CTX is among the most common opportunistic infections in patients with HIV/AIDS [3, 13]. The pathogenesis of the disease is attributed to the reactivation of the latent T. gondii infection, particularly in patients with immunocompromising conditions, such as HIV/AIDS [17]. This study investigated the prevalence, clinical course, and mortality rate of CTX in hospitalized HIV-positive patients. Our study showed a prevalence of 4% for toxoplasmosis and 2.17% for CTX among all patients with HIV/AIDS admitted over ten years to two main hospitals of Shiraz University of Medical Sciences. In 2007, Davarpanah et al. reported the seroprevalence of toxoplasmosis among patients with HIV/AIDS at 18.2% in Shiraz [15]. Additionally, the authors addressed a 10.4% prevalence of CTX in these patients. The relatively smaller sample size and the shorter period of the study by Davarpanah et al. may partly explain the differences between the findings of these two studies. However, the most important difference is that our study was focused on hospitalized patients with HIV/AIDS, while in the study by Davarpanah et al., the patients were included from an outpatient setting.
Although several previous studies did not address this [3, 15, 18,19,20], our findings revealed a significantly higher prevalence of both toxoplasmosis (as a clinical cause for hospitalization) and CTX among HIV-positive females compared to HIV-positive males (4.32% vs. 1.59% and 7.03% vs. 3.18%, respectively). Previous research has highlighted the seroprevalence of toxoplasmosis among men and women with HIV/AIDS [21, 22]; however, our study focused on toxoplasmosis as a clinical diagnosis that necessitated hospital admission, rather than mere seropositivity. This distinction may explain the discrepancy in prevalence between our study and others. Thus, future systematic reviews and meta-analyses are needed to provide a more comprehensive and reliable conclusion.
An important finding of our study was that more than half (57.89%) of the CTX patients were newly diagnosed with HIV infection. This aligns with findings from a case series study in Brazil, where CTX was reported as the first manifestation of HIV infection in 48.21% of patients [20]. Our study further revealed that the odds of developing CTX in HIV-positive patients increased as age decreased. Additionally, the mean age of CTX patients was 36.13 ± 9.20 years, compared to 40.25 ± 11.30 years in patients with a prior HIV diagnosis. Although the small sample size within these two subgroups limits the reliability of statistical analysis, these observations highlight the need for effective HIV screening programs, targeting at-risk young adults. Furthermore, similar to previous studies [8], the four most common symptoms among our patients were FND, decreased LOC, headache, and fever. Although with such symptoms, other differential diagnoses, such as brain stroke, encephalitis, meningitis, or bacterial brain abscess are at the top of the differential diagnosis list, special consideration should be given to HIV infection and CTX, particularly in young adults who are not previously diagnosed with HIV infection.
Brain MRI is a more sensitive tool for diagnosing CTX lesions [8]; however, brain CT scans are more widely available as an initial imaging modality. The typical appearance of CTX lesions in brain CT scans may consist of ring-enhanced lesions with peripheral vasogenic edema and mass effect, particularly in basal ganglia and frontal and parietal lobes. In the brain MRI, typical lesions may appear as “eccentric target sign”, with an enhanced eccentric core and hypointense intermediate zones, surrounded by a hyperintense enhanced rim in a T1-weighted image. The lesions in T2-weighted MRI images are seen as “concentric target sign” with a concentric zone of hypo and hyperintensity [8, 23]. There are few case reports on unusual radiological findings of CTX, such as multiple hemorrhagic abscess lesions and diffuse white matter involvement with ependymal enhancement [24, 25]. Along with related neurological symptoms and physical exam findings, all of our patients underwent neuroimaging. While all of the patients had evidence of single or multiple brain lesions, in only eight initial imaging reports (42.11%), CTX was listed as a probable differential diagnosis by radiologists. Additionally, in six patients (31.58%), lymphoma/malignancies were reported as a suspected diagnosis.
The suspicion of CTX is primarily based on a compatible clinical history, physical examination, neuroimaging findings, and serological evidence. Moreover, a positive radiological response to anti-Toxoplasma treatment also augments the primary diagnosis. A useful classification for diagnosing CTX has been proposed by Dian et al [7]. The four categories include histology- and laboratory-confirmed CTX, as well as probable and possible CTX. Histology- and laboratory-confirmed CTX require a compatible clinical syndrome, the presence of lesions in neuroimaging plus evidence of T. gondii tachyzoites in brain biopsy or its DNA in CSF-PCR, respectively. Probable CTX consists of a compatible clinical syndrome, presence of lesions in neuroimaging, and anti-Toxoplasma IgG seropositivity or radiological improvement in response to 10-14 days of empirical treatment. Finally, possible CTX applies in cases of death or absence of radiologic confirmation. We demonstrated that CTX was confirmed in the majority of the cases based on imaging and serological workups; however, in seven patients (36.84%) CSF analysis or brain biopsy (or both) was performed, probably due to a high suspicion for other diagnoses, such as lymphoma, or fungal and mycobacterial infections. In other words, our CTX cases were mostly (89.47%) diagnosed using probable CTX classification, that is, they were diagnosed based on compatible clinical presentation, presence of radiological lesions, and anti-T. gondii IgG seropositivity. However, only two patients could be labeled as histology- and laboratory-confirmed CTX, who had positive brain biopsy and CSF-PCR results for T. gondii.
Interestingly, one of our patients was seronegative for T. gondii IgG, and the diagnosis was established based on radiological findings and clinical improvement following anti-Toxoplasma therapy. This observation aligns with previous reports indicating that a small but significant subset of patients with CTX may be IgG seronegative [26]. Additionally, we encountered another patient who presented with clinical features consistent with CTX and was seropositive for both IgG and IgM antibodies. The diagnosis was further confirmed by a positive brain biopsy and CSF-PCR for T. gondii. This case may reflect a primary infection leading to CTX, particularly in light of the patient’s markedly low CD4+ T-cell count (50 cells/μL). However, given the rarity of primary T. gondii infections among patients with CTX [27], a false-positive IgM result cannot be ruled out. A much less likely possibility is reinfection with a different strain of T. gondii [4, 28].
A three-drug regimen of pyrimethamine (50 mg/day), sulfadiazine (4 g/day), and folinic acid (25 mg/day) for six weeks is the most effective and preferred treatment for CTX in patients with HIV/AIDS [8, 29]. In our study, all nineteen patients were treated with three-drug anti-Toxoplasma regimens during hospitalization. Some studies have shown that TMP-SMX could be as effective as pyrimethamine-sulfadiazine in curative treatment. Moreover, TMP-SMX prophylaxis is recommended for Patients with HIV/AIDS with a CD4+ count of less than 200 cells/µL. Thus, in low- and middle-income counties, where pyrimethamine is unavailable or expensive, TMP-SMX is a good choice for induction and maintenance treatment. It has been shown that TMP-SMX has fewer toxic or adverse reaction, less cost, and is better tolerated by patients compared to pyrimethamine-sulfadiazine [6, 7, 30,31,32]. In our study, TMP/SMX was added to the treatment of nine patients who had CD4+ counts less than 100 cells/µL. Clindamycin plus pyrimethamine is a reasonable alternative for sulfadiazine in patients with an allergy to sulfadiazine [8]. Additionally, TMP/SMX and clindamycin were replaced with sulfadiazine in one patient due to a new onset drug allergy to sulfadiazine and in another patient due to the temporary unavailability of pyrimethamine and sulfadiazine. Discontinuing maintenance therapy could be considered based on the clinical improvements and in patients with CD4+ above 200 cells/µL who received cART for at least 6 months on maintenance treatment [6].
We showed an in-hospital mortality rate of 21.05% in patients with CTX. A prospective study of 55 HIV+/AIDS patients with CTX in Brazil, showed that after 6 weeks of treatment, 42% and 46% of patients had complete and partial response to therapy, respectively, while 13% died [18]. Two other similar studies in Taiwan and Mali also reported 16.7% (3 out of 18) and 15.4% (4 out of 26) mortality rates, respectively [33, 34]. It should be noted that various factors affect the prognosis and mortality rates of CTX, and thus they may explain the observed differences between studies. First, the number of included patients with CTX in studies is usually few and the calculated mortality rates might not represent the actual population. Second, in our study, all four dead patients were brought to the hospital with decreased LOC, indicating the severity and progression of the disease. In addition, the age, comorbid conditions, and timing of treatment initiation are not the same among the studies. Three of our deceased patients suffered from other comorbid infections, including hepatitis C virus (HCV) infection, and one had concomitant pulmonary TB. Finally, all of these four patients did not receive cART within the first two weeks of CTX diagnosis. According to our findings, six patients who had CD4+ counts below 100 cells/µL received cART. It has been shown that early initiation of cART within two weeks of anti-Toxoplasma therapy could significantly reduce the mortality of CTX and improve its prognosis [8, 18, 20]. For example, a study in Brazil showed a significant reduction in mortality rates from over 90% in the pre-cART era to less than 30% in recent years with cART [19].
It is important to note that our study has several limitations. The findings could be influenced by various confounding factors, including limited access to detailed clinical and paraclinical data due to the study’s retrospective design. Improving medical record management during admission and archiving would enhance the accuracy and completeness of future data analysis and research. Despite the ten-year duration of our study, the relatively low prevalence of CTX may have affected the statistical analyses, potentially limiting the generalizability of the results and reducing the statistical power to detect significant associations. Finally, the patients were recruited from two referral hospitals of Shiraz University of Medical Sciences, which may not fully represent the outpatient population. Thus, a potential selection bias from including patients from tertiary referral hospitals may have impacted the results, as these institutions typically manage more severe or complex cases. Future studies with larger sample sizes and more diverse clinical settings could help address these limitations and provide more robust conclusions.
