Global and Regional Prevalence and Burden of Latent and Acute Toxoplasmosis in People Living With HIV: an Updated Systematic Review and Meta-analysis

Abstract

Background: Toxoplasma gondii infection is one of the most prevalent opportunistic and life-threatening infections in people living with HIV (PLWH). Here, we undertook a meta-analysis to estimate the global prevalence of latent (LT) and acute (AT) toxoplasmosis in PLWH.

Methods: Eligible studies reporting the prevalence of LT or AT in PLWH were searched from January 1980 to July 2020, using PubMed/MEDLINE, Scopus, Web of Sciences, SciELO and Embase databases. We used a random effects model to calculate pooled prevalence estimates with 95% confidence intervals (CI) and evaluated overall burden of co-infection worldwide. Countries were categorised based on World Health Organization regions. Multiple subgroup and meta-regression analyses were performed.

Results: From 4,024 studies identified, 150 (involving 44,473 PLWH) and 65 (involving 17,705 PLWH) studies met the inclusion criteria, for LT and AT in PLWH, respectively. The overall prevalence rates of LT and AT in PLWH were 37.4% (95% CI, 33.4–4.4) and 1.3% (95%CI, 0.9–1.8%), respectively. We estimated that, worldwide, approximately 14.2 and 0.5 million PLWH are affected by LT and AT, respectively. The highest and lowest burden of LT and AT were seen in the African and Western Pacific regions, respectively. Moreover prevalence rates were highest in countries with low levels of income and human development indexes. We indicated that eating raw/undercooked meat, frequent contact with soil, low numbers of CD4+ T lymphocytes and older age were significant risk factors of toxoplasmosis in PLWH.

Conclusion: Our findings revealed that, a high number of PLWH are exposed to or infected with T. gondii. These findings suggest a need for more routine testing, care of, and treatment for T. gondii infection in all PLWH, and educating these patients about risk factors and preventive measures to reduce the burden of both latent and acute toxoplasmosis.

Introduction

Toxoplasma gondii infection or toxoplasmosis is one of the most prevalent opportunistic and life-threatening infections in people living with human immunodeficiency virus (PLWH) [1]. Toxoplasmic encephalitis (TE) is the second most common opportunistic infection of the central nervous system in PLWH, especially in patients with CD4 + T lymphocyte counts less than 200 cells per µL [2, 3]. In addition toxoplasmosis in PLWH can be a cause of other neurological symptoms (including epilepsy, disorientation, headache, drowsiness and hemiparesis,) and can result in clinical symptoms such as disseminated infection, pneumonitis, and retinochoroiditis [4, 5].

Primary T. gondii infection is acquired by ingestion of sporulated oocysts present in contaminated soil, water, and on contaminated fruits and vegetables; by ingestion of infectious stages in raw or undercooked meat from infected animals; by vertical transmission from an infected mother to the fetus; and rarely by blood transfusion or organ transplantation [6, 7, 8, 9, 10, 11]. Primary toxoplasmosis in PLWH can result in severe clinical symptoms, because overall antibody production in these patients is decreased due to immunodeficiency [12]. More commonly in PLWH, clinical toxoplasmosis results from the reactivation of a latent infection [5].

Generally detection of IgG antibodies to T. gondii indicates latent toxoplasmosis (LT); whereas the presence of anti-Toxoplasma IgG combined with detection of specific IgM, detection of low avidity serum anti-Toxoplasma IgG antibodies, or seroconversion from IgG negative to IgG positive status sequential tests could be marker of acute toxoplasmosis (AT) [10, 13, 14].

Estimating the burden of opportunistic infections and assessment of the related risk factors for PLWH will help to establish parameters for the effective use of specific prophylaxis [15]. Previous efforts to quantify toxoplasmosis in PLWH were limited to specific countries, geographical regions, or single-year estimates. One previous meta-analysis [14], included studies up to 2016 and estimated only LT, not AT, in PLWH; further it did not assess risk factors related to toxoplasmosis and prevalence. In the present study, we performed an updated systematic review of observational studies to better understand the epidemiology toxoplasmosis in PLWH at the global, regional, and national levels. The specific aims of this study were to: (1) estimate the prevalence and burden of LT in PLWH; (2) estimate the prevalence and burden of AT in PLWH; (3) evaluate the prevalence of latent and acute toxoplasmosis in PLWH based to socio-economic variables; (4) determine the change in prevalence rates over time; (5) estimate the prevalence of LT in PLWH in relation to CD4 + cell counts; and (6) determine associated risk factors of Toxoplasma infection in PLWH.

Methods

We followed the recommendations established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to perform this study [16]. All procedures including the literature search, assessing full texts, quality appraisal and data extraction were performed independently by trained researchers. Disagreements were resolved by discussion with the senior author (A.R.) and consensus.

Search strategy and selection criteria

A systematic review of the literature was performed using PubMed/MEDLINE, Scopus, Web of Sciences, SciELO and Embase to identify all peer-reviewed articles reporting data on the prevalence of LT or AT in PLWH from January 1980 to July 2020, without language and geographical restriction. We used relevant keywords for searching the databases (S1 Fig). The search strategy was discussed with a medical librarian for optimal inclusion sensitivity. To identify gray literature and missing studies, we searched Google Scholar database and also checked the reference list retrieved papers and relevant reviews. Inclusion criteria were: (i) observational studies that had data to estimate the prevalence of LT or AT in PLWH; (ii) studies that had sample size of more than 30 individuals; and (iii) studies that used serological assays to detect specific anti-Toxoplasma antibodies or antigens. Note that in case-control studies, data were extracted only for PLWH (i.e. cases). We excluded studies if they not meet the criteria; if they were not representative of the general population with HIV infection (e.g., patients with encephalitis especially whose with TE, psychiatric patients and drug users); if the diagnostic methods were unclear or used molecular assays; were comparative studies of diagnostic methods; if they included overlapping participation in multiple studies; or were experimental studies, if they were case-reports, case-series, reviews, systematic reviews or meta-analyses. With regard to AT, we applied definitions of acute toxoplasmosis [10], including: (a) low IgG avidity; (b) Toxoplasma seropositivity for both IgG and IgM, or (c) seroconversion from a Toxoplasma IgG negative status to an IgG positive status.

Data extraction and quality assessment

We extracted the following variables from each study: first author’s name, country, city, year of publication, study design, the number of participants, number of PLWH seropositive for LT or AT, and the type of diagnostic methods. Countries were grouped according to the WHO-defined regions [17], per capita income [18] and the human development index [HDI] [19]. Moreover, we extracted patient data on the number of CD4+ T cells (<200, 200-500, and > 500 cells/μL) and number of patients in distinct age groups (<20, 20–40, 41–60, >60), if available. In order to identify associated risk factors for toxoplasmosis in PLWH, we extracted data including place of residence (urban/rural), gender (male or female), close contact with dogs or cats, contact with soil, consumption of raw/undercooked meat, consumption of raw/unwashed vegetables, and drinking untreated water. To evaluate the methodological quality of included studies, we used the JBI (Joanna Briggs Institute) Prevalence Critical Appraisal Tool, as described by Munn et al [20].

Statistical analysis

Analyses were performed using Stata statistical software (v.16 Stata Corp., College Station, TX, USA). For each individual study, the prevalence rate was defined as the number of PLWH with LT or AT divided by the total number of PLWH screened. We used the variance of the study-specific prevalence estimates with the Freeman-Tukey double arcsine transformation before pooling the data using the DerSimonian-Laird random-effects meta-analysis model to minimise the effect of studies with extremely small or extremely large prevalence [21, 22]. The random-effects model was selected in anticipation of substantial variation in prevalence estimates of LT or AT across the included studies [23]. The between-studies heterogeneity was evaluated by Cochran’s Q test and I² index. I² values of 25%, 50% and 75% represented low, medium and substantial heterogeneity, respectively [24]. To explore potential drivers of heterogeneity, several subgroup and meta-regression analyses were performed considering the following study features: (i) WHO region, (ii country, (iii) type of diagnostic method, (iv) type of study design, (v) country income level, and (vi) country HDI level. Moreover, to calculate the global burden of LT and AT in PLWH, we followed the method used in the most recently published meta-analysis on this subject [14] and used data from WHO showing the number of PLWH in 2018 [25]. We then multiplied this number by our calculated percentages of PLWH with LT or AT (with a 95% CI) at the global and national levels. We did not undertake an assessment of publication bias, as it is not relevant for prevalence studies [26]. A P value < 0.0 5 was considered statistically significant.

Results

Study characteristics

From 4024 citations, 150 studies (155 datasets), involving 44,473 PLWH, met the inclusion criteria for eligibility in a quantitative analysis of the prevalence of HIV–LT co-infection. Moreover, 65 studies, involving 17,705 PLWH, had data for HIV-AT co-infection (S2 Fig). Considering WHO regions, most studies were from Africa (45 for LT and 15 for AT), then the Eastern Mediterranean (23 for LT and 15 for AT); the fewest were in South America (nine for LT and four for AT). Supplementary Table 1 summarizes the characteristics of, and references to, included studies as well as geographic location of each.

Global prevalence of LT in PLWH

For the 155 data sets in 49 countries, 14,913 of 44,473 PLWH were diagnosed as having LT, resulting in an overall, pooled global prevalence of 37.4% (95% CI, 33.4–4.4) (Table 1; Fig. 1A), with evidence of heterogeneity among studies (I² = 98.7%, P < 0.001). In WHO-regions, the pooled prevalences (in descending order, with a 95% CI) were 46.2% (37.7–54.7%) in Africa, 46.2% (29.6–62.6%) in South America, 45.8% (36.3–55.5%) in the Eastern Mediterranean region, 41.1% (33.0–49.4%) in Europe, 29.9% (22.0–38.3%) in South-East Asia, 25.5% (19.2–32.4%) in North America and 18.4% (12.4–25.3%) in the Western Pacific. For countries with two or more eligible studies, Ethiopia (80.5%), Ghana (70.6%), and Cameroon (54.5%) in Africa; Iran (45.7%) in the Middle East; France (72.5%) and Austria (57.3%) in Europe; Brazil (48.8%) in America and Indonesia (38.5%), Thailand (37.5%) and Malaysia (36.1%) in East Asia exhibited some of the highest seroprevalence rates (Table 1 and Fig. 1A). Moreover, we estimated that approximately 14,174,600 (12,658,600–15,690,600) PLWH worldwide were seropositive for LT. Our estimates demonstrated that countries in the African region, which has a large proportion of PLWH, also has the largest number of people with LT 11,873,400 (9,688,900–14,057,900), accounting for approximately 84% of cases of HIV-LT coinfection worldwide. Additional details pertaining to the prevalence and burden of LT in PLWH in WHO-regions and individual countries are given in Table 1 and Fig. 1A.

Subgroup and meta-regression analyses according to socio-demographic and study characteristics

In subgroup analyses, with respect to income level and HDI, the highest prevalence of LT was in low-income countries (58.2%, 46.2–69.8%) and the lowest prevalence was in high-income countries (28.0%, 21.3–35.2%). The pooled prevalence of LT in PLWH in countries with low, medium, high and very high levels of HDI were 51.9% (42.8–60.8%), 29.3% (20.9–38.4%), 38.0% (22.6–33.1%), and 27.6% (22.6–33.1%), respectively (Table 2). Meta-regression analyses revealed a significant decreasing trend in prevalence in countries with increasing per capita income (C = -2.97^e − 06; P-value = 0.004) and HDI levels (C = -0.473; P-value < 0.001) (Fig. 2A and B). Studies that were performed after 2005 showed slightly higher prevalence rates than other periods, although this increasing trend (1980–2020) was non-significant in meta-regression analysis (C = 0.0016; P value = 0.46) (Table 2 and Fig. 2C). In subgroup analyses, according to type of study, the highest and lowest prevalence rates were estimated in case-control (40.4%, 30.7–50.6%) and retrospective cohorts (26.5%, 17.1–37.2%), respectively. Subgroup analysis based on diagnostic methods revealed the lowest (30.5%, 14.9–48.9%) and highest (57.2%, 47.0–67.1%) prevalences in studies that used the Sabin-Feldman (SFT) and immunofluorescence (IFAT) methods, respectively. The prevalence rate in studies using ELISA, the most commonly used method, was 35.5% (31.1–40.1%). More subgroup analyses and details are given in Table 2. With respect to age, prevalence rates of LT in PLWH < 20, 20–40, 40–60 and > 60 years were (13.8%, 11.8–15.7%), (39.5%, 38.7–40.4%), (46.3%, 44.9–47.7%) and (43.7%, 37.1–50.3%), respectively (Table 3). With respect to the number of CD4 + lymphocytes in patients, prevalence rates of LT in PLWH with CD4 + counts of < 200, 200–500 and > 500 were (18.4%, 16.8–20.0%), (33.8%, 32.6–34.9%) and (21.9%, 20.5–23.3%), respectively (Table 3).

Risk factors for prevalence of latent Toxoplasmosis

With respect to risk factors associated with LT, our results showed that PLWH who consumed raw/undercooked meat (Odds Ratio [OR], 2.01; 95% CI, 1.19–3.9) and those who were in frequent contact with soil (OR, 3.01; 95% CI, 1.5–6.04) were more likely to be seropositive compared with other PLWH (S3 and S4 Figs). Moreover prevalence rates with significantly higher in PLWH who were older in age and had lower CD4 + lymphocyte counts. PLWH in ages 20–40 (OR, 1.63; 95% CI, 1.15–2.61), 40–60 (OR, 2.49; 95% CI, 1.62–3.82) and > 60 (OR, 2.39; 95% CI, 1.56–3.66) (S5-7 Figs) and those with number of CD4 200–500 (OR, 1.71; 95% CI, 1.08–2.72) and lower than 200 (OR, 1.04; 95% CI, 0.79–1.37) were more likely to be seropositive as compared with other PLWH (S8-9 Figs). With respect to other risk factors associated with LT, our results showed that female patients, those who lived in rural areas, those who were cat or dog owners, and those who consumed raw/unwashed vegetables or consumed untreated water were at more, but non-significant greater, risk to acquire infection. More details are given in Table 3 and S10-15 Figs. In Egger’s test we did not identify any significant publication bias (Table 3).

Global prevalence of acute Toxoplasmosis

The global prevalence of AT in PLWH, when data for all 65 datasets representing 32 countries were pooled, was 1.3% (95%CI, 0.9–1.8%; 289/17,705). The heterogeneity between studies was significant (I² = 79.1%, P < 0.001). With respect to WHO-epidemiological regions, the highest prevalence rates were found in South America (2.0%; 0.1–5.4%), and then the Eastern Mediterranean region (1.8%; 0.7–3.3%), and the lowest prevalence rate was found in the European region (0.6%; 0.2–1.3%). The pooled prevalence rates in other WHO regions were: 1.6% (0.5–3.1%) in North America, 1.3% (0.9–1.8%) in South-East Asia, 1.2% (0.2–2.6%) in the Western Pacific and 0.9% (0.2–1.2%) in Africa (Table 4 and Fig. 1B). Moreover, we estimated that approximately 492,700 (341,100–682,200) PLWH worldwide were affected by AT. Our estimates demonstrated that countries in the African region, has the largest number of PLWH with AT (231,300; 51,400–308,400), accounting for approximately 47% of cases of HIV-AT co-infection worldwide. Additional details pertaining to the prevalence and burden of AT in PLWH in WHO-regions and individual countries are given in Table 4 and Fig. 1B.

Subgroup and meta-regression analyses according to socio-demographic and study characteristics

In subgroup analyses, when the pooled prevalence was stratified according to the income-level of a country, the highest prevalence rates of AT were estimated for countries with lower-middle income-levels (1.8%, 0.7–3.2%) and the lowest for those with low income-levels (0.4%, 0.0–1.9%). Based on HDI level, the highest prevalence rates were seen in countries with low HDI-levels (1.4%, 0.1–1.3%) and the lowest prevalence rates in countries with high HDI-levels (1.3%, 0.7–2.0%) (Table 2). Moreover meta-regression analyses revealed a non-significant decreasing trend in prevalence in countries with increasing per capita income (C = -0.00082; P-value = 0.88) and HDI levels (C = -0.0056; P-value = 0.92) in a country (Fig. 2D and E). Sub-group analysis on year of study showed higher prevalence rates after 2010. This increasing trend was non-significant in meta-regression analysis (C = 0.0002; P-value = 0.7) (Fig. 2F). In subgroup analyses, according to type of study, the highest prevalence rates were estimated in the case-control (2.6%, 0.8–5.0%), and then in prospective cohort (2.6%, 0.8–5.0%) studies, and the lowest prevalence rates were estimated in retrospective cohorts (1.0%, 0.3–2.0%). Subgroup analysis based on diagnostic methods showed that prevalence rates were similar when studies used both IgG-IgM tests (1.2%, 0.7–1.8%) and seroconversion (1.2%, 0.8–1.7%). More subgroup analyses and details are given in Table 2.

Discussion

This systematic review and meta-analysis is the first global assessment of the prevalence of AT and the most comprehensive assessment of the prevalence of LT among HIV-infected people. Our findings highlight the high prevalence and burden of LT (37.4%, approximately 14.2 million people) and AT (1.3%, approximately 0.5 million people) in PLWH. Estimates reported here are similar to the prevalence rates for LT and AT observed in recent meta-analyses that we have conducted among pregnant women [10, 11], and also corroborate a general assumption that one-third of humans are infected with Toxoplasma [27]. Our estimate for LT (37.4%) is slightly higher than a previous meta-analysis by Wang et al. (35.8%) in the same population [14], although they included only 74 studies (49% of those included in our meta-analysis) and 25,989 HIV-infected people (approximately 58% of individuals in our meta-analysis) [14].

In the present study, the overall prevalence and burden of LT and AT varied across regions, with the highest prevalence in African and South-American countries and the lowest prevalence in the Western Pacific region. These findings are in agreement with previous global studies in pregnant women [10, 11]. In a study by Wang et al. among PLWH, the prevalence of LT was highest in countries located at sub-Saharan Africa, Latin America and the Caribbean regions [14]. The variability in prevalence in these different regions could be related to differences in climate (e.g. temperature and humidity) [10, 28], the degree of contamination of the environment (e.g., soil and water) with cat feces and T. gondii oocysts, cultural or culinary habits, particularly the consumption of semi-cooked or raw meat [7, 9], infectivity of the diversity of T. gondii genotypes present, accessibility to public health and sanitary services, control measures for stray cats, income and HDI status of a country [10, 11]. A detailed explanation about effects of these variables on the prevalence of toxoplasmosis in different populations is available in previous publications [10, 11, 27].

Considering risk factors for exposure to T. gondii, our analyses found that eating raw/undercooked meat, frequent contact with soil, older age, and low number of CD4 + lymphocytes were associated with increased seropositivity for LT. The risk factors for acquisition of toxoplasmosis are well documented and have been reviewed in previous studies [29, 30, 31, 32, 33]. Consumption of raw/undercooked meat is assumed to be a major source of T. gondii infection, however, as a risk factor, this depends on the kind of meat consumed and local culinary habits of meat preparation; for example in China who used duck and beef meat had higher seropositivity for T. gondii infection compared to those who used other kinds of meat including pork, lamb and chicken [34]. Lamb and pork are major dietary risk factors in European and American countries and lamb is a major risk factor in Middle Eastern countries [30, 31, 35, 36]. Contact with soil is an important source of exposure to infectious oocysts [37, 38, 39, 40, 41, 42, 43, 44, 45, 46]. We identified an increasing prevalence with age, which can be explained by the fact that risk of Toxoplasma infection is constant over time and older PLWH have had a longer period of time for exposure to Toxoplasma [7, 47]. This observation is in agreement with our previous study in pregnant women [11]. Our findings indicated that another, and maybe most important risk factor for toxoplasmosis in PLWH, is a low number of CD4 + lymphocytes. It is well known that decline in CD4 + T cells is the main reason for reactivation of latent infection in PLWH and can lead to severe toxoplasmosis and TE in these patients [48, 49].

The findings from this study must be interpreted in consideration of certain limitations. First, and common to systematic reviews, we found a high statistical heterogeneity between studies, which could not be explained by the subgroup and meta-regression analyses; the major sources of heterogeneity might result from the study characteristics including differences in study design, geographical distribution, sample size, publication year, and detection methods, including differences in the performance of these methods and differences in cut-off values for test-positivity. Second, most studies in the literature have used serological methods to detect latent or acute toxoplasmosis in PLWH; serological methods are unreliable in PLWH due to profound immunodeficiency. While bioassays (in mice or cats) are considered as the gold standard for the definitive diagnosis of toxoplasmosis, these methods are not applicable in humans. Moreover due to variation in the sensitivity and specificity (and, thus, positive and negative predictive values) of serological methods, the findings from the present study might underestimate or overestimate the prevalence of latent or active toxoplasmosis in PLWH. In addition our estimates of acute toxoplasmosis might not be the true prevalence, since relatively few studies were included; we did not include studies using data on DNA, due to a paucity of such data and the fact that the majority of molecular studies were done in HIV patients suspected to TE or pulmonary toxoplasmosis. Thus, the estimated rates reported here must be considered as apparent prevalence rates of latent or acute toxoplasmosis in PLWH. We lastly acknowledge that despite our comprehensive systematic search, the eligible studies and data were not available for many countries and some regions of the world were not appropriately covered, which may hinder the translatability of our results at a global scale.

Conclusion

In conclusion, our findings revealed that, globally, more than one third of PLWH are exposed to, or infected with. Toxoplasma. International guidelines recommend toxoplasmosis screening for all PLWH and also prophylactic measures (e.g. co-trimoxazole) should be implemented for all T. gondii-seropositive PLWH with < 100 CD4 + cells/µL. This approach is currently not well implemented in many countries.

In our study, the prevalence rates was higher in less developed countries and regions; therefore these countries, in particular, should promote routine testing, care, and treatment for T. gondii infection in all PLWH.

We also determined potential risk factors related to toxoplasosis in PLWH. T. gondii-seronegative PLWH should be aware and educated about these risk factors and related preventive measures to reduce the risk of health problems arising from both latent and acute toxoplasmosis.

Declarations

Compliance with ethical standards

Acknowledgements

Sincere thanks to Malihe Nourollahpour Shiadeh for critical reading of the manuscript and comments.

Funding

This research received no specific grant from any funding agency, commercial or non-profit

Conflict interest

The authors declare no conflict of interest.

Ethical approval

This study was supported by the Health Research Institute at the Babol University of Medical Sciences, Babol, Iran (IR.MUBABOL.REC.1399.037).

Informed consent

not applicable

Authors' contributions

A.R., S.A.S and M.S conceived the study. A.R., A.T., and S.A.S. conducted the searches and collected data. A.R., M.S., and S.M.R. analysed and interpreted the data sets. A.R., and R.G. drafted and edited the manuscript. All authors commented on, or edited drafts and approved the final version of the manuscript.

Availability of data and material

All data are available in main manuscript and supplementary files. Further data would be provided by corresponding author if requested.

References

1. Belanger F, Derouin F, Grangeot-Keros L, Meyer L, HEMOCO, Groups SS. Incidence and risk factors of toxoplasmosis in a cohort of human immunodeficiency virus-infected patients: 1988–1995. Clinical infectious diseases. 1999;28 3:575-81.
2. Richards Jr FO, Kovacs JA, Luft BJ. Preventing toxoplasmic encephalitis in persons infected with human immunodeficiency virus. Clinical infectious diseases. 1995;21 Supplement_1:S49-S56.
3. Luft BJ, Remington JS. Toxoplasmic encephalitis in AIDS. Clinical infectious diseases. 1992;15 2:211-22.
4. Robert-Gangneux F, Dardé M-L. Epidemiology of and diagnostic strategies for toxoplasmosis. Clinical microbiology reviews. 2012;25 2:264-96.
5. Basavaraju A. Toxoplasmosis in HIV infection: an overview. Tropical parasitology. 2016;6 2:129.
6. Rostami A, Karanis P, Fallahi S. Advances in serological, imaging techniques and molecular diagnosis of Toxoplasma gondii infection. Infection. 2018;46 3:303-15.
7. Rostami A, Seyyedtabaei SJ, Aghamolaie S, Behniafar H, Lasjerdi Z, Abdolrasouli A, et al. Seroprevalence and risk factors associated with Toxoplasma gondii infection among rural communities in Northern Iran. Revista do Instituto de Medicina Tropical de São Paulo. 2016;58.
8. Foroutan M, Rostami A, Majidiani H, Riahi SM, Khazaei S, Badri M, et al. A systematic review and meta-analysis of the prevalence of toxoplasmosis in hemodialysis patients in Iran. Epidemiology and Health. 2018;40.
9. Foroutan M, Fakhri Y, Riahi SM, Ebrahimpour S, Namroodi S, Taghipour A, et al. The global seroprevalence of Toxoplasma gondii in pigs: a systematic review and meta-analysis. Veterinary parasitology. 2019;269:42-52.
10. Rostami A, Riahi SM, Contopoulos-Ioannidis DG, Gamble HR, Fakhri Y, Shiadeh MN, et al. Acute Toxoplasma infection in pregnant women worldwide: A systematic review and meta-analysis. PLoS neglected tropical diseases. 2019;13 10:e0007807.
11. Rostami A, Riahi SM, Gamble HR, Fakhri Y, Shiadeh MN, Danesh M, et al. Global prevalence of latent toxoplasmosis in pregnant women: a systematic review and meta-analysis. Clinical Microbiology and Infection. 2020;26 6:673-83.
12. Gazzinelli RT, Hartley J, Fredrickson T, Chattopadhyay S, Sher A, Morse Hd. Opportunistic infections and retrovirus-induced immunodeficiency: studies of acute and chronic infections with Toxoplasma gondii in mice infected with LP-BM5 murine leukemia viruses. Infection and immunity. 1992;60 10:4394-401.
13. Dzitko K, Staczek P, Gatkowska J, Dlugonska H. Toxoplasma gondii: serological recognition of reinfection. Experimental parasitology. 2006;112 2:134-7.
14. Wang Z-D, Wang S-C, Liu H-H, Ma H-Y, Li Z-Y, Wei F, et al. Prevalence and burden of Toxoplasma gondii infection in HIV-infected people: a systematic review and meta-analysis. The Lancet HIV. 2017;4 4:e177-e88.
15. Kaplan JE, Benson C, Holmes KK, Brooks JT, Pau A, Masur H, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents. MMWR Recomm Rep. 2009;58 4:1-207.
16. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Systematic reviews. 2015;4 1:1.
17. Organization WH. List of Member States by WHO region and mortality stratum [Internet]. World Health Organization. 2017.
18. World Bank Group database. [Accessed June 2020]. Available from: https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-world-bank-country-and-lending-groups.
19. United Nations Development Program. [Accessed June 2019]. Available from: http://hdr.undp.org/en/composite/HDI.
20. Munn Z, Moola S, Riitano D, Lisy K. The development of a critical appraisal tool for use in systematic reviews addressing questions of prevalence. International journal of health policy and management. 2014;3 3:123.
21. Barendregt JJ, Doi SA, Lee YY, Norman RE, Vos T. Meta-analysis of prevalence. J Epidemiol Community Health. 2013;67 11:974-8.
22. DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled clinical trials. 1986;7 3:177-88.
23. DerSimonian R, Kacker R. Random-effects model for meta-analysis of clinical trials: an update. Contemporary clinical trials. 2007;28 2:105-14.
24. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta‐analysis. Statistics in medicine. 2002;21 11:1539-58.
25. World Health Organization (WHO). Number of people (all ages) living with HIV. Available at https://apps.who.int/gho/data/view.main.22100?lang=en.
26. Hunter JP, Saratzis A, Sutton AJ, Boucher RH, Sayers RD, Bown MJ. In meta-analyses of proportion studies, funnel plots were found to be an inaccurate method of assessing publication bias. Journal of clinical epidemiology. 2014;67 8:897-903.
27. Hill D, Dubey J. Toxoplasma gondii: transmission, diagnosis and prevention. Clinical microbiology and infection. 2002;8 10:634-40.
28. Dubey J. Toxoplasma gondii oocyst survival under defined temperatures. The Journal of parasitology. 1998:862-5.
29. Gao X-J, Zhao Z-J, He Z-H, Wang T, Yang T-B, Chen X-G, et al. Toxoplasma gondii infection in pregnant women in China. Parasitology. 2012;139 2:139-47.
30. Jones JL, Dargelas V, Roberts J, Press C, Remington JS, Montoya JG. Risk factors for Toxoplasma gondii infection in the United States. Clin Infect Dis. 2009;49 6:878-84.
31. Kapperud G, Jenum PA, Stray-Pedersen B, Melby KK, Eskild A, Eng J. Risk factors for Toxoplasma gondii infection in pregnancy: results of a prospective case-control study in Norway. Am J Epidemiol. 1996;144 4:405-12.
32. Boyer KM, Holfels E, Roizen N, Swisher C, Mack D, Remington J, et al. Risk factors for Toxoplasma gondii infection in mothers of infants with congenital toxoplasmosis: implications for prenatal management and screening. Am J Obstet Gynecol. 2005;192 2:564-71.
33. Baril L, Ancelle T, Goulet V, Thulliez P, Tirard-Fleury V, Carme B. Risk factors for Toxoplasma infection in pregnancy: a case-control study in France. Scand J Infect Dis. 1999;31 3:305-9.
34. Li M, Wu J. Toxoplasma infection among pregnant women in Zhoushan city, Zhejiang Province. Chin J Health Educ. 2002;18:734-5.
35. Cook A, Holliman R, Gilbert R, Buffolano W, Zufferey J, Petersen E, et al. Sources of toxoplasma infection in pregnant women: European multicentre case-control studyCommentary: Congenital toxoplasmosis—further thought for food. BMJ. 2000;321 7254:142-7.
36. Rostami A, Seyyedtabaei SJ, Aghamolaie S, Behniafar H, Lasjerdi Z, Abdolrasouli A, et al. Seroprevalence and risk factors associated with toxoplasma gondii infection among rural communities in northern Iran. Rev Inst Med Trop Sao Paulo. 2016;58:70.
37. Afonso E, Lemoine M, Poulle M-L, Ravat M-C, Romand S, Thulliez P, et al. Spatial distribution of soil contamination by Toxoplasma gondii in relation to cat defecation behaviour in an urban area. Int J Parasitol. 2008;38 8-9:1017-23.
38. Lass A, Pietkiewicz H, Modzelewska E, Dumètre A, Szostakowska B, Myjak P. Detection of Toxoplasma gondii oocysts in environmental soil samples using molecular methods. Eur J Clin Microbiol Infect Dis. 2009;28 6:599-605.
39. Siyadatpanah A, Tabatabaei F, Zeydi AE, Spotin A, Fallah-Omrani V, Assadi M, et al. Parasitic contamination of raw vegetables in Amol, North of Iran. Archives of Clinical Infectious Diseases. 2013;8 2:e15983.
40. Lass A, Pietkiewicz H, Szostakowska B, Myjak P. The first detection of Toxoplasma gondii DNA in environmental fruits and vegetables samples. Eur J Clin Microbiol Infect Dis. 2012;31 6:1101-8.
41. Sotiriadou I, Karanis P. Evaluation of loop-mediated isothermal amplification for detection of Toxoplasma gondii in water samples and comparative findings by polymerase chain reaction and immunofluorescence test (IFT). Diagn Microbiol Infect Dis. 2008;62 4:357-65.
42. Sroka J, Wójcik-Fatla A, Szymanska J, Dutkiewicz J, Zajac V, Zwolinski J. The occurrence of Toxoplasma gondii infection in people and animals from rural environment of Lublin region-estimate of potential role of water as a source of infection. Ann Agric Environ Med. 2010;17 1:125-32.
43. Sacks JJ, Roberto RR, Brooks NF. Toxoplasmosis infection associated with raw goat's milk. JAMA. 1982;248 14:1728-32.
44. Mancianti F, Nardoni S, D'Ascenzi C, Pedonese F, Mugnaini L, Franco F, et al. Seroprevalence, detection of DNA in blood and milk, and genotyping of Toxoplasma gondii in a goat population in Italy. Biomed Res Int. 2013;2013:905326.
45. Dubey J, Verma S, Ferreira L, Oliveira S, Cassinelli A, Ying Y, et al. Detection and survival of Toxoplasma gondii in milk and cheese from experimentally infected goats. J Food Prot. 2014;77 10:1747-53.
46. Boughattas S. Toxoplasma infection and milk consumption: Meta-analysis of assumptions and evidences. Crit Rev Food Sci Nutr. 2017;57 13:2924-33.
47. Rostami A, Keshavarz H, Shojaee S, Mohebali M, Meamar AR. Frequency of Toxoplasma gondii in HIV positive patients from West of Iran by ELISA and PCR. Iranian journal of parasitology. 2014;9 4:474.
48. Khan IA, Hwang S, Moretto M. Toxoplasma gondii: CD8 T cells cry for CD4 help. Frontiers in cellular and infection microbiology. 2019;9:136.
49. Shearer G, Bernstein D, Tung K, Via C, Redfield R, Salahuddin S, et al. A model for the selective loss of major histocompatibility complex self-restricted T cell immune responses during the development of acquired immune deficiency syndrome (AIDS). The Journal of Immunology. 1986;137 8:2514-21.