients who present with severe disease with pulmonary, CNS or cardiac involvement, disseminated disease with multiorgan failure, or FUO. Detailed exposure history should always be obtained. However, the classic risk factors and common manifestations of toxoplasmosis (mononucleosis-like illness, lymphadenopathy, and chorioretinitis) may not be always present; their absence thereof should not exclude the diagnosis. Anti-Toxoplasma treatment can be lifesaving.

Additional Information
For assistance in the laboratory diagnosis and management of toxoplasmosis the Remington's Lab (Jack S. Remington Laboratory for Specialty Diagnostics, Palo Alto, CA, USA) can be contacted at https://www.sutterhealth.org/services/lab-pathology/toxoplasmaserology-laboratory, remingtonlab@sutterhealth.org, 650-853-4828 (Pacific Time) for regular hours, and 650-438-4427 cell phone (JG Montoya) for urgent questions/consults. Institutional Review Board Statement: Not applicable (Only published data were used for this project).

Data Availability Statement:
Individual study-level data are available upon request by the corresponding author (Contopoulos-Ioannidis, email: dcontop@stanford.edu).

Conflicts of Interest
Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

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Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.

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Data items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g., for all measures, time points, analyses), and if not, the methods used to decide which results to collect.

Page 5 10b
List and define all other variables for which data were sought (e.g., participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.

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Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

N/A
Effect measures 12 Specify for each outcome the effect measure(s) (e.g., risk ratio, mean difference) used in the synthesis or presentation of results. N/A

Synthesis methods 13a
Describe the processes used to decide which studies were eligible for each synthesis (e.g., tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)). Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. N/A

Study selection 16a
Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.

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Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded. N/A Study characteristics 17 Cite each included study and present its characteristics.
Appendix B, page 21-25, Appendix C- Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.       Table A5. CNS imaging findings.

CNS Imaging Findings N CNS toxoplasmosis cases
• Brain MRI T1 images show multiple hypointense lesions involving the right frontal and left temporoparietal lobes///T2 and FLAIR images of the brain show multiple hyperintense lesions involving the right frontal and the left temporoparietal lobes/////Pre-and postcontrast brain CT images show multiple intensely enhancing lesions (star) involving the bilateral cerebral hemispheres////T2W and DWI images show new hyperintense lesions with restricted diffusion in the left thalamus and the globus pallidus///ADC image shows low signal in the left thalamus suggestive of true restriction///MR spectroscopy of the lesion involving the right frontal lobe shows elevated lipid lactate peak.

1
• Brain CT (non-contrast): Cerebral edema, flattening of the grooves and disappearance of contrast between white matter and cortex; Brain MRI: confirmed brain edema and picture of hemorrhagic cortical infarct. (brain biopsy was not diagnostic) 1 • Brain CT and MRI: normal.(patient with hemidystonia) 1 • Brain CT and brain MRI were normal (in this case of NMDA encephalitis associated with acute Toxoplasmosis in this 9 yr old immunocompetent girl, who presented with personality and behavioral changes, fever, recurring seizures, headache and vomiting and whose symptoms rapidly improved (except for residual agitation) and completely resolved 2 months after a 10 ds course of anti-Toxoplasma treatment with azithromycin and without the need for immunotherapy///A repeat brain MRI was normal. (The EEG demonstrated 14Hz sporadic positive spikes without diffuse slow activity, and epileptiform discharges) 1 • Brain CT showing multiple calcifications involving the basal ganglia and semioval centers//Brain MRI T2 weighted images showing multiple cystic lesions surrounded by brain edema, non-enhancing after contrast (in a 30 yr old immunocompetent man with a 5 yr hx of monthly frontal headache, with worsening intensity and frequency over the last month, with associated episodes of sudden falls without loss of consciousness, followed by unjustified crying, after eating poorly cooked pork meat; with EEG showing mild slowing over left temporal region// with no follow up for 20 mo, but due to daily severe headaches and secondary generalized seizures patient was readmitted)///with repeat Brain CT and MRI showing marked size increase of cystic lesions with ring enhancement and diffuse perilesional edema with mildline shift (S/P emergency surgical removal of 2 large brain cysts, histopathologically showing several bradyzoites and positive T.gondii DNA PCR//with initiation of anti-Toxoplasma treatment with pyrimethamine/sulfadiazine + dexamethasone and at f/up 20 mo later with resolution of Headaches and persistence of sporadic partial motor seizures)//With f/up brain MRI 20 mo after treatment showing mild decease in size of cystic lesions with reduction of perilesional edema and contrast enhancement 1 • Brain CT w contrast: multiple ring enhancing lesions; moderate hydrocephalus and meningeal enhancement (first diagnosis was TB meningoencephalitis although CSF AFB stain and Cultures were negative; patient was started on anti-TB therapy + steroids-> fever, HA and irritability persisted over the next 10 ds)// After 10 ds of anti-TB treatment +Steroids Brain MRI showed: T1 isointense to hyperintense exudate in the suprasellar cistern; T2 images showed dilation of lateral, 3d and 4th ventricles w periventricular hyperintensity and multiple widely scattered ring lesions with hypointense center and hyperintense rim peripherally in b/l cerebral hemispheres including thalamus and basal ganglia (also in pons, middle cerebellar peduncles and b/l cerebellar hemispheres) associated with perifocal edema (initial diagnosis TB meningitis w multiple tuberculomas)//////After 6 weeks of anti-Toxoplasma treatment: all lesions showed regression in size and some lesions became calcified 1 • Brain CT: disclosed an isodensity lesion encapsulated by surrounding edema//Brain MRI revealed a space-occupying lesion with isointense in T1 and hypointensity in T2-weighted imaging and adjacent cerebral edema.// Mushroom-shaped ring enhancing lesions with irregular-enhanced rim were observed in MRI after contrast injection; with perilesional brain edema in the left temporal lobe.///Postoperative brain MRI showed total excision of the lesion with no recurrence 2.5 years after surgery///(Histological examination demonstrated the presence of protozoan parasite in a pseudocyst structure and a capsule consisted of lymphocytes, plasmacytes, and macrophages among the inflammatory infiltrate tissues///A typical ring like pseudocyst structure was surrounded by different inflammatory cells) 1 • Brain CT: hypodense lesions in temporo-occipital region, w vasogenic edema and adjacent hemorrhagic focus 1 • Brain CT: low-grade edema in the area of the posterior skull but without lateralized displacement of the 4th ventricle. 1  • Brain MRI did not show any abscess lesions 1 • Brain MRI on admission showed a lesion in the right globus pallidus and adjacent genu of the right internal capsule, which is a hypointense on T1-weighted images and hyperintense on T2-weighted images. //DWI and ADC (apparent diffusion coefficient) of the brain showed the lesion to have a peripheral rim of restricted diffusion, with a central area of facilitated diffusion///Fluid attenuated inversion recovery magnetic resonance images (FLAIR-MRI) on admission showed the heterogeneously hyperintense lesion in the right basal ganglia with repeat images at 5 mo f/up showing significant reduction in size///Postcontrast coronal T1-weighted images on admission show the same lesion enhancing peripherally, which on follow-up after 5 months shows significantly reduced enhancement. ///Postcontrast coronal T1-weighted images on admission showing another enhancing nodular lesion in the right superior frontal gyrus; that is not seen on follow-up FLAIR MRI (Fluid-attenuated, inversion-recovery axial magnetic resonance imaging) disclosed high-intensity lesions in the periventricular white matter, corona radiata, centrum semiovale, and left parietal lobe///There was no mass effect and no contrast enhancement. All the lesions were hyperintense on both diffusion-weighted imaging and apparent diffusion coefficient images///MRI of the spinal cord revealed diffuse abnormal signal intensity between the cervical C4 to the thoracic T6 level, which showed no enhancement Head CT: showed multifocal white matter lesions//Brain MRI revealed extensive bilateral cortical and subcortical concentric ring-enhancing white matter lesions throughout both cerebral hemispheres. The lesions were more prominent in left parietal and frontal lobes//Treatment with steroids for presumed multiple sclerosis caused worsening of symptoms and increase in size of the brain MRI lesions//Brain biopsy confirmed T.gondii infections by histopathology and PCR and treatment with Pyrimethamine/Sulfadiazine decreased the size of the brain lesions dramatically///The initial differential diagnosis was brain abscesses vs demyelinating disease (multiple sclerosis

Vignettes of Severe Toxoplasmosis Cases
Nelwan 2022 Acute toxoplasmic myocarditis in a 28-yr-old male who presented w fever x8 wks and chest pain x1 wk PTA; cardiac MRI showing Late Gadolinium Enhancement (LGE) areas consistent with myocardial necrosis but w normal LV systolic function; elevated cardiac enzymes (hs-Troponin, CK-MB and proBNP), transaminitis, lymphopenia, hyponatremia//Patient responded initially to steroid treatment but relapsed again within 2 wks from the first hospital admission//This led to the diagnosis of Acute Toxoplasmosis (Acute Primary Infection) and initiation of anti-Toxoplasma treatment with Pyrimethamine + Clindamycin Encephalitis with Right hemiparesis (but without altered level of consciousness) in a 60-yr-old male presenting with a 2 ds hx of HA and R sided weakness (R hemiparesis); with CSF mild pleocytosis (CSF WBC 15 cells/mm3), predominantly lymphomononuclear and brain MRI showing a peripheral enhancing lesion with central diffusion restriction and perivascular enhancing lesion with restricted diffusion with vasogenic edema and leptomeningeal enhancement in the white matter//w brain biopsy, revealing diffuse encephalitis with necrotic brain parenchyma and predominantly acute inflammation, AND T.gondii cysts with bradyzoites seen in the brain parenchyma//Anti-Toxoplasma treatment initiated with P/S x 6 weeks with complete clinical improvement of neurologic symptoms and MRI findings with regression of the brain lesion with no pathologic contrast enhancement Table A8. Cont.

Mustafa 2021
Acute myocarditis with heart failure in a 2-yr-old male, presenting with recurrent acute chest pain over 1 week period (w the first 2 episodes having self-resolved), w EKG with subtle lateral ST segment elevation//with elevation of cardiac enzymes (peak troponin 12.8 ng/mL; unl < 0.   NMDA encephalitis///in a 9-yr-old immunocompetent who presented with seizures, headaches and vomiting CSF and Brain MRI initially normal and self-recovered without any treatment //1 weeks later development of unexplained personality and behavior changes, recurrence of seizures and fever//Repeated CSF with lymphocytic pleocytosis and positive anti-NMDAR antibody. //Had positive Toxoplasma IgM and IgG.//Diagnosed with anti-NMDA encephalitis associated with acute acquired toxoplasma gondii infection//Treated with 10 days azithromycin with substantial recovery from clinical symptoms (immunotherapy was been refused)//F/up 2 mo later patient completely asymptomatic Cortes 2018 Disseminated disease, with rapid neurologic deterioration and multiorgan failure that led to death in a 72-yr-old immunocompetent patient from Chocó, Colombia; who presented with a 12-day hx of fever, headache//with Brain CT showing hydrocephalus and fronto-parietal periventricular hypodensities //with histopathologic findings at autopsy showing tissue cysts morphologically suggestive of being bradyzoites of Toxoplasma gondii; confirmed by immunohistochemistry in heart, brain, and striated muscle.

Author Vignettes of Severe Toxoplasmosis Cases
Henao-Martinez, Montoya 2018 Myocarditis (and mild transaminitis and bilateral retinitis)//in a 29-yr-old immunocompetent woman (HIV negative) from the US (after a trip to Nicaragua x 10 ds; ate undercooked meat during the trip)//presented with acute onset of fever, retroorbital headache, myalgias and rash//LADP also developed 12 ds later//, with transaminitis, anemia and lymphocytosis//Continued fevers, malaise and had new onset of blurry vision within 1 mo into her illness// Toxoplasma IgG and IgM were high positive; Toxoplasma IgA and IgE high positive//Troponin was mildly elevated (0.26; unl < 0.05 ng/mL)//Started TMP/SMX; and switched to Clindamycin (without Pyrimethamine) due to severe nausea with TMP/SMX //Got anti-Toxoplasma treatment for 8 wks and symptoms gradually resolved (including resolution of retinal findings), & troponin normalization (for ocular findings also received intravitreal clindamycin) Henao-Martinez, Montoya 2018 Myocarditis

Harbada 2016
Toxoplasma cerebritis and encephalitis///23-yr-old immunocompetent male residing in Oman with a 2 wks Hx of weakness, incoordination of R upper and lower extremities, 5 ds Hx of throbbing headache, and visual blurring//Brain MRI T2 weighted images showing ill-defined hyperintense lesion in Right cerebellar hemisphere with perilesional edema, extending along the right foramen of Luschka///Post Contrast T1 images showing heterogeneous post-contrast enhancements with peripheral enhancing ring ///Underwent surgical excision due to concern for malignant space occupying lesions///histopathology showed necrosis, hemorrhage, perivascular infiltrates, T.gondii cysts and evidence of cerebritis and encephalitis///treated with Clindamycin + Azithromycin due to G6PD deficiency//post surgery neurologic status deteriorated and Brain MRI showing increase in perilesional edema and inflammation involving the brain stem (Steroid doses were increased//Patient clinically deteriorated despite anti-Toxoplasma treatment and died the 10th postsurgical day due to spreading Toxoplasma cerebritis and encephalitis) Hoti 2016 Toxoplasmic encephalitis //in a 45-yr-old immunocompetent HIV negative woman from Pakistan, with headaches and vomiting x 2 months; with confusion, behavioral problems, weakness in R upper limb//Brain CT showing a hypodense lesion in left Frontoparietal region; with Brain MRI T1 images showing a hypodense lesion in left parietal area; contrast enhancing in T1 contrast images; and T2 hyperintense//S/P total surgical excision of the mass due to concern for neoplasm; with Brain histopathology showing inflammatory features of toxoplasmosis in cerebral cortex and grey matter, with bradyzoite encased within cysts; Positive Toxoplasma IgG and IgM//Post surgery her Right upper limb weakness grossly improved and speech and higher motor functions remained intact//Was treated with TMP/SMX x 14 ds and 6 months post OP her condition was stable//No immunosuppression concern at 1 year of f/up.

Manwani 2016
CNS toxoplasmosis//in a 14-yr-old immunocompetent boy (HIV negative × 2) from India with a 10 ds Hx of difficulty closing R eye, deviation of angle of the mouth on the left, nasal regurgitation of feeds and unsteady wide-based gait; central R facial nerve palsy, with involvement also of the IX and X cranial nerves//Brain MRI showing a hypodense lesion in the pons extending into the medulla, with heterogeneous enhancement with contrast, with vague ring enhancement dorsally, with initially concern for Tuberculoma//Due to progressive increasing difficulty in swallowing, absent gag reflex and R hemiparesis, underwent surgical excision of the brain mass that showed zones of necrosis, thrombosed vessels and aggregate large histiocytes with a single T.gondii bradyzoite with positive Toxoplasma immunostaining//Positive Toxoplasma IgM//Despite initiation of TMP/SMX there was NO neurologic improvement within 1 week of treatment; w subsequent development brain stem dysfunction and eventually cardiac arrest and death 2 weeks after anti-Toxoplasma treatment initiation.

Azarpira 2014
ABSTRACT: Cerebral toxoplasmosis is the most important opportunistic infection in patients with acquired immunodeficiency syndrome. However, it is a rare finding in immunocompetent persons. The patient was a 14 yr-old boy who presented with headache and vertigo. Toxoplasma serology revealed raised IgG antibody level. No primary or secondary immune deficiency was found. Radiologic examination revealed ventriculitis. Microscopically, the lesion consisted of reactive gliosis and calcification. After antitoxoplasma treatment, the patient condition improved. Brain toxoplasmosis usually presented as periventricular/basal ganglial lesions. We report a case of a child patient with an atypical pattern of toxoplasma encephalitis, presenting with ventriculitis.

Vignettes of Severe Toxoplasmosis Cases
Paruthikunnan 2014 Disseminated toxoplasmosis with pulmonary and CNS involvement//in a 28-yr-old immunocompetent (HIV negative) pregnant woman from India, with intermittent fever and cough × 1 month; with elevated inflammatory markers, Eosinophilia (18%)//Patient had an abortion at the time of high fever//CXR showed multiple ill-defined nodular opacities in both lungs and patchy areas of consolidation in R upper and mid zones//Chest CT showing an area of consolidation the RUL and multiple nodules with GGO haloes around them-There was no pleural effusion and no significantly enlarged mediastinal LN//Due to high suspicion for TB initially; patient was treated with anti-TB therapy///Subsequently patient became drowsy with deteriorating level of consciousness//Brain MRI showed an irregular ring enhancing lesion in the R globus pallidus and R internal capsule; Hypointense on T1 and Hyperintense in T2 images/ with ADC (apparent

Vignettes of Severe Toxoplasmosis Cases
De  Demar 2012 19-yr-old male from French Guiana, admitted to ICU, needed IMV, for hypoxia, pneumonia "white lung", meningismus//ABSTRACT: A newly described form of toxoplasmosis, 'Amazonian toxoplasmosis' (AT), has been reported since 2002 in French Guiana. It is characterized by severe cases and atypical strains linked to a neotropical forest-based cycle. We report on the cases of AT that required intensive care management. We performed a prospective observational study on hospitalized adults in the Intensive Care Unit (ICU) from 2002 to 2008. Clinical and laboratory data, microbiological findings and outcomes were recorded. Data, including the ICU simplified acute physiology score and the pneumonia severity index, were calculated. Epidemiological risk factors for AT were assessed through questionnaires. Eleven non-immunodeficient patients were admitted to the ICU in Cayenne for life-threatening pneumonia associated with disseminated toxoplasmosis. Table A8. Cont.

Vignettes of Severe Toxoplasmosis Cases
Demar 2012 30-yr-old male from French Guiana, admitted to ICU, needed IMV for hypoxia, B/L interstitial pneumonia; had cardiac arrhythmia//ABSTRACT: A newly described form of toxoplasmosis, 'Amazonian toxoplasmosis' (AT), has been reported since 2002 in French Guiana. It is characterized by severe cases and atypical strains linked to a neotropical forest-based cycle. We report on the cases of AT that required intensive care management. We performed a prospective observational study on hospitalized adults in the Intensive Care Unit (ICU) from 2002 to 2008. Clinical and laboratory data, microbiological findings and outcomes were recorded. Data, including the ICU simplified acute physiology score and the pneumonia severity index, were calculated. Epidemiological risk factors for AT were assessed through questionnaires. Eleven non-immunodeficient patients were admitted to the ICU in Cayenne for life-threatening pneumonia associated with disseminated toxoplasmosis.
Demar 2012 38-yr-old male from French Guiana, admitted to ICU, needed IMV for B/L interstitial pneumonia//ABSTRACT: A newly described form of toxoplasmosis, 'Amazonian toxoplasmosis' (AT), has been reported since 2002 in French Guiana. It is characterized by severe cases and atypical strains linked to a neotropical forest-based cycle. We report on the cases of AT that required intensive care management. We performed a prospective observational study on hospitalized adults in the Intensive Care Unit (ICU) from 2002 to 2008. Clinical and laboratory data, microbiological findings and outcomes were recorded. Data, including the ICU simplified acute physiology score and the pneumonia severity index, were calculated. Epidemiological risk factors for AT were assessed through questionnaires. Eleven non-immunodeficient patients were admitted to the ICU inCayenne for life-threatening pneumonia associated with disseminated toxoplasmosis.
Demar 2012 28-yr-old female from French Guiana, admitted to ICU, with B/L interstitial infiltrated, had myopericarditis, cardiomegaly, low EF 26%, Hypokinesia/ABSTRACT: A newly described form of toxoplasmosis, 'Amazonian toxoplasmosis' (AT), has been reported since 2002 in French Guiana. It is characterized by severe cases and atypical strains linked to a neotropical forest-based cycle. We report on the cases of AT that required intensive care management. We performed a prospective observational study on hospitalized adults in the Intensive Care Unit (ICU) from 2002 to 2008. Clinical and laboratory data, microbiological findings and outcomes were recorded. Data, including the ICU simplified acute physiology score and the pneumonia severity index, were calculated. Epidemiological risk factors for AT were assessed through questionnaires. Eleven non-immunodeficient patients were admitted to the ICU in Cayenne for life-threatening pneumonia associated with disseminated toxoplasmosis.
Demar 2012 22-yr-old female from French Guiana, admitted to ICU, needed IMV for hypoxia, B/L interstitial pneumonia, had pericarditis//ABSTRACT: A newly described form of toxoplasmosis, 'Amazonian toxoplasmosis' (AT), has been reported since 2002 in French Guiana. It is characterized by severe cases and atypical strains linked to a neotropical forest-based cycle. We report on the cases of AT that required intensive care management. We performed a prospective observational study on hospitalized adults in the Intensive Care Unit (ICU) from 2002 to 2008. Clinical and laboratory data, microbiological findings and outcomes were recorded. Data, including the ICU simplified acute physiology score and the pneumonia severity index, were calculated. Epidemiological risk factors for AT were assessed through questionnaires. Eleven non-immunodeficient patients were admitted to the ICU in Cayenne for life-threatening pneumonia associated with disseminated toxoplasmosis.
Demar 2012 24-yr-old male from French Guiana, admitted to the ICU for hypoxia and B/L interstitial pneumonia; had meningismus//ABSTRACT: A newly described form of toxoplasmosis, 'Amazonian toxoplasmosis' (AT), has been reported since 2002 in French Guiana. It is characterized by severe cases and atypical strains linked to a neotropical forest-based cycle. We report on the cases of AT that required intensive care management. We performed a prospective observational study on hospitalized adults in the Intensive Care Unit (ICU) from 2002 to 2008. Clinical and laboratory data, microbiological findings and outcomes were recorded. Data, including the ICU simplified acute physiology score and the pneumonia severity index, were calculated. Epidemiological risk factors for AT were assessed through questionnaires. Eleven non-immunodeficient patients were admitted to the ICU in Cayenne for life-threatening pneumonia associated with disseminated toxoplasmosis.
Demar 2012 11-yr-old male from French Guiana, admitted to ICU, needed IMV for hypoxia, B/L interstitial pneumonia, had cardiomegaly, pericarditis, low EFABSTRACT: A newly described form of toxoplasmosis, 'Amazonian toxoplasmosis' (AT), has been reported since 2002 in French Guiana. It is characterized by severe cases and atypical strains linked to a neotropical forest-based cycle. We report on the cases of AT that required intensive care management. We performed a prospective observational study on hospitalized adults in the Intensive Care Unit (ICU) from 2002 to 2008. Clinical and laboratory data, microbiological findings and outcomes were recorded. Data, including the ICU simplified acute physiology score and the pneumonia severity index, were calculated. Epidemiological risk factors for AT were assessed through questionnaires. Eleven non-immunodeficient patients were admitted to the ICU in Cayenne for life-threatening pneumonia associated with disseminated toxoplasmosis.  Toxoplasma IgG Antibodies, negative Toxoplasma IgM and negative CSF T.gondii PCR)//with repeat brain MRI due to worsening level of consciousness showing Bilateral temporal and frontal lesions with T2 target signs (on T2 weighted image a three-layered structure with low signal, high signal, and low signal)//(Due to suspicion of Toxoplasma encephalitis Pyrimethamine + Sulfadiazine was started with gradual improvement in patient's level of consciousness, disappearance of involuntary limb movements AND ultimately disappearance of brain MRI lesions //((T2 target sign (core is iso-signal or low signal, the exterior is a high signal and the outermost side is iso-signal or iso-signal); an abscess core with an iso-signal or low signal compared with normal white matter of diffusion weighted imaging and the core with high signal on ADC mapping: are distinct imaging findings of toxoplasmic encephalitis)

Roubille 2012
Myopericarditis w mild pericardial effusion in a 24-yr-old male, who presented with acute chest pain and SOB (with mild pericardial effusion developing after onset of fever), with elevated inflammatory markers, elevated troponin (peak Troponin 17. The authors report a 5-yr-old boy who presented with cervical lymphadenopathy because of acquired toxoplasmosis accompanied with unilateral facial nerve paralysis. Toxoplasma gondii DNA detection in blood by polymerase chain reaction, as well as elevated specific immunoglobulin M antibodies against it, established the diagnosis. Characteristic brain lesions on magnetic resonance imaging were absent and ophthalmologic examination revealed no inflammatory lesions in the retina and choroid. Treatment with pyrimethamine, sulfadiazine, and folic acid resulted in a complete recovery after 2 months of therapy

Jimenez-Caballero 2010
Case of ADEM in a 76-yr-old immunocompetent male (HIV negative) from Spain; who presented with a 7 ds Hx of fever, malaise, inability to walk, and drowsiness//ALOC, Stupor, nystagmus, dysarthria, R dysmetria, ataxia, global hypereflexia//Toxoplasma IgG and IgM were positive //CSF analysis showed hypoglycorrhachia (CSF Gl = 50/serum 93 mg/dl) and elevated CSF protein, but without CSF pleocytosis///Brain MRI showed multiple Hyperintense T2 lesions//FLAIR images showed pseudonodules with vascular distribution//Given presumed diagnosis of ADEM after acute Toxoplasma infection, patient was initiated on Steroids;(5 ds with a 15 ds tapering with good clinical response and progressively there was recovery in the LOC, hemiparesis, ataxia and dysarthria///At 3 mo f/up he was asymptomatic and brain MRI at 6 mo F/up showed resolution of the brain lesions (at that time there was significant rise in Toxoplasma IgG and IgM had become negative) Table A8. Cont.

Vignettes of Severe Toxoplasmosis Cases
Nunura 2010 Pneumonia, retinochoroiditis, hepatitis, synovitis and myositis//in a 37-yr-old immunocompetent male (HIV negative) marine on a military operation by the Peruvian Amazon x prior 4 mo///who presented with R hip pain and limping; subsequently on HD 5 developed Fever, Dyspnea, tachypnea, rales in the left hemithorax and decreased Visual acuity//Also had leukocytosis, transaminitis, CXR with diffuse interstitial infiltrates////Chest CT with multiple nodular cavities and pleural effusions//Eye findings suggestive of Toxoplasma chorioretinitis//On HD15 results of Toxoplasma serology showed positive Toxoplasma IgG, IgM, a thick blood smear was positive for tachyzoites//Initially was started on Clarithromycin + TMP/SMX+ Clindamycin +CTX (but on HD5 was changed to Vanco + Imipenem and his fever/cough and dyspnea persisted//After the Toxoplasma serology results had become available was started on Pyrimethamine + Sulfadoxine (Clindamycin + TMP/SMX were discontinued) and patient defervested on the 2nd d of this treatment //R hip MRI showed avascular necrosis and mild synovial effusion and R hip muscle biopsy showed T. Toxoplasmic encephalitis, rapidly progressing dementia///69 yr old immunocompetent HIV negative male from Croatia, with a 2 mo hx of rapidly progressive cognitive decline with poor speech, dyslexia, dysgraphia, constructional apraxia, verbal and visual memory deficits, positive Babinski and left side and gait apraxia//Brain MRI T2 images showed Hyperintense lesions in both thalami and putamina and head of caudate nucleus without diffusion restriction on DWI sequences (T2 shine through) ///CSF showed elevated protein (1.08 g/L) without pleocytosis and elevated CRP//Clinical course complicated by gram negative sepsis and patient died, with toxoplasmic encephalitis revealed at the autopsy///Brain autopsy showed confluent small and soft partially hemorrhagic lesions in basal ganglia with few cysts containing T.gondii bradyzoites (per authors conclusion: Toxoplasmic encephalitis should be considered in the differential diagnosis as a rare cause of rapidly progressive dementia in immunocompetent patients. Moreover, in the presence of multiple hyperintense lesions on T2 and hypointense lesions on T1 images without diffusion restriction, toxoplasmosis should also be considered even in the absence of CSF pleocytosis, particularly so though in the presence of elevated CSF protein) Table A8. Cont.

Vignettes of Severe Toxoplasmosis Cases
Pino Salinas 2009 23-yr-old male from Colombia Armed Forces, admitted to ICU with Respiratory failure, NYHAIII, myalgias, arthralgias, HA, LADP////ABSTRACT: Toxoplasmosis is a common opportunistic infection in patients infected with HIV/AIDS while in immunocompetent patients this infection causes symptoms only in 10% to 20% of the cases, generally with a benign and autoresolutive course. In the last decade some severe cases with visceral involvement has been reported in immunocompetent patients, though they were isolated or recovered during years. //We present the first Colombian report of an epidemic outbreak caused by Toxoplasma gondii in military personnel deployed to rural areas located at La Macarena, Meta, Colombia. All 18 cases were confirmed by IgG indirect immunofluorescence (IFI) with titers higher than 1:1024 (normal range: 1:16). Their main symptoms were fever, adenopathies and pulmonary and gastrointestinal compromise. One patient developed severe myocardial compromise. All the patients recovered after treatment with pyrimethamine/sulfadoxine and clindamycin for 3 weeks. A possible hypothesis for this out-break was the consumption of contaminated water with oocysts, and probably the severity of the compromise could be elicited by a "wild" strain of the parasite as it is reported in the literature. Unfortunately, it was impossible to isolate and identify the specific strain.

Pino Salinas 2009
31-yr-old male from Colombia Armed forces, who presented with dyspnea NYHA III, HA, myalgias, sweating, LADP//ABSTRACT: Toxoplasmosis is a common opportunistic infection in patients infected with HIV/AIDS while in immunocompetent patients this infection causes symptoms only in 10% to 20% of the cases, generally with a benign and autoresolutive course. In the last decade some severe cases with visceral involvement has been reported in immunocompetent patients, though they were isolated or recovered during years. //We present the first Colombian report of an epidemic outbreak caused by Toxoplasma gondii in military personnel deployed to rural areas located at La Macarena, Meta, Colombia. All 18 cases were confirmed by IgG indirect immunofluorescence (IFI) with titers higher than 1:1024 (normal range: 1:16). Their main symptoms were fever, adenopathies and pulmonary and gastrointestinal compromise. One patient developed severe myocardial compromise. All the patients recovered after treatment with pyrimethamine/sulfadoxine and clindamycin for 3 weeks. A possible hypothesis for this out-break was the consumption of contaminated water with oocysts, and probably the severity of the compromise could be elicited by a "wild" strain of the parasite as it is reported in the literature. Unfortunately, it was impossible to isolate and identify the specific strain.

Pino Salinas 2009
24-yr-old male from Colombia Armed Forces, admitted to ICU with respiratory failure, cough, dyspnea NYHA IV, HA, malaise, LADO///ABSTRACT: Toxoplasmosis is a common opportunistic infection in patients infected with HIV/AIDS while in immunocompetent patients this infection causes symptoms only in 10% to 20% of the cases, generally with a benign and autoresolutive course. In the last decade some severe cases with visceral involvement has been reported in immunocompetent patients, though they were isolated or recovered during years. //We present the first Colombian report of an epidemic outbreak caused by Toxoplasma gondii in military personnel deployed to rural areas located at La Macarena, Meta, Colombia. All 18 cases were confirmed by IgG indirect immunofluorescence (IFI) with titers higher than 1:1024 (normal range: 1:16). Their main symptoms were fever, adenopathies and pulmonary and gastrointestinal compromise. One patient developed severe myocardial compromise. All the patients recovered after treatment with pyrimethamine/sulfadoxine and clindamycin for 3 weeks. A possible hypothesis for this out-break was the consumption of contaminated water with oocysts, and probably the severity of the compromise could be elicited by a "wild" strain of the parasite as it is reported in the literature. Unfortunately, it was impossible to isolate and identify the specific strain.

Pino Salinas 2009
21-yr-old male from Colombia Armed Forces, who presented w cough/dyspnea, NYHAII, HA, malaise, LADP///ABSTRACT: Toxoplasmosis is a common opportunistic infection in patients infected with HIV/AIDS while in immunocompetent patients this infection causes symptoms only in 10% to 20% of the cases, generally with a benign and autoresolutive course. In the last decade some severe cases with visceral involvement has been reported in immunocompetent patients, though they were isolated or recovered during years. //We present the first Colombian report of an epidemic outbreak caused by Toxoplasma gondii in military personnel deployed to rural areas located at La Macarena, Meta, Colombia. All 18 cases were confirmed by IgG indirect immunofluorescence (IFI) with titers higher than 1:1024 (normal range: 1:16). Their main symptoms were fever, adenopathies and pulmonary and gastrointestinal compromise. One patient developed severe myocardial compromise. All the patients recovered after treatment with pyrimethamine/sulfadoxine and clindamycin for 3 weeks. A possible hypothesis for this out-break was the consumption of contaminated water with oocysts, and probably the severity of the compromise could be elicited by a "wild" strain of the parasite as it is reported in the literature. Unfortunately, it was impossible to isolate and identify the specific strain. In the last decade some severe cases with visceral involvement has been reported in immunocompetent patients, though they were isolated or recovered during years. //We present the first Colombian report of an epidemic outbreak caused by Toxoplasma gondii in military personnel deployed to rural areas located at La Macarena, Meta, Colombia. All 18 cases were confirmed by IgG indirect immunofluorescence (IFI) with titers higher than 1:1024 (normal range: 1:16). Their main symptoms were fever, adenopathies and pulmonary and gastrointestinal compromise. One patient developed severe myocardial compromise. All the patients recovered after treatment with pyrimethamine/sulfadoxine and clindamycin for 3 weeks. A possible hypothesis for this out-break was the consumption of contaminated water with oocysts, and probably the severity of the compromise could be elicited by a "wild" strain of the parasite as it is reported in the literature. Unfortunately, it was impossible to isolate and identify the specific strain.

Gupta 2008
Toxoplasma granuloma of the brainstem in a 27-yr-old immunocompetent male (HIV negative) from India with sudden onset of headache, left sided weakness and vomiting; with a similar prior episode 1 mo earlier that had self-resolved//Had anisocoria, crossed hemiplegia with left hemiparesis and Righ V, VII, Xi, and X cranial nerves involvement//Brain MRI showed on T1 images a hypotense pontine lesion with extension to midbrain; with heterogeneous contrast enhancement and vague ring enhancement//brain biopsy (due to concern for neoplasm) showed an inflammatory lesion (with dense microglia reaction mixed with foamy histiocytes; focal areas of active necrosis; with foci of spotty calcifications along the edge of the necrotic zone, along with few ruptured but calcified Toxoplasma cysts characteristic of Toxoplasmosis (Toxoplasma granuloma of the brainstem) (Risk factors: Prior Hx of owing a cat)//(Serial Toxoplasma IgG and IgM were within normal range)//Based on the histopathologic findings was started on P/S x4 wks //At 6 mo f/up had complete recovery with no residual neurologic deficits; with repeat brain MRI showing complete resolution of brain lesion//At 2 yrs f/up remained asymptomatic  Myopericarditis with acute heart failure (NYHA IV), large pericardial effusion and B/L pleural effusions in a 67 y F, who presented w severe dyspnea at rest, left pleuritic chest pain, high fever, generalized LADP (w a PMH of suspected myocarditis 3 mo PTA with LVEF 35% but w normal troponin)//w CXR showing B/L pleural effusions and cardiomegaly//w ECHO showing LV systolic dysfunction with LVEF 33% and large pericardial effusion//w Chest CT confirming the presence of pericardial and pleural effusions//w markedly elevated inflammatory markers (CPR 232 mg/dl; ESR 100 mm/h); with slightly high Troponin (0.10-1.12 ng/dl)//With significant clinical improvement of cardiac symptoms after 3 wks of Spiramycin treatment (Spiramycin was used because of sulfa allergy); with normalization of inflammatory markers; resolution of CXR and ECHO findings with increase in LVEF to 50%//Patient was discharged after 7 wks of treatment with no further evidence of Heart Failure///Also with elevated serum CA-125 during acute presentation and normal CA-125 at 1 year follow up Demar 2007 The hospitalized patients, who did not have any immunodeficiencies, presented with an infectious disease with multivisceral involvement. Serological examination confirmed acute toxoplasmosis. One adult died, and a neonate and a fetus with congenital toxoplasmosis also died. During the investigation, 4 additional acute cases of toxoplasmosis were diagnosed among the 33 villagers. Only 3 inhabitants had serological evidence of previous T. gondii infection. In total, we reported 11 cases of toxoplasmosis: 8 multivisceral cases in immunocompetent adults, resulting in 1 death; 2 cases of lethal congenital toxoplasmosis in a neonate and a fetus; and 1 symptomatic case in a child. Molecular analysis demonstrated that identical isolates of only 1 atypical strain were responsible for at least 5 of the 11 cases of toxoplasmosis in the outbreak. No epidemiological sources could be linked to this severe community-wide outbreak of toxoplasmosis.  41-yr-old immunocompetent male (HIV negative) from Brazil w 8 ds of fever, myalgias, HA; this occurred 20 ds after eating semiraw beef 20 ds earlier,//Progressed to Respiratory failure w B/L interstitial infiltrates///Toxoplasma IgM+, Positive Toxoplasma PCR from CSF, nl CSF count/ positive mice subinoculation/ w marked clinical radiographic and laboratory improvement after 4 ds of anti-Toxoplasma treatment Pyrimethamine/Sulfadiazine/ Steroids (after treatment CD4 increased from 435 to 921 /mm3)//ABSTRACT: Pulmonary toxoplasmosis is rare in immunocompetent subjects. Here, we describe a 41-year-old previously healthy male patient who presented to the emergency department of a hospital with a life-threatening case of pneumonia due to Toxoplasma gondii infection, which responded to specific therapy. Clinical and image-based findings overlap with those for atypical pneumonias, and toxoplasmosis should be considered in the differential diagnosis-especially if immunoglobulin M-specific antibodies are detected.

Mariani 2006
ABSTRACT: We report a case of toxoplasma myocarditis in a young healthy man.///Patient had 2 Toxoplasmosis manifestations: myocardial involvement with complete AV block and cerebral lesions. This patient is the second AV block case related to toxoplasma infection described in the literature.

De Salvador 2005
ABSTRACT: We report a case of severe acute primary pulmonary toxoplasmosis in an immunocompetent young man living in Nice (Southern France). The Toxoplasma DNA extracted from the broncho-alveolar lavage fluid allowed a genetic characterization of the responsible strain which displayed an atypical genotype of Toxoplasma gondii. This unusual genetic composition of the parasite may have influenced, among other factors, the severity of the disease.///The 11-yr-old sister of the patient also developed Acute toxoplasmosis with fever and LADP, but without pulmonary findings//Thus for the severity of the presentation the atypical implicated T.gondii genotype might not be solely responsible. //A massive parasite load in the 19-yr-old pt might have overwhelmed the immune response and led to a severe toxoplasmosis. //In such cluster cases differences in inoculum size are more likely explained by ingestion of oocysts rather than ingestions of cysts in infected meat  Meningoencephalitis//in a 28-yr-old immunocompetent F from India (HIV negative x2) with 2 mo Hx of low grade fever, Headache and vomiting; with worsening headache and deterioration of level of consciousness, confusion, irritability, neck rigidity and hepatomegaly//Spinal tap showed elevated opening pressure; Pleocytosis (495 cells/mm3); elevated CSF protein 210 mg/dl(unl < 50 mg/dl) and low CSF glucose (24 mg/dl)//Head CT showed multiple ring lesions with hypointensive centre and moderate hydrocephalus, with meningeal enhancement ///T2 weighted images showed moderate dilatation of the lateral, third and fourth ventricles with periventricular hyperintensity, and multiple widely scattered ring lesions with a hypointense centre and a peripheral hyperintense rim in both the cerebral hemispheres including the thalamus and basal ganglia. Lesions were also visualized in the pons, middle cerebellar peduncles and both the cerebellar hemispheres. The majority of these lesions was associated with perifocal edema//Patient was initially started on anti-TB therapy+ steroids for suspected TB meningoencephalitis with multiple tuberculomas)///After 10 ds Brain MRI T1 images showed isointense to Hyperintense exudate in the supra-cellar cistern///Repeat CSF analysis showed decrease in pleocytosis (from 495 to 250 cells/mm3; probably due to the Steroid treatment); increase in CSF protein (From 210 to 440 mg/dl) and increase in CSF glucose (From 24 to 60 mg/dl); probably due to steroids//Failure to respond to anti-TB treatment led to the suspicion of Toxoplasmosis///Toxoplasma

Paspalaki 2001
Polymyositis and myocarditis (severe proximal muscle weakness, elevated muscle enzymes, positive EMG consistent with subacute inflammatory myopathy; ECHO: dilation of Left ventricle w poor contractility suggestive of myocardial involvement)//////(13-yr-old immunocompetent girl with 3 wk hx of high fevers, malaise, mild proximal muscle weakness, weight loos, and vomiting; transaminitis, and a round 2 cm non cystic liver lesion by abdominal US and CT//initially presumed to have bacterial liver abscess; with rapid neurologic deterioration with dysphagia, inability to walk and raise arms, further weight loss, fine tremor of hands, maculopapular rash on palms and soles; with EMG consistent with subacute inflammatory myopathy//with ECHO showing left ventricle dilation with poor contractility///With rising and eventually very high Toxoplasma IgG titers (up to 1:109,350 4 weeks later prior to any Tx/steroids) and positive Toxoplasma IgM)//Had favorable response to steroids only treatment; with resolution of fever within 2 wks; and improvement of clinical and laboratory findings; with resolution of rash on palms and resolved within 3 months//Authors' presumed diagnosis with Toxoplasmic acute myositis and myocarditis; the liver lesion might also be attributed to Toxoplasmosis//The improvement with prednisolone along was suggestive of immunologic disturbances contributing to the development of inflammatory myositis//With patient remaining completely asymptomatic at the 4 yr f/up)

Silva 2001
46-yr-old immunocompetent woman (HIV negative) from Brazil; presented with fainting and decreased visual acuity x 8 ds, and inability to perform usual tasks as housewife (with hx of partial seizures due to intracranial calcifications secondary to neruocysticercosis)//with Paresis of Left upper limb; Head CT showed hypodense lesion with vasogenic edema in the R occipital lobe, with heterogeneous contrast uptake around the lesion//MRI revealed an occipital lobe mass measuring 3.5 × 2.9 × 3 cm with perilesional edema and areas of high signal on T1 and T2//Underwent neurosurgical exploration due to concern for CNS neoplasm; and complete surgical excision of two nodular lesions with a yellowish-brown appearance with areas of central necrosis and cavitation; revealing chronic inflammation surrounding the necrotic material; with pseudocysts filled with bradyzoites seen in immunostaining for T.gondii//Toxoplasma IgG was positive but negative Toxoplasma IgM// diagnosis of Brain abscess due to Toxoplasmosis was made ///it was not possible to define whether there was a RLI triggered by an unidentified immunosuppressive factor, or an API with negative IgM in the serum// treatment with P/S was initiated with progressive improvement of initial neurological s/s//At f/up 6 months after diagnosis (without any treatment) reported only hypoesthesia in the feet and NO evidence of immunosuppression 1 year after diagnosis Sugane 2001 Meningoencephalitis (preceding headache x 2 wks ( associated with high fever and urinary retention)//subsequently facial numbness, gait disturbances progressing to extreme unsteadiness, delirium, positive Kernig's sign ABSTRACT: We report herein a rare case of Toxoplasma gondii meningoencephalitis in a non-AIDS patient. Although T. gondii itself was not detected in nucleated cells in peripheral blood and cerebrospinal fluid under the microscope, the polymerase chain reaction method effectively detected the B1 gene of T. gondii in the cells. A serological examination showed increased levels of the IgG but not the IgM antibody to T. gondii, suggesting reactivation of the infection in the brain.

Chandenier 2000
Acute myocarditis with rapid onset of CHF (congestive heart failure) shortly after acute infection//in a 21-yr-old immunocompetent woman (HIV negative) living in France, who was admitted in the Cardiac ICU with chest pain with deep inspirations, fever and dyspnea.//ECHO showed global hypokinesia with SF 17% (nl range 30-35%) and EF 36% (nl range 60%) but no pericardial effusion; High CPK, LDH, transaminitis, elevated inflammatory markers//Serial Toxoplasma serology was positive for Toxoplasma IgG, IgM and IgA, confirming recent seroconversion (rising Toxoplasma IgG titers))///CHF and myocardial contractility self-normalized within 8 ds, NO anti-Toxoplasma treatment was given; (in HD12 suffered bilateral Pulmonary Emboli and recovered ONLY with anti-coagulation treatment)

Chandenier 2000
Cardiac dysfunction, dyspnea, pulmonary edema, transaminitis//in a 9-yr-old immunocompetent girl (HIV negative) living in France, who presented with Acute Pulmonary Edema, Dyspnea and Tachycardia, with 1 wk prior having had fever and dyspnea for which treated with Amoxicillin (fever subsided by dyspnea worsened)//CXR showed Pulmonary edema and cardiomegaly //ECHO showed systolic Left ventricular dysfunction with akinetic basal and median septum and hypokinesia of other ventricular walls//SF 10% (nl 30-35%) and EF 35% (nl 60%)//Cardiac enzymes were normal (CPK, LDH, troponin and Myoglobin), transaminitis//Her clinical condition improved on symptomatic treatment //Toxoplasma serology showed positive Toxoplasma IgG, IgM and IgA, Blood Toxoplasma PCR was negative, but Toxoplasma IgG avidity and Agglutination test implied an infection acquired 6-12 mo prior to testing//(Risk factor: contact with kittens 3 mo prior) //Pyrimethamine + Sulfadiazine given later (x 4 wks) led to improvement in cardiac function//(at 6 mo f/up the cardiac function was completely normal) Table A8. Cont.

Sanchez 2000
Toxoplasmic encephalitis //in a 61-yr-old immunocompetent male from Recurrent seizures within an 8 mo period (2 episodes 8 mo prior and 1 current episode); multiple nodular brain calcifications along the convexity, paracortical regions and brain base; otherwise normal CSF analysis (normal cells, protein and glucose), +Toxoplasma IgG, +IgM, +IgA but high avidity at the time of the 3d seizure episode.///Seizures resolved -with not recurrence over subsequent 6 months-without specific anti-Toxoplasma treatment.

Sano 2000
ABSTRACT: There have been several case reports, a total of 22 up to the present, of toxoplasma pericarditis. Out of them, in only a few cases the diagnosis was properly made with a proof of the microscopic presence of Toxoplasma gondii. This is the first report of toxoplasma pericarditis in which the presence of Toxoplasma gondii was detected by polymerase chain reaction of pericardial effusion. In addition, the previous reports will be reviewed, and compared to this present case. A 29 yr-old woman, without immunosuppressant disorder, suffering from fever and orthopnea was admitted to our hospital. Blood chemistry findings indicated mild liver dysfunction and inflammation. Chest radiography showed cardiac enlargement. Electrocardiography showed sinus tachycardia and ST elevation. Echocardiography revealed a massive pericardial effusion. Pericardiocentesis demonstrated 638 mL of bloody fluid. Cytologic study of the fluid was class II for malignancy, and polymerase chain reaction to tuberculosis was negative. However, a high titer of the antitoxoplasma antibody of 1: 20,480 (passive hemagglutination) indicated pericarditis caused by Toxoplasma gondii. Subsequently, Toxoplasma gondii was identified in the pericardial effusion by polymerase chain reaction. Clinical symptoms improved after pericardiocentesis, but 2 months later pericarditis recurred. Treatment was started with 800 mg acetylspiramycin daily but failed to improve the symptoms. Because of the development of pleuritis, treatment was changed to sulfadoxine 1000 mg/pyrimethamine 50 mg. After the treatment with them, her symptoms improved. Only 22 cases of toxoplasma pericarditis have been reported worldwide and 15 of those cases were without immunosuppressant disorder. The usual symptoms at the onset of pericarditis without immunosuppressant disorder are fever, dyspnea and chest pain. Seven patients developed cardiac tamponade. Pericardiocentesis was performed in 8 cases and the pericardial fluid was hemorrhagic in 6. Pericardial thickening was detected in 5 cases. The diagnosis of toxoplasma infection is very difficult, because asymptomatic infection of Toxoplasma gondii is very common. Pericarditis is a disease difficult to confirm the etiology. Detection of Toxoplasma gondii in pericardial effusion by the polymerase chain reaction is very useful for its diagnosis.

Calore 2000
ABSTRACT: Skeletal muscle can be the site of inflammatory diseases that lead to muscle weakness, pain, and increased myogenic serum enzymes. Most of these inflammatory myopathies are idiopathic. In some cases, inflammatory myopathies are due to infectious agents. We describe the pathological aspects of muscle biopsies of 2 Brazilian siblings who acquired toxoplasmosis at the same time and in similar conditions. One developed a tetraplegia that was confirmed to be due to inflammatory myositis due to toxoplasma. The other developed myocarditis, with heart failure, without skeletal muscle weakness. In both cases many toxoplasma organisms were observed in the muscle biopsies, but in case 1 only was there an inflammatory myopathy with myofiber necrosis; the inflammatory cells were predominantly macrophages with some CD4+ cells and rare CD20+ cells.
In case 1, expression of CD54 was observed in many inflammatory cells as well in endothelial cells, but only in endothelial cells in case 2. After treatment with clindamycin and corticosteroids both cases had only partial improvement, case 1 with a residual muscle weakness and case 2 with residual cardiac insufficiency (requiring digoxin). These cases show that the presence of the parasite in myofibers is not enough to induce an inflammatory myositis with muscle cell necrosis. This suggests that immunological disturbances may contribute to the development of inflammatory myositis due to toxoplasma.

Bossi 1998
ABSTRACT: Cases of severe toxoplasmosis have been reported involving immunocompetent patients living in French Guyana, where oocysts are found in river water and wild animals (2). A poor host adaptation to the uncommon highly virulent tropical strains of T. gondii can explain these unusual clinical presentations. In our case, Guillain-Barre' syndrome was observed in an immunocompetent patient during a disseminated infection with a new strain of T. gondii. This strain was highly virulent, as confirmed by the rapid death of the mice (within 3 days). Moreover, this strain was not altered by a 10-day treatment with spiramycin (which is ineffective in toxoplasmosis with central nervous system symptoms), and parasitemia remained after this therapy. The combination of Guillain-Barre syndrome, massive alteration of the patient's condition, and skin, pulmonary, liver, pancreatic, and ocular involvement is unique for toxoplasmosis. Only the standard treatment for toxoplasmosis was effective, whereas spiramycin and intravenous IGs were ineffective.//His symptoms started 2 mo PTA= 15 ds after eating undercooked meat of warthog and doe during a 3 ds tour in the tropical forest of French Guyana (fever, HA, maculopapular rash, dry cough, diarrhea//1 mo later admitted with high fever 15 Kg weight loss) ABSTRACT: Objectives: Over a period of 13 years (1982-1995), 49 cases of acquired toxoplasmosis complicated with ocular and/or neurologic or meningeal involvement were observed in our toxoplasmosis laboratory. This series includes 43 cases of isolated ocular lesions, 3 cases of meningoencephalitis (associated with retinochoroiditis in 1 case), 1 case of meningitis with uveitis, 1 case of polyradiculoneuritis and 1 case of facial nerve palsy.Methods: The patients were aged 1 to 62 years. None had either spontaneous or iatrogenic immunodeficiency. There were two steps in the diagnosis. First congenital infection was eliminated on one or several of the following criteria: any possibility of maternal infection during pregnancy ruled out in 26 cases, evidence of recent acquired infection (i.e., clinical and/or serological evidence of recent acquired toxoplasmosis in 17 cases, retinochoroiditis in non-twin siblings in 3 cases). The second step was to confirm the diagnosis of toxoplasma infection. Apart from serological evidence of recent infection, confirmation included specific local antibody synthesis in the aqueous humor of the eye and/or in cerebro-spinal fluid or ocular lesions characteristic of toxoplasmosis and absence of other etiology.Results: Ocular lesions were unilateral in 43 cases among 45. A mean follow-up of 37.9 months revealed relapses in 14 among 36 patients (39%). As routine serological examination for toxoplasmosis is compulsory in France since 1978, it was possible to document retrospectively the immune status of the mothers of many of the patients of the present series during pregnancy and to rule out congenital toxoplasmosis in a number of cases. This might explain the discrepancy between the relatively large number of cases in the present series and the fact that complicated acquired toxoplasmosis has been considered hitherto as relatively rare in immunocompetent patients.Conclusion: Based on the epidemiology of ocular toxoplasmosis and the data obtained here, it is suggested that the acquired pattern of ocular toxoplasmosis might be more frequent than estimated up to now.

Vignettes of Severe Toxoplasmosis Cases
Duffield 1996 Toxoplasmic myocarditis resulting in recurrent symptomatic AV dissociation in a 25-yr-old immunocompetent patient (HIV Not performed, but was well at 1 yr f/up) presented initially w 10 ds Hx of Fever, Myalgias, lethargy that self-resolved//then 1 wk later acute unwell with hypotension, dizziness, chest tightness, EG showed AV dissociation, normal cardiac enzymes//1 mo later also LADP//Excision of LN showed Toxoplasmosis//Had new episode of Collapse again with AV dissociation, and profound hypotension, ECHO showed impaired LVF, hypotension//Responded to Dual chamber pacing///Positive Toxoplasma IgG Dye test and positive Toxoplasma IgM///After the 3d recurrence of AV block started Pyrimethamine + Spiramycin and a permanent dual chamber pacemaker was implanted//ABSTRACT: "We believe this case is unique in that Toxoplasma gondii myocarditis resulted in recurrent, symptomatic AV dissociation with interference. During each attack an identical pattern of AV dissociation was present. Resolution of hypotension and symptoms followed AV sequential pacing. The patient was not bradycardic and LV dysfunction occurred only once. Thus, AV dissociation caused hypotension. This pattern suggests that the patient was experiencing a condition similar to pacemaker syndrome, which occurs in some patients with a ventricular demand pacemaker. The severity of the condition is variable, ranging from flushing to hypotensive collapse, and is not always reproducible. There is often a delay of hours or days in the development of symptoms. The condition is thought to be mediated by several mechanisms including the activation of atrial stretch receptors during AV dissociation, causing an inappropriate reduction in peripheral resistance, and retrograde VA conduction. The latter does not occur during AV dissociation with interference. However, VA conduction is not a prerequisite for development of pacemaker syndrome".

Lesenne 1996
ABSTRACT: Acute myocarditis due to toxoplasmosis infection has been previously reported, usually in patients suffering from immuno-depression. Cardiac involvement by toxoplasmosis is rare in subjects with a normal immunological status. The authors report the case of a 16-yr-old immunocompetent (HIV negative) patient without immuno-depression with acute myocarditis caused by toxoplasmosis simulating myocardial infarction. //Patient's symptomatology rapidly resolved//Patient had a favorable outcome without complications from the Toxoplasmic myocarditis//Toxoplasmic myocarditis in IC patients has a good prognosis//////(Acute onset of symptoms of chest pain, fever, EKG ST changes, initial diagnosis of myocarditis mimicking acute MI, had LADP, and splenomegaly, elevated CPK and MB fraction//Toxoplasma serology initially Toxoplasma IgG, IgM and IgA negative with f/up serology showing seroconversion (positive IgG, high positive IgM and IgA) Treated with Spiramycin and f/up ECHO 2 mo later was normal (also the previously abnormal scintigraphy scan was subsequently normalized) Lescop 1995 Diffuse toxoplasmic encephalitis with rapidly fatal outcome (within HD #6); Brain CT and MRI showing non-specific finding of brain swelling (Figiure 1) and cortical infarcts due to vasculitis; Spine-echo pTw: flatening of the grooves and the periencephalic cisterns; Spine-echo pT1: small haemorrhagic zone in the R parietal cortex, Spin Echo pT1: minimal enhancement after gadolinium injection (Figiure 2)

Micheli 1994
ABSTRACT: We discuss the unusual presentation of acquired toxoplasmosis in a girl with severe and transient hemidystonia as a unique symptom. Serum titers of anti-toxoplasma antibodies increased whereas no specific antibody response in the CSF was observed. While symptomatic drugs were inefficacious, specific anti-toxoplasmosis therapy led to complete and permanent recovery within 2 months. ///1 d of fever 4 wks PTA for repetitive contractures of right thumb, with progressive worsening of involuntary movement and within subsequent 20 ds unable to handle objects or write//Toxo IgG serology showed significant rise in titers (CSF toxo IgG was negative)//The neurologic symptoms progressively worsened with athetoid like movements and Ballistic like hyperkinesia on the R//Eye exam, abd Brain CT and Brain MRI were all normal///treatment with symptomatic drugs (benzodiazepines etc) was not effective//When specific anti-Toxoplasma treatment with Pyrimethamine + Spiramycin+ Sulphonamides was instituted, the clinical condition progressively improved and within 2 mo the girl completely recovered; while the EEG normalized in 8 mo (of note earlier EEG showed posterior pseudoperiodic synchronous sharp waves during eye closure, 2 later EEG showed no paroxysmal activity excluding epilepsy) (the absence of CSF Toxoplasma antibodies supports the hypothesis of focal vasculitis)  Pulmonary Toxoplasmosis (Pneumonia)//in a 33-yr-old immunocompetent (HIV negative) pregnant woman from Cambodia; with a 7 d Hx of dyspnea, fever, dry cough, CXR with reticulondular opacities B/L//BAL showed T.gondii by immunoperoxidase staining//Toxoplasma IgG and IgM initially negative, but had seroconversion 2 wks later with positive Toxoplasma IgG and IgM//Was treated initially with Spiramycin (before the BAL results) and symptoms improved within 1 week; subsequently given Pyrimethamine/Sulfadiazine x 5 wks (until delivery)//Initially had low CD4 count (CD4: 250) which normalized after anti-Toxoplasma treatment Table A8. Cont.

Vignettes of Severe Toxoplasmosis Cases
Desguerre 1993 Acute respiratory distress with interstitial pneumonia, myocarditis and pericardial effusion and subsequently also meningoencephalitis //in a 2 yr old immunocompetent child (HIV negative) living in Guyana, who presented with respiratory distress, fever; pericardial fluid was drained//Subsequently within 1 mo developed also spastic quadriparesis and chorioretinitis; with emotional liability and limited expressive language; nystagmus//Toxoplasma IgG and IgM positive///Treated with Fansidar + Spiramycin but without response///Elevated CSF protein (100mg/dl) without pleocytosis initially, but subsequently developed pleocytosis (CSF WBC 47/mm3,high CSF protein (80 mg/dl) and positive CSF Toxoplasma IgG and Toxoplasma IgM (this, along with the presentation with acute pneumonia and myocarditis, argues against a case of congenital Toxoplasmosis and favored the diagnosis of acquired toxoplasmosis)//Brain CT: w numerous calcifications and Hypodense areas//Brain MRI with high T2 signal in periventricular white matter, internal capsule, and "centres semi-ovales"//Treated with 6 weeks of P/S (Fansidar) with stabilization of the diseases and then placed in maintenance treatment with weekly Fansidar x 2 years//At 2 years f/up: has persistent asymetric tetraparesis and had 2 seizures and the previously noted MRI white matter increased signals in the periventricular area and internal capsule had persisted but had decreased in intensity Guerot 1992 Pericarditis//in a 20 yr-old immunocompetent man living in France (HIV negative) who presented with fever and LADP, Toxoplasma IgG and IgM were positive///treated with Spiramycin x 8 ds with resolution of fever, that subsequently relapses with onset of new chest pain suggestive of pericarditis, w characteristic EKG findings and cardiomegaly on CXR //ECHO showed a large pericardial effusion without cardiac tamponade///Cardiac symptoms persisted with anti-inflammatory treatment x 10 ds and then Pyrimethamine/Sulfadiazine was given, with rapid resolution of clinical symptoms and pericardial fluid///At 3 months of f/up patient remained well Lyngberg 1992 Severe exudative pericarditis w cardiac tamponade in a F patient with SLE like musculoskeletal symptoms for the 8 preceding months; with relapsing pericarditis despite 2 anti-Toxoplasma treatment courses with Pyrimethamine/Sulfadiazine (x 3 wks and 7 wks respectively)//61-yr-old immunocompetent woman (HIV negative) from Denmark who presented with SLE like symptoms (synovitis R knee, bursitis, finger stiffness and generalized malaise, myalgias, and weight loss (not responding to 8 months treatment with NSAIDS and Sulfasalazine)///Toxoplasmosis reactivation was suspected based on high Toxoplasma IgG, Toxoplasma IgM Negative// treatment with pyrimethamine/Sulfadiazine given x 3 wks//1 wk after the end of the anti-Toxoplasma treatment there was relapse with worsening clinical symptoms, dyspnea, pericarditis symptoms (patient refused further treatment) and pericarditis progressed to cardiac tamponade; Cardiomegaly in CXR and pericarditis EKG findings//ECHO showed severe exudative pericarditis with normal myocardium//Pericardial fluid was Toxoplasma POSITIVE (Mice sub-inoculation with pericardial fluid was positive and mice died from Toxoplasmosis)///Pericardiocentesis showed marked leukocytosis// treated with Pyrimethamine/Sulfadiazine + Prednisone (after the cardiac tamponade had already occurred) x 7 weeks and cardiac symptoms gradual resolved////2 months after the 7 wks anti-Toxoplasma treatment there was another relapse of Symptoms that was treated again with anti-Toxoplasma treatment x 4 wks of P/S and clinical condition improved again with resolution of the SLE like symptoms and decrease in the ANA//Patient remained well at 9 months follow up. (diagnosis in patients with Rheumatic mimicking disease may be delayed, and false positive Toxoplasma IgG and IgM results in patients with ANA antibodies have been described. Patients with SLE should be screened for Toxoplasmosis)

Shimoni 1989
Pneumonitis with pulmonary infiltrate in right upper lobe//in a 51-yr-old immunocompetent man (HIV negative) living in Israel with inactive RA + (treated only with indomethacin, without any steroids or immunosuppressive medications), who presented with a 2 wk Hx of generalized LADP and RUL pneumonia, not responding to Amoxicillin//Toxoplasma Dye test positive and Toxoplasma IgM positive//His general condition otherwise was excellent//Was D/C home on TMP/SMX and at 2 mo f/up was clinically asymptomatic, with resolution of CXR findings//At 1 yr f/up patient continued to remain healthy Rafiqul Islam 1989 FUO (low grade Fever 100-1011) and malaise x 5 months and lymphadenopathy///(in a 17-yr-old immunocompetent male from Bangladesh//with 5 months of FUO, malaise and generalized LADP, thrombocytopenia //Strongly positive Latex Agglutination test for Toxoplasmosis (no known risk factors for toxoplasmosis)//LN biopsy suggestive of toxoplasmic lymphadenitis//With Response to anti-Toxoplasma treatment (P/S x4 wks) with resolution of fever and disappearance of LADP)//(not known risk factors for toxoplasmosis reported) Table A8. Cont.

Vignettes of Severe Toxoplasmosis Cases
Oseroff 1988 Fever, polymyositis, myocarditis, hepatitis, nephrotic syndrome and transaminitis//in a 48-yr-old woman with high fever (that lasted x 6 weeks), dyspnea, generalized myalgias, muscle weakness, N/V/D and pitting edema in extremities; with leukocytosis (WBC = 35K); eosinophilia (548-> 1500/mm3), transaminitis, Elevated CPK, with high MB fraction, elevated LDH and elevated inflammatory markers (ESR = 70 mmHg)///Subsequently developed non cardiogenic pulmonary edema (with large proteinuria) requiring IMV//Fever persisted x 6 weeks; Chest CT and Gallium scan were normal////Toxoplasma serology showed rising Toxoplasma IgG titers over a 3 month period//By the time the Toxoplasmosis diagnosis was made, patient was already clinically improving with just supportive care and NO anti-Toxoplasma treatment //No anti-Toxoplasma treatment was given//At 2 mo after D/C clinically asymptomatic

McCabe, Remington 1987
Transient R lung pneumonia with pleural effusion at the onset of the illness; with persistence of fever, LAPD and HSM for 7 months///in a 32 yr-old woman, missionary in the jungles of Venezuela, who presented with fevers, chills, malaise, myalgias, headaches and anorexia not responding to malaria treatment ///generalized LADP and HSM present//Transient R pneumonia with pleural effusion detected///ON HD45 subinocculation to mice of LN biopsy tissue was positive for Toxoplasmosis //Toxoplasma serology consistent with acute acquired Toxoplasmosis infection with high positive IgG and IgM //5 family members were also Toxoplasma positive Cottrell 1986 Encephalitis//in a 4-yr-old immunocompetent boy, living in England, with a 3 week Hx of recurrent generalized seizures, increasing in frequency and ataxia, tremor, dysarthria//Brain CT and CSF were normal; EEG showed seizure activity/ Toxoplasma IgG was positive and "subsequently" Toxoplasma IgM also became positive//Before the Toxoplasmosis results were available, child was started on Steroids and Phenobarbital with dramatic decrease in seizures and ataxia within 3 ds////At steroid tapering there was recurrence of seizures and ataxia and had continuous myoclonic jerks and was drowsy///Once Toxoplasma results became available started on Pyrimethamine/Sulfadimidine (x6 mo) with improvement within the first 2 wks of anti-Toxoplasma treatment, and then rapidly returned to normal; although some myoclonic seizures persisted until clonazepam was added///After d/c of anti-Toxoplasma treatment after 6 mo he remained well, and EEG showed improvement although some R sided predominance remained////

Michel 1986
Acute pulmonary toxoplasmosis//in a 21-yr-old immunocompetent Portuguese man living in Belgium, who presented w high fever, shivers, dry cough, myalgia, arthralgia and rash (duration not given); cervical LADP, b/l lung crackles, hepatomegaly//CXR: b/l interstitial infiltrates//Hypoxia (PaO2 52 mmHg); elevated LDH and CPK//PFTS with mild restrictive patterns//BAL with excess lymphocytes///Patient responded to treatment with Erythromycin and after 10 ds of treatment with resolution of fever and hypoxia and normalization of CXR.//With rising and highly positive Toxoplasma IgG and IgM serology (with Toxoplasma IgG from 1:1000 to 1:4000 and Toxoplasma IgM from 1/320 to 1/12(x 3 mo)//after 3 mo of anti-