Seroprevalence of Toxoplasma gondii infection in cancer patients: A systematic review and meta-analysis

Microbial Pathogenesis 129 (2019) 30–42

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Seroprevalence of Toxoplasma gondii infection in cancer patients: A systematic review and meta-analysis

T

Davood Anvaria,b,c, Mehdi Sharifa,b, Shahabeddin Sarvia,b, Sargis A. Aghayand, Shirzad Gholamia,b, Abdol Sattar Pagheha,b,c, Seyed Abdollah Hosseinia,b,c, Reza Saberia,b,c, Tooran Nayeri Chegenia,b,c, Zahra Hosseininejada,b,c, Ahmad Daryania,b,∗ a

Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran Department of Parasitology and Mycology, School of Medicine, Mazandaran University of Medical Science, Sari, Iran c Student Research Committee, Mazandaran University of Medical Science, Sari, Iran d Laboratory of Zoology, Research Institute of Biology, Yerevan State University, Alex Manoogian 1, Yerevan, Armenia b

ARTICLE INFO

ABSTRACT

Keywords: Toxoplasmosis Toxoplasma gondii Cancer patients Systematic review Meta-analysis

Toxoplasmosis, caused by Toxoplasma gondii, is a great public health concern in cancer patients, which can induce serious pathological effects. This systematic review and meta-analysis was performed to evaluate the worldwide seroprevalence rate of T. gondii infection among cancer patients. A search was conducted on five electronic databases that reported data on T. gondii seroprevalence in cancer patients. The searching process resulted in the inclusion of 57 studies. The results showed that T. gondii had the pooled prevalence of 30.8% in cancer patients using a random-effect model (95% CI: 26.3–35.6). Cancer patients had a higher overall prevalence of T. gondii infection, compared to those without cancer. Furthermore, the odds ratio of toxoplasmosis in cancer patients was 3.1 times, compared to that of controls (95% CI: 2.5–3.8, P < 0.0001). Toxoplasmosis had a higher prevalence in females (40%) than in males (33%). Furthermore, the age group of upper 40 years had the highest prevalence infection rate (30%). In addition, a significant association was also observed between toxoplasmosis infection and year (P < 0.001), type of cancer (P < 0.001), country (P < 0.001), gender (P < 0.001), age (P = 0.006) and diagnostic method (P < 0.001) in cancer patients. Considering the high prevalence of T. gondii infection in cancer patients and its serious outcomes, the researchers are suggested to carry out further studies to prevent and control toxoplasmosis among this population.

1. Introduction Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan parasite that invades a broad variety of host cells and causes toxoplasmosis disease. This zoonotic parasite can infect all warm-blooded animals. However, based on the evidence, it infects one-third of the global human population [1,2]. The ingestion of water or food contaminated by oocysts or undercooked meat containing tissue cysts are the two major causes of T. gondii transmission [3]. In addition, this infection can be vertically transmitted to the fetus during gestation and sometimes lead to serious consequences [4]. The routine diagnosis of toxoplasmosis is most commonly made by the identification of the parasite-specific antibodies (i.e., IgG and IgM) in the serum samples of patients by means of serological techniques, such as enzyme-linked immunosorbent assay (ELISA) and

immunofluorescence antibody assay (IFA) [5]. This infection is usually asymptomatic and self-limiting in healthy humans due to the efficiency of their immune responses, especially macrophages and T-lymphocytes, which play an important role in limiting the dissemination of tachyzoites in different organs [6,7]. This parasite remains viable in form of tissue cysts in the host, especially in less immunologically active tissues, such as the central nervous system [8]. T. gondii can cause life-threatening infections, along with mild or severe complications, in immunocompromised individuals [9]. The immunocompromised hosts (e.g., patients with cancer, AIDS, and transplant recipients) have ineffective immune responses, resulting in the transition of the resting or bradyzoite stage to the active and rapidly replicating tachyzoite form, and then acute infection [10]. Cancer is one of the major causes of mortality in the world. In this

∗ Corresponding author. Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari Medical School, 18th Km of Khazar Abad Road, Sari, Iran, PC 48168-95475, Sari, Iran. E-mail address: [email protected] (A. Daryani).

https://doi.org/10.1016/j.micpath.2019.01.040 Received 15 November 2018; Received in revised form 11 January 2019; Accepted 28 January 2019 Available online 29 January 2019 0882-4010/ © 2019 Elsevier Ltd. All rights reserved.

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regard, it is the second leading cause of death in the developing countries [11]. Mortality due to cancer is on a growing trend worldwide; accordingly, this disease has been estimated to account for 11 million deaths in 2030 [12]. Meanwhile, the diagnosis and treatment at an early stage can decrease nearly one third of the cancer cases. There is substantial evidence indicating that a large number of cancer-related deaths are preventable [13]. Previous studies have suggested that infection with pathogenic organisms, such as bacteria, viruses, and parasites, may be associated with cancer development. Several parasite species can result in the development of various types of cancer. In this regard, T. gondii, Schistosoma haematobium, Paragonimus westermani, and Plasmodium species can lead to meningioma, bladder cancer, cerebral rhabdomyosarcoma, and Burkitt lymphoma, respectively. Additionally, Schistosoma mansoni and Schistosoma japonicum can result in colonic carcinoma, as well as Opisthorchis viverrini and Clonorchis sinensis can cause cholangiocarcinoma [14,15]. Toxoplasmosis as an opportunistic infection is a great public health concern in cancer patients. The treatment of cancer patients with antitumor agents can predispose them to the reactivation of the dormant toxoplasmosis [16]. Based on the evidence, a variety of malignancies, including leukemia, lymphoma, and myeloma, can reactivate toxoplasmosis [17]. Furthermore, experimentally it was found that T. gondii is an important pathogen associated with the occurrence of meningioma and gliomas through the infection-induced modulation of the mouse macrophage proteome [18]. Toxoplasma gondii is known to induce specific changes in the cellular immunity of the hosts. In addition, T. gondii changes the phenotype and behavior of the infected macrophages [19]. There is evidence confirming the interactive relationship between T. gondii and the host macrophages [20]. Considering the importance of reactivated toxoplasmosis in cancer patients, it is necessary to obtain clinical information on the seroprevalence rate of toxoplasmosis in these patients in order to plan and implement prevention, control, and therapeutic programs. With this background in mind, a meta-analysis was carried out to evaluate the seroprevalence rate of T. gondii among patients with cancer and determine the relationship between the prevalence of T. gondii and cancer.

2.3. Quality assessment and study selection To provide complete information, all cross-sectional and case-control studies that were carried out across the world to estimate the seroprevalence of T. gondii infection among cancer patients with common serologic test were included in this review. Each identified study was independently evaluated by two researchers. In addition, the repetitive papers, studies without random sampling, and those performed on other groups (e.g., pregnant women and general population) were excluded from the research. In our study, the Newcastle-Ottawa Scale was utilized to assess the cross-sectional (Low quality: < 3.5, moderate quality: 3.6–5.25, and high quality: 5.26–7) [21] and case-control studies (low quality: < 4.5, moderate quality: 4.6–6.7, and high quality: 6.8–9) [22]. Consequently, the articles with an acceptable quality (> 3.5 for cross-sectional studies and > 4.5 for case-control studies) were included in the meta-analysis. 2.4. Data extraction The eligible papers were investigated carefully, and data were extracted. The data extracted from each study included first author, publication year, study location, total sample size of patients and controls, number of male and female participants, number of patients with positive IgG and IgM results, diagnostic methods, and type of cancer. 2.5. Statistical analysis In this study, forest plots were used to estimate pool effect size and effect of each study with their confidence interval (CI) to provide a visual summary of the data. Moreover, the odds ratio (OR) was used to determine the association between the seroprevalence of T. gondii and cancer in the world population. Heterogeneity index was expected among studies using the Cochran's Q test and I2 index. Furthermore, based on Egger's regression test, a funnel plot was designed to check for the existence of publication bias. The meta-analysis was performed using Stata software, version 14 (StataCorp, College Station, TX, USA). P-value less than 0.05 was considered statistically significant [23]. The protocol of this systematic review is available in the PROSPERO international prospective register of systematic reviews with a code of CRD42017070676 [24].

2. Materials and methods 2.1. Search strategy

3. Results

For the purpose of the study, the investigations that were related to infection with T. gondii in cancer patients and published until December 2018 were searched in several English databases, including PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar. The searching process was carried out using the following keywords: ‘‘Toxoplasmosis’‘, “Toxoplasma gondii’‘, “T. gondii’‘, ‘‘cancer’‘, ‘‘malignant neoplasm’‘, ‘‘malignant tumor’‘, and ‘‘oncology’‘.

3.1. Characteristics of the included studies Our preliminary search of five databases yielded 66521 papers. 3064 articles were excluded from the study due to duplication. After exclude duplicate papers, 63457 were screened. After a primary screening based on title and abstract, 63353 papers excluded and 104 studies were extracted. By screening the full texts of the articles and based on the inclusion/exclusion criteria, 47 articles were excluded. Finally, 57 eligible studies were identified for systematic review and meta-analysis. Fig. 1 illustrates a flowchart presenting the process of article selection. Table 1 tabulates the data related to the quality assessment of the included studies with a higher score indicating better study quality. Since all 57 included studies entailed data on the prevalence of T. gondii in cancer patients, they were analyzed statistically. In this review, most of the studies (n = 45) used the ELISA method, followed by indirect haemagglutination assay (IHA) (n = 8), immunofluorescence antibody test (IFAT) (n = 1), haemagglutination assay method (HA) (n = 1), lateral flow immunoassay (LFIA) (n = 1), electro chemiluminescence immunoassay (ECLIA) (n = 1). In all 57 studies, IgG antibodies were measured against T. gondii (Table 1).

2.2. Inclusion and exclusion criteria Inclusion criteria were including: (1) cross sectional articles that investigated the seroprevalence of T. gondii in cancer patients, (2) casecontrol studies about the relationship between toxoplasmosis as an exposure and cancer as a disease, (3) the studies conducted only on humans, (4) the studies that toxoplasmosis was diagnosed by detecting IgG and/or IgM antibodies against T. gondii in cancer patients. The exclusion criteria comprised: (1) studies that were review, (2) studies that only presented the final result and did not provide the raw data, (3) articles that were not available in English language, (4) the studies conducted on animals, and (5) articles that used non-serological tests. 31

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Fig. 1. Flow diagram of systematic review and meta-analysis process.

female (40%) (95% CI: 25–56) was more than male (33%) (95% CI: 20–46).

3.2. Seroprevalence rate of T. gondii in cancer patients Based on the random-effects model meta-analysis, the pooled seroprevalence of T. gondii infection among cancer patients worldwide was 30.8% (95% CI = 26.3–35.6). Fig. 2 depicts the forest plot diagram of our review.

3.2.5. Prevalence of T. gondii in cancer patients based on age According to the random effects models, the pooled prevalence in > 40 years individuals (30%) (95% CI: 16–47) was more than < 40 years individuals (23%) (95% CI: 15–32).

3.2.1. Prevalence of T. gondii in cancer patients based on year According to the random effects models, the pooled prevalence of T. gondii in cancer patients based on the year was as follows: ≥ 2016 38% (95% CI: 30–46), 2011–2015 year 32% (95% CI: 17–49), 2001–2005 year 30% (95% CI: 13–51), ≤2000 year 27% (95% CI: 21–35) and 2006–2010 year 19% (95% CI: 12–28).

3.2.6. Prevalence of T. gondii in cancer patients based on diagnostic method The pooled prevalence by ELISA and IHA method was 33% (95% CI: 27–39) and 16% (95% CI: 11–21), respectively.

3.2.2. Prevalence of T. gondii in cancer patients based on type of cancer The pooled prevalence of T. gondii in cancer patients based on type of cancer was as follows: Breast cancer 81% (95% CI: 72–89), lymphoma 49% (95% CI: 27–70), leukemia 35% (95% CI: 22–49), malignancy 27% (95% CI: 22–33) and liver cancer 24% (95% CI: 21–28).

3.2.7. Subgroup analysis Results revealed a strong heterogeneity (Q = 1786.6, df = 56, I2 = 96.9%, P < 0.001) among the selected studies. Subgroup analysis was performed and its details are summarized in Table 2. Subgroup analysis revealed that there were statistically significant differences between the overall prevalence of T. gondii in cancer patient and year (X2 = 165.7, P < 0.001), country (X2 = 931.1, P < 0.001), type of cancer (X2 = 311.1, P < 0.001), age (X2 = 7.5, P = 0.006), diagnostic method (X2 = 83.7, P < 0.001) and sex (X2 = 27.9, P < 0.001). Based on the results of Egger's regression test (Fig. 3) the publication bias among included studies could not be ignored (Egger; bias: 6.9, P < 0.001).

3.2.3. Prevalence of T. gondii in cancer patients based on country The pooled prevalence of T. gondii in cancer patients based on different countries was as follows: Turkey 62% (95% CI: 54–70), Iraq 54% (95% CI: 38–70), Iran 51% (95% CI: 40–61), Egypt 41% (26–57), Australia 35% (95% CI: 26–45) and China 18% (95% CI: 14–21). 3.2.4. Prevalence of T. gondii in cancer patients based on gender According to the random effects models, the pooled prevalence in 32

First Author

Vogel.CL [25] Knecht.H [26] Khalil.HM [27] Wei.RM [28] Ryan.P [29] Ryan.P [29] Ekweozor.CC [30] Peng.LJ [31] Wu.ZQ [32] El Shazly.AM [33] Zhang.WZ [34] Liu.AQ [35] Lai.XQ [36] Zhang.WZ [37] Huang.H [38] Huang.H [38] Wang.BL [39]

First Author

Yang.ZJ [40] Huang.L [41] Zhang.LX [42] Yazar.S [43] Huang.L [44] Gulesci.E [45] Zheng.SL [46] Ma.XB [47] Yuan.Z [48] Ghasemian.M [49] Sun.YF [50] Liu.Q [51] Baiomy.AM [52] Lian.XW [53] Khabaz.MN [54]

Study

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Study

33

18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

2001 2002 2003 2004 2004 2005 2006 2006 2007 2007 2008 2008 2010 2010 2011

Year

1969 1986 1991 1991 1993 1993 1994 1994 1994 1996 1997 1998 1998 1998 2000 2000 2000

Year

China China China Turkey China Turkey China China China Iran China China Egypt China Jordan

Country

USA Switzerland Egypt China Australia Australia Nigeria China China Egypt China China China China China China China

Country

Malignancy Malignancy Malignancy Malignancy Malignancy Lymphoma Lung cancer Malignancy Malignancy Malignancy Malignancy Malignancy Malignancy Malignancy Malignancy

Type of Cancer

85 232 50 108 232 40 168 202 267 252 372 267 40 435 99

33 24 6 68 24 24 27 15 64 114 33 64 7 68 63

38.82 10.34 12.00 62.96 10.34 60.00 16.07 7.42 23.97 45.23 8.87 23.97 17.50 15.63 63.63

– – – 7 – – – – 6 26 – – – – 0

No.

No.

%

IgM +

IgG +

2.24 10.31

6.48

%

– – 0 – – – – – – 3 – – – – 10 8 – 20.00 13.55

12.00

– – 20 1228 67 348 112 75 738 10 238 49 150 238 – – 100 8.38 32.83 33.04 68.75 5.33 4.20 20.00 2.94 6.12 2.66 2.94 5.00

103 22 115 77 4 31 2 7 3 4 7 5

21 260 450 108 260 40 90 722 148 252 932 148 – 50 100

9.52 1.53 4.00 19.44 1.53 62.50 4.44 3.87 6.08 36.50 2.89 6.08 6.00 58.00

3 58

% 2 4 18 21 4 25 4 28 9 92 27 9

No.

IgG+

Control

29.16 28.57 36.03 8.10 34.09 35.84 66.00 33.33 12.61 88.00 15.16 26.49 29.00 15.64 20.00 11.86 10.43

%

Total Patients

70 8 40 6 15 19 33 25 27 22 27 84 38 28 10 7 12

No.

Control subjects (N = 11118)

240 28 111 74 44 53 50 75 214 25 178 317 131 179 50 59 115

%

No.

%

No.

IgG+

0

No.

IgM +

0

15

1

No.

IgM +

Control

IgM +

Total Patients

IgG +

Control subjects (N = 11118)

Cancer patients (N = 11654)

Cancer patients (N = 11654)

Malignancy Leukemia Malignancy Malignancy Glioma Meningioma Lymphoma Malignancy Malignancy Malignancy Malignancy Malignancy Malignancy Malignancy Cervical cancer Gynaecologic neoplasms Malignancy

Type of Cancer

Table 1 Characteristics of the included studies for toxoplasmosis in cancer patients and controls.

0.00

5.95

0.92

%

0.00

%

ELISA IHA ELISA ELISA IHA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA

Method

HA ELISA IFAT IHA ELISA ELISA ELISA IHA IHA ELISA IHA IHA ELISA IHA ELISA ELISA ELISA

Method

8 7 8 8 8 9 6 9 8 8 7 7 6 7 8

Quality assessment

5 4 5 9 5 5 8 8 8 8 8 8 8 8 5 5 8

Quality assessment

Yes Yes Yes Yes ND No Yes Yes Yes No Yes Yes ND Yes No

CC CC CC CC CC CC CC CC CC CC CC CC CS CC CC

Type of study

CS CS CS CC CC CC CC CC CC CC CC CC CC CC CS CS CC

Type of study

(continued on next page)

Correlation

ND ND No Yes No Yes Yes Yes Yes ND Yes Yes Yes Yes ND ND Yes

Correlation

D. Anvari et al.

Microbial Pathogenesis 129 (2019) 30–42

First Author

Study

34

2017 2017 2017 2017 2018 2018 2018 2018 2018 2018

Year

2014 2014 2015 2015 2015 2015 2015 2016 2016 2016 2017 2017 2017 2017 2017

Year

Iran Iran Iraq Saudi Arabia Egypt China Egypt Iran China Egypt

Country

Iran China China China Iran China China Korea Iraq Egypt China Romania China Iraq Iraq

Country

535 356 900 1014 66 150 150 93 300 150 100 51 253 80 100

% – – 900 – 60 110 110 93 150 50 – – 1142 112 100 17.44 78.33 8.60 19.33 8.00 12.17 20.53 11.00

157 47 8 29 4 139 23 11

170 372 137 137 180 300 150 101 861 156

96 155 82 71 100 78 30 37 144 87

56.47 41.66 59.85 51.82 55.55 26.00 20.00 36.63 16.72 55.76

10 24 2 1 – – 6 – 54 6 6.27 3.84

4.00

5.88 6.45 1.45 0.72

%

No.

No.

%

IgM +

IgG +

170 – 118 – – – 50 138 861 90

8.00 8.70 8.24 30.00

20.33

24

4 12 71 27

42.35

%

72

No.

IgG+

IgM +

9 5

1

2

3

No.

1.04 5.55

2.00

1.69

1.76

%

0.00 2.00

0.90

1 0 1

5.00

%

3

Control

0.33 4.00

2.36 7.57 2.66 1.33

9.53 2.24

No.

Total Patients

51 8 – 24 5 4 2 – 1 6 – – – – –

%

Control subjects (N = 11118)

38.87 5.89 35.55 6.80 86.36 16.00 20.00 18.27 49.00 20.00 30.00 47.05 22.13 77.50 30.00

No.

IgM +

Cancer patients (N = 11654)

208 21 320 69 57 24 30 17 147 30 30 24 56 62 30

No.

%

No.

IgG+

Control

IgM +

Total Patients

IgG +

Control subjects (N = 11118)

Cancer patients (N = 11654)

Leukemia Malignancy Malignancy Malignancy Malignancy Liver cancer Malignancy Leukemia & Lymphoma Oral cancer Malignancy

Type of Cancer

Leukemia Malignancy Malignancy Malignancy Breast cancer Leukemia Lymphoma Malignancy Malignancy Malignancy Malignancy Lymphoma Liver cancer Breast cancer Malignancy

Type of Cancer

ND = Not Described, CS = Cross-sectional, CC = Case-control.

Gharavi.MJ [69] Saki.J [70] Al-Bayati.NY [71] Imam.AM [72] Wassef.R [73] Jian-Feng.H [74] Malek.RA [75] Kalantari.N [76] Zhou.N [77] Mostafa.NE [78]

Fallahi.Sh [55] Shen.Q [56] Cong.W [57] Wang.L [58] Kalantari.N [59] Tian.MY [60] Tian.MY [60] Jung.BK [61] Molan.AL [62] Wassef.RM [63] Ru-Jin.X [64] Messinger.CJ [65] Tian.AL [66] Ahmed.DF [67] AL-Aboody.B [68]

33 34 35 36 37 38 39 40 41 42 43 44 45 46 47

48 49 50 51 52 53 54 55 56 57

First Author

Study

Table 1 (continued)

ELISA ELISA ELISA ELISA ELISA ELISA LFIA ELISA ELISA ECLIA

Method

ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA ELISA

Method

5 6 9 5 8 5 5 8 8 8 7 7 9 9 9

8 6 8 7 7 7 9 9 9 9

Quality assessment

Quality assessment

Yes ND Yes No ND Yes Yes Yes Yes Yes

Correlation

ND ND Yes ND No Yes Yes Yes Yes Yes Yes ND Yes Yes Yes

Correlation

CC CS CC CS CS CS CC CC CC CC

Type of study

CS CS CC CS CC CS CS CC CC CC CS CS CC CC CC

Type of study

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Fig. 2. Forest plot of the prevalence of Toxoplasma gondii seropositivity in patients with cancer.

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Table 2 Subgroup analysis of Toxoplasma gondii in cancer patients. Subgroup variable Year ≤ 2000 2001–2005 2006–2010 2011–2015 ≥ 2016 Type of cancer Breast cancer Leukemia cancer Liver cancer Lymphoma cancer Malignancy Country Australia China Egypt Iran Iraq Turkey Gender Male Female Age < 40 > 40 Diagnostic method ELISA IHA

Prevalence (95% CI)

I2 (%)

Heterogeneity (X2)

P-value

Interaction test (X2)

P-value

27 30 19 32 38

(21–35) (13–51) (12–28) (17–49) (30–46)

91.1% 97% 95.4% 98.9% 96.2%

179.6 166.6 151.3 649.6 452.6

P P P P P

0.001 0.001 0.001 0.001 0.001

165.7

P < 0.001

81 35 24 49 27

(72–89) (22–49) (21–28) (27–70) (22–33)

0.0% 93.6% 0.0% 92.1% 97.1%

1.8 62.5 1.1 50.5 1297.7

P = 0.173 P < 0.001 P = 0.292 P < 0.001 P < 0.001

311.1

P < 0.001

35 18 41 51 54 62

(26–45) (14–21) (26–57) (40–61) (38–70) (54–70)

0.0% 94.3% 95.3% 93.4% 93.7% 0.0%

0.02 492.5 127.6 75.8 47.8 0.11

P = 0.862 P < 0.001 P < 0.001 P < 0.001 P < 0.001 P = 0.729

931.1

P < 0.001

33 (20–46) 40 (25–56)

96.9% 97.7%

196.6 344.7

P < 0.001 P < 0.001

27.9

P < 0.001

23 (15–32) 30 (16–47)

89.7% 98.4%

58.1 319.3

P < 0.001 P < 0.001

7.5

P = 0.006

33 (27–39) 16 (11–21)

97.2% 86.7%

1578.4 52.45

P < 0.001 P < 0.001

83.7

P < 0.001

3.3. Relationship between T. gondii and cancer

< < < < <

prevalence of T. gondii in cancer patients and control group (Chi2 = 117.6, df = 1, P < 0.0001) (Fig. 4). In case-control studies, the assessment of the publication bias by means of Egger's regression test and bias plot demonstrated that the publication bias was not significant (Egger's test: bias = 1.4, P = 0.06) (Fig. 5).

Out of the 57 included studies, 40 papers were case-control studies. Regarding the association between toxoplasmosis and cancer, there was a wide variation in the included studies (Cochran Q = 150.6, df = 39 I2 = 74.1%, P < 0.0001). The overall seroprevalence of T. gondii was higher in the population with cancer, compared to that in the controls. This meta-analysis demonstrated that the common Odds Ratio by a random effect model was 3.1 (95% CI: 2.5–3.8), revealing a significant association between the

4. Discussion Infections associated with cancers are increasing at a rapid rate

Fig. 3. A bias assessment plot from Egger for seroprevalence of Toxoplasma gondii among cancer patients. 36

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Fig. 4. Forest plot of relationship between Toxoplasma gondii seropositivity in cancer patients and controls.

37

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Fig. 5. LAbbe plots of the log (odds ratio) for case-controls in the systematic review and meta-analysis.

with Breast cancer (81%), lymphoma (49%), leukemia (35%), malignancy (27%) and liver cancer (24%), respectively. Several studies have reported a significant relationship between the incidence of toxoplasmosis and breast cancer [59,82,83]. These findings could be due to many reasons such as the geographical variation, customs and habits, difference in genetic susceptibility and the possible risk factors contributing to the acquisition of Toxoplasma infection [49]. The mechanisms that T. gondii initiates tumorigenesis are unclear. T. gondii has been reported to be involved in Toxoplasma lymphadenitis (Piringer's lymphadenopathy), a potentially malignant disease in which polyclonal B cells transform to the monocytoid B cells [91]. The malignant diseases have an association with defects in cell-mediated immunity, which is described as a T-cell exhaustion phenomenon. The T-cell exhaustion phenomenon, when strengthened by immunosuppressive therapies, leads to the development of toxoplasmosis, thereby disabling the host's immune system to control intracellular pathogen infections or tumors [43,92,93]. This phenomenon is also a major cause of morbidity and mortality. Some studies have also suggested other apicomplexan parasites, such Plasmodium species (a cause of malaria), as the causes or risk factors for a type of lymphoma called Burkitt's lymphoma [94]. Reports showed that T. gondii can export miRNAs into its host cell, which might regulate the hosts' gene expression, and consequently causes cancer onset [95]. By modifying the host miRNA expression, toxoplasmosis has been reported to initiate and develop the carcinoma of the brain [96]. The genes involved in apoptosis or anti-apoptosis are both targeted by the differentially-expressed miRNAs. As a result, the change in the balance of power between the miRNAs-targeted host apoptosis genes and those modulating host anti-apoptosis genes leads to the fate of the host apoptosis process [97]. This evidence might be useful in explaining the role of T. gondii in the genesis of leukemia. Therefore, future studies are needed to provide more precise evidence in this regard. In current study, the highest prevalence of T. gondii in cancer patients observed in Turkey, Iraq, Iran, Egypt, Australia and China, respectively. Our statistical analysis also showed that there is a significant relationship between the incidence of toxoplasmosis in cancer patients and the country (P < 0.001). The different cancer profiles in individual countries signify that marked geographic diversity still exists, with permanence of local risk factors in populations at quite different

worldwide. There is a controversy over the association of apicomplexan species, such as T. gondii, with neoplastic changes in the tissues of their hosts [79]. T. gondii has been proposed as an important opportunistic parasitic pathogen in immunocompromised patients [80]. Although most of the infections caused by T. gondii are clinically asymptomatic, this parasite can cause severe and dangerous diseases and even death in immunocompromised patients [81]. Several studies have indicated an association between toxoplasmosis and various malignancies, such as cancers of brain, head, and neck [82,83]. The present study is the first meta-analysis that aimed to assess and compare the seroprevalence and ORs of T. gondii in the world population suffering from cancer with those of the healthy people. The results revealed that T. gondii had the pooled prevalence of 30.3% in cancer patients worldwide, which is higher than the rate reported in some other studies. For example, in a meta-analysis performed among Chinese population with cancer, the overall seroprevalence of T. gondii was reported as 20.59% [84]. In another review article, T. gondii was reported to have a seroprevalence of 26.0% among cancer patients in several countries (i.e., Iran, China, Turkey, and Australia) [17]. In contrast, Liu et al. in their review article obtained a higher serologic prevalence of toxoplasmosis infection in AIDS/HIV patients (46.12%), compared to our result [85]. The statistical analysis of the prevalence of toxoplasmosis in cancer patients by years has shown that toxoplasmosis is increasing in these individuals (P < 0.001). According to GLOBOCAN, 12.7, 14.1, 18.1 million new cancer cases and 7.6, 8.2, 9.6 million cancer deaths occur in 2008 [86], 2012 [87] and 2018 [88], respectively. The number of cancer cases and deaths is expected to grow rapidly as populations grow, age, smoking, excess body weight, physical inactivity, inappropriate food habits and adopt lifestyle behaviors that increase cancer risk [89]. On the other hand, in cancer patients, because of the use of immunosuppressive drugs, they are more susceptible to toxoplasmosis infection. Moreover, the bradyzoites of T. gondii in latent phase of toxoplasmosis develop into tachyzoites, causing active toxoplasmosis [90]. Our results showed a significant relationship between the type of cancer and prevalence of T. gondii (P < 0.001). In this regard, the highest prevalence of toxoplasmosis infection was observed in patients 38

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Fig. 6. Sensitivity analysis for assessing the effect of each primary study on the total estimates.

phases of economic and social transition. The regional variations of incidence of toxoplasmosis and cancer type signal the extent to which lifestyle, food habits, economic and societal changes interplay to differentially impact on the profile of these diseases [88]. The prevalence of toxoplasmosis varies by gender and age. Our finding showed a significant association between toxoplasmosis and gender in cancer patients (P < 0.001). In this regard, this infection was more prevalent in females (40%) than in males (33%) (Table 2). It is not common to detect a significant association between the seroprevalence of T. gondii and gender [98]. Nonetheless, some studies reported a significant association between these variables [99–101], and some of them indicated a higher seroprevalence of toxoplasmosis in women than in men [102,103]. The reason for this difference may be due to spending a lot of time for household activities, taking care of pets at home, gardening, cleaning, and washing vegetables and fruit by women. Therefore, women are more exposed to risk factors in different ways than men [104–107]. Our findings revealed a significant association between toxoplasmosis infection and age in cancer patients (P = 0.006). Accordingly, in a number of studies investigating the association

between T. gondii infection and age, age was reported as having a positive relationship with toxoplasmosis [49,57,108,109]. The seroprevalence of toxoplasmosis caused by T. gondii is known to increase by age [110]. No clear reason has been identified for this issue yet; however, it may be due to longer exposure to the risk factors and transmission routes [111]. Our finding showed a significant association between toxoplasmosis and diagnostic method in cancer patients (P < 0.001). The prevalence of T. gondii in cancer patients by ELISA more than IHA method. The most important of the serology methods for diagnosis of Toxoplasma is ELISA, IHA and IFA [112]. The results of our study emphasize that the ELISA method is more useful in detecting toxoplasmosis due to its high sensitivity and specificity. This systematic review showed that the overall seroprevalence of T. gondii was higher in cancer patients than in healthy people, with a statistically significant difference between the two groups (OR = 3.1, 95% CI: 2.5–3.8, P < 0.0001). The patients with cancer have impaired immune function; therefore, they are significantly more susceptible to this infection than those without malignancies [113]. Accordingly, this may be the major reason for the high seroprevalence of T. gondii in 39

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Conflicts of interest

cancer patients. T. gondii has been associated with some specific malignancies, such as lymphoma, acute and chronic leukemia, and multiple myeloma [43]. According to Fig. 4, Nigeria and Egypt have the lowest and highest ORs, respectively. The difference in ORs can be attributed to the significant difference in the host response and virulence of parasitic strains [114]. In addition, we found a high heterogeneity in the relationship between toxoplasmosis and cancer in this systematic review. The high heterogeneity index is suggestive of potential variations that could be due to the variability in the genetic predisposition to cancer among people, which is affected by lifestyle and environmental factors, such as dietary habits, exposure to ultraviolet radiation, environmental pollution, socioeconomic status, and various types of infections [115]. In the present study, our results showed that publication bias was not significant (Egger's test: 1.4, P = 0.06) for the case-control studies. On the other hand, it was significant (Egger's test: 6.9, P < 0.001) for the cross-sectional studies. To solve this problem, the sensitivity analysis test was run, and each study was analyzed individually. The results of the sensitivity analysis showed that one of the studies, namely that of Wang et al., 2015, exerted a significant impact on overall prevalence (Fig. 6). Therefore, this study was not included in the meta-analysis. This systematic review has several limitations mentioned as follows: (I) the reviewed studies used different diagnostic methods without similar specificities and sensitivities, (II) few studies evaluated variable factors influencing toxoplasmosis disease, (III) there is insufficient information about the condition or severity of the disease, and (IV) most of the included case-control studies did not have the exact matching. The above mentioned items may have affected the overall seroprevalence rate of T. gondii in cancer patients in our study. For instance, the use of different laboratory diagnostic methods with different specificities and sensitivities has a high influence on the results of these studies. Therefore, we suggest using a trustworthy test, such as ELISA, with high specificity and sensitivity to achieve accurate results in different countries. The use of this precise method can help to correctly interpret the results of the studies on the serology of T. gondii. Moreover, it is necessary that researchers evaluate some of the risk factors and variable factors influencing toxoplasmosis infection. Further research is still required to figure out the association between T. gondii and cancer to design better control programs that focus on minimizing the risk of infection. The aim of such studies should be to assist monitoring the changes in the epidemiology of toxoplasmosis and preventing the transmission of infection that cannot be controlled by medications alone by strengthening educational efforts in this regard. The prevention and control of toxoplasmosis disease depend on the possession of sufficient information about the epidemiology of this disease [116]. Knowledge of T. gondii seroprevalence, risk factors, complications of disease, as well as prevention and control procedures could lead to a significant reduction in the incidence of the disease [117–119].

None declared. Informed consent All authors approved the final version of the manuscript. Acknowledgments The authors thank all colleagues working in Toxoplasmosis Research Centre (TRC) at Mazandaran University of Medical Sciences, Sari, Iran. This work was supported by a grant (No. 10414) from the Deputy of Research, Mazandaran University of Medical Sciences, Sari, Iran. References [1] F. Robert-Gangneux, M.-L. Dardé, Epidemiology of and diagnostic strategies for toxoplasmosis, Clin. Microbiol. Rev. 25 (2012) 264–296. [2] D. Anvari, D. Saadati, R. Nabavi, M. Alipour Eskandani, Epidemiology and molecular prevalence of Toxoplasma gondii in cattle slaughtered in zahedan and zabol districts, south East of Iran, Iran. J. Parasitol. 13 (2018) 114–119. [3] J.P. Dubey, C.P. Beattie, Toxoplasmosis of animals and man, CRC Press, Inc. (1988) 45–100. [4] X. Xu, T. Liu, A. Zhang, X. Huo, Q. Luo, Z. Chen, L. Yu, Q. Li, L. Liu, Z. Lun, Reactive oxygen species-triggered trophoblast apoptosis is initiated by endoplasmic reticulum stress via activation of caspase-12, CHOP, and the JNK pathway in Toxoplasma gondii infection in mice, Infect. Immun. 80 (2012) 2121–2132. [5] M.A. Bacigalupo, P. Bazzini, L. Farina, A. Ius, Evaluation of three immunoassays for detection of Toxoplasma-specific immunoglobulin G and M, Eur. J. Clin. Chem. Clin. Biochem. J. Forum Eur. Clin. Chem. Soc 34 (1996) 503–505. [6] M.H. Shaw, T. Reimer, C. Sánchez-Valdepeñas, N. Warner, Y.-G. Kim, M. Fresno, G. Nuñez, T cell–intrinsic role of Nod2 in promoting type 1 immunity to Toxoplasma gondii, Nat. Immunol. 10 (2009) 1267–1274. [7] D. Schlüter, L.-Y. Kwok, S. Lütjen, S. Soltek, S. Hoffmann, H. Körner, M. Deckert, Both lymphotoxin-α and TNF are crucial for control of Toxoplasma gondii in the central nervous system, J. Immunol. 170 (2003) 6172–6182. [8] B.J. Luft, F. Conley, J.S. Remington, M. Laverdiere, K.F. Wagner, J.F. Levine, P.C. Craven, D.A. Strandberg, T.M. File, N. Rice, F. Meunier-Carpentier, Outbreak of central-nervous-system toxoplasmosis in western Europe and North America, Lancet 1 (1983) 781–784. [9] E. Ahmadpour, A. Daryani, M. Sharif, S. Sarvi, M. Aarabi, A. Mizani, M.T. Rahimi, A. Shokri, Toxoplasmosis in immunocompromised patients in Iran: a systematic review and meta-analysis, J. Infect. Dev. Ctries 8 (2014) 1503–1510. [10] L.M. Weiss, K. Kim, The development and biology of bradyzoites of Toxoplasma gondii, Front. Biosci. a J. Virtual Libr 5 (2000) D391. [11] A. Jemal, F. Bray, M.M. Center, J. Ferlay, E. Ward, D. Forman, Global cancer statistics, CA, Cancer J. Clinic 61 (2011) 69–90. [12] WHO, Cancer, Fact. Sheet vol. 297, (2011). [13] S. Fallahi, S.J.S. Tabaei, Y. Pournia, N. Zebardast, B. Kazemi, Comparison of loopmediated isothermal amplification (LAMP) and nested-PCR assay targeting the RE and B1 gene for detection of Toxoplasma gondii in blood samples of children with leukaemia, Diagn. Microbiol. Infect. Dis. 79 (2014) 347–354. [14] O.H. Del Brutto, M. Dolezal, P.R. Castillo, H.H. Garcı́a, Neurocysticercosis and oncogenesis, Arch. Med. Res. 31 (2000) 151–155. [15] A. Muehlenbachs, J. Bhatnagar, C.A. Agudelo, A. Hidron, M.L. Eberhard, B.A. Mathison, M.A. Frace, A. Ito, M.G. Metcalfe, D.C. Rollin, Malignant transformation of Hymenolepis nana in a human host, N. Engl. J. Med. 373 (2015) 1845–1852. [16] O. Strannegard, S.E. Holm, A. Weinfeld, J. Westin, Serologic studies of infections in patients with hematologic malignancy, Scand. J. Infect. Dis. 5 (1973) 181–186. [17] Z.D. Wang, H.-H. Liu, Z.-X. Ma, H.-Y. Ma, Z.-Y. Li, Z.-B. Yang, X.-Q. Zhu, B. Xu, F. Wei, Q. Liu, Toxoplasma gondii infection in immunocompromised patients: a systematic review and meta-analysis, Front. Microbiol. 8 (2017). [18] F. Thomas, K.D. Lafferty, J. Brodeur, E. Elguero, M. Gauthier-Clerc, D. Missé, Incidence of adult brain cancers is higher in countries where the protozoan parasite Toxoplasma gondii is common, Biol. Lett. 8 (2012) 101–103. [19] F. Aosai, H.S. Mun, K. Norose, M. Chen, H. Hata, M. Kobayashi, M. Kiuchi, H.J. Stauss, A. Yano, Protective immunity induced by vaccination with SAG1 genetransfected cells against Toxoplasma gondii-infection in mice, Microbiol. Immunol. 43 (1999) 87–91. [20] D.H. Zhou, Z.G. Yuan, F.R. Zhao, H.L. Li, Y. Zhou, R.Q. Lin, F.C. Zou, H.Q. Song, M.J. Xu, X.Q. Zhu, Modulation of mouse macrophage proteome induced by Toxoplasma gondii tachyzoites in vivo, Parasitol. Res. 109 (2011) 1637–1646. [21] P.A. Modesti, G. Reboldi, F.P. Cappuccio, C. Agyemang, G. Remuzzi, S. Rapi, E. Perruolo, G. ParatiE.S.H.W.G. on C.V.R. in L.R, Settings, panethnic differences in blood pressure in europe: a systematic review and meta-analysis, PLoS One 11 (2016) e0147601.

5. Conclusions The results of the meta-analysis revealed a higher prevalence of T. gondii infection in cancer patients than in controls. Furthermore, a significant relationship was observed between T. gondii prevalence in cancer patients and control group. Accordingly, it is suggested to conduct a routine serological screening test for T. gondii infection among cancer patients in endemic areas. Cancer patients with a positive result for T. gondii are at the risk of toxoplasmosis reactivation. On the other hand, the patients with a negative result should be also informed to prevent primary infection. Consequently, clinicians should be more careful about the patients with cancer. Ethical approval Not required. 40

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