ORIGINAL RESEARCH

published: 09 March 2017

doi: 10.3389/fmicb.2017.00389

Toxoplasma gondii Infection in

Immunocompromised Patients:
A Systematic Review and
Meta-Analysis
Ze-Dong Wang 1, 2, 3 , Huan-Huan Liu 3 , Zhan-Xi Ma 4 , Hong-Yu Ma 3 , Zhong-Yu Li 3 ,
Zhi-Bin Yang 5 , Xing-Quan Zhu 2 , Bin Xu 6 , Feng Wei 1* and Quan Liu 3, 7*
1
College of Life Science, Jilin Agricultural University, Changchun, China, 2 State Key Laboratory of Veterinary Etiological
Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese
Academy of Agricultural Sciences, Lanzhou, China, 3 Key Laboratory of Jilin Province for Zoonosis Prevention and Control,
Military Veterinary Institute, Academy of Military Medical Sciences, Changchun, China, 4 Department of Emergency Medicine,
Inner Mongolia General Forestry Hospital, Yakeshi, China, 5 Medical Library of the Chinese people’s Liberation Army, Beijing,
China, 6 Center for Prevention and Control of Animal Diseases of Banan District in Chongqing, Chongqing, China, 7 Key
Laboratory of Zoonoses, Ministry of Education, Changchun, China

Edited by:
James H. McKerrow, Toxoplasma gondii has been suggested as an important opportunistic pathogen
University of California, San Diego, in immunocompromised patients. We conducted a global meta-analysis to assess
USA
the prevalence and odds ratios (ORs) of T. gondii infection in immunocompromised
Reviewed by:
Lars Eckmann, individuals. Electronic databases were reviewed for T. gondii infection in HIV/AIDS
University of California, San Diego, patients, cancer patients, and transplant recipients, and meta-analyses were conducted
USA
to calculate overall estimated prevalence and ORs using random or fixed-effects
Veeranoot Nissapatorn,
University of Malaya, Malaysia models. Totally, 72 eligible studies were included. The estimated pooled prevalence
Ziguo Yuan, of T. gondii infection in immunocompromised patients and the control was 35.9 and
South China Agricultural University,
China 24.7% (p < 0.001), with an OR of 2.24, i.e., 42.1 and 32.0% for HIV/AIDS patients
*Correspondence: and the control (p < 0.05), 26.0 and 12.1% for cancer patients and the control (p <
Quan Liu 0.001), and 42.1 and 34.5% for transplant recipients and the control (p > 0.05), whose
liuquan1973@hotmail.com
estimated pooled ORs were 1.92 (95% CI, 1.44–2.55), 2.89 (95% CI, 2.36–3.55), and
Feng Wei
jlccwf@126.com 1.51 (95% CI, 1.16–1.95), respectively. This study is the first to demonstrate that the
immunocompromised patients are associated with higher odds of T. gondii infection,
Specialty section:
and appropriate prevention and control measures are highly recommended for these
This article was submitted to
Infectious Diseases, susceptible populations.
a section of the journal
Keywords: Toxoplasma gondii, immunocompromised patients, HIV/AIDS patients, cancer patients, transplant
Frontiers in Microbiology
recipients, prevalence, odds ratio
Received: 25 October 2016
Accepted: 24 February 2017
Published: 09 March 2017
INTRODUCTION
Citation:
Wang Z-D, Liu H-H, Ma Z-X, Ma H-Y, The protozoan parasite Toxoplasma gondii can infect nearly all warm-blooded animals, including
Li Z-Y, Yang Z-B, Zhu X-Q, Xu B, Wei F humans (Robert-Gangneux and Darde, 2012; Liu et al., 2015). Approximately 30% of the world’s
and Liu Q (2017) Toxoplasma gondii
population is estimated to be infected with T. gondii (Montoya and Liesenfeld, 2004). Humans
Infection in Immunocompromised
Patients: A Systematic Review and
become primarily infected by ingesting raw or undercooked meat containing viable tissue cysts,
Meta-Analysis. or by ingesting water or food contaminated with oocysts from infected cat feces (Baldursson and
Front. Microbiol. 8:389. Karanis, 2011; Meireles et al., 2015). In healthy humans, the infection with T. gondii is usually
doi: 10.3389/fmicb.2017.00389 asymptomatic, but it can be fatal in the immunocompromised individuals, such as HIV/AIDS

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Wang et al. Toxoplasma gondii Infection in Immunocompromised Patients

patients, cancer patients, and organ transplant recipients (Da different immunocompromised populations. The databases
Cunha et al., 1994; Pott and Castelo, 2013; Agrawal et al., 2014; were searched using the keywords “Toxoplasma gondii”
Lu et al., 2015). and “toxoplasmosis” cross-referenced with “HIV,” “AIDS,”
Toxoplasmosis of immunosuppressed individuals is most “acquired immune deficiency syndrome”, “cancer,” “tumor,”
often the result of reactivation of latent infection, which “malignancy,” “carcinoma,” “transplantation,” “organ grafting,”
presents neurological signs, including headache, disorientation, “immunodeficiency,” and “immune deficiency.” We included
drowsiness, hemiparesis, reflex changes, and convulsions (Barratt studies without language limitation.
et al., 2010; Robert-Gangneux and Darde, 2012). Acute acquired We systematically searched the scientific literatures for
T. gondii infection in immunocompromised patients may also case-control, cohort, and cross-sectional studies that reported
occur and involve multiple organs. Pneumonia, retinochoroiditis, T. gondii infection in immunocompromised individuals,
and other disseminated systemic diseases, can also be seen, but stratified by one of the following criteria: population with
are not as common as encephalitis in immunocompromised HIV/AIDS or without HIV/AIDS; population with cancer or
patients (Machala et al., 2015). without cancer; transplant or non-transplant population. Studies
An increased frequency of Toxoplasma encephalitis has been were excluded if they were reviews, repeated studies, or animal
reported in AIDS patients, especially those with significant studies. Studies were excluded if they provided the final result
immunosuppression when CD4 T lymphocyte cell counts is without raw data. Studies were excluded if the sample size from
<200 cells/µL, and T. gondii infection is regarded as an one of the two groups was <30.
important opportunistic pathogen that lead to the death of All identified titles and abstracts were carefully examined
AIDS patients (Luft et al., 1993; Jones et al., 1996). The by two independent reviewers (HHL and HYM). The full text
cancer can also reactivate latent T. gondii infection during of articles considered as potentially relevant based on title
antitumor treatment process (Frenkel et al., 1978). A variety and abstract were independently examined by the same two
of malignancies, including lymphoma, leukemia, and myeloma, reviewers. Any disagreements with the selected studies were
can reactivate toxoplasmosis (Maciel et al., 2000; Kojima et al., resolved by discussion and the involvement of another two
2010). Transplantation of an organ from seropositive donor can authors (ZDW and QL).
activate latent infection in a seronegative recipient receiving
immunotherapy (Chehrazi-Raffle et al., 2015). Transplantation of Data Extraction and Quality Assessment
an organ from seronegative donor can also initiate fatal infection The following information was extracted from each study: first
by activation of the latent infection in a seropositive recipient author, publication year, country of the study, the number
receiving immunosuppressive therapy. It seems that danger of of patients and control, diagnostic methods, and demographic
transplanting an infected organ into a seronegative recipient characteristics. Two reviewers (ZDW and YZL) independently
is greater than that of transplanting a non-infected organ into extracted the data and reached a consensus after a discussion on
a seropositive recipient (Chehrazi-Raffle et al., 2015). Fatal the controversial literatures.
toxoplasmosis has been reported in heart, liver and bone marrow, The quality of the included publications was assessed based
haematopoietic stem cell transplant recipients (Castagnini et al., on the criteria (Liu et al., 2009; Speich et al., 2016). These
2007; Caner et al., 2008; Stajner et al., 2013; Gajurel et al., 2015). criteria were created based on the Grading of Recommendations
Toxoplasmosis can be complicated and is considered a Assessment, Development and Evaluation method (Atkins et al.,
serious disease in immunocompromised patients, in which the 2004), and including the diagnostic approach of T. gondii
reactivation of a latent infection can be fatal. The incidence infection and matching of case and control subjects (Table 1).
of reactivated toxoplasmosis may rely on the prevalence and A scoring approach was used for grading, and up to 11 points
concentration of IgG antibodies (Robert-Gangneux and Darde, assigned to each study. Studies that were awarded 6–11 points
2012). It is necessary to obtain information concerning the were considered to be of high quality, 4–5 points were moderate
prevalence of T. gondii infection in different special populations quality, whereas lower scores indicated low quality.
worldwide. We conducted a global meta-analysis to assess the
seroprevalence and odds ratios (ORs) of T. gondii infection in Statistical Analysis
immunocompromised patients compared with those in control We estimated prevalence of T. gondii infection by pooling of data
individuals. from each study. Data were pooled with a DerSimonian-Laird
random-effects model (DerSimonian and Laird, 1986; Borenstein
MATERIALS AND METHODS et al., 2010), whose difference was compared using Wilcoxon two-
sample test or t-test. The risk of T. gondii infection in patient
Search Strategy and Selection Criteria and control groups was estimated by odds ratio (OR). It was
We reported this meta-analysis in accordance with the considered statistically significant when p < 0.05. In the forest
Preferred Reporting Items for Systematic Reviews and Meta- plots, OR > 1 showed a risk effect and OR < 1 showed a protective
Analysis (PRISMA) statement (Moher et al., 2009). We effect. Statistical heterogeneity of results was appraised using a
searched PubMed, Embase, Google scholar, ScienceDirect, x2 -based Q-test and I 2 statistic. The heterogeneity was considered
Chinese Web of Knowledge, Wanfang, and Chongqing VIP not significant only when p > 0.1 and I 2 < 50%. The fixed-
databases from inception to February 29, 2016, for all reports effects model was used when literature heterogeneity not existed;
that possibly contained data for T. gondii prevalence in otherwise, the random-effects model was employed. Sensitivity

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Wang et al. Toxoplasma gondii Infection in Immunocompromised Patients

TABLE 1 | Quality criteria for the included studies.

Quality Score
parameter
2 1 0

Diagnostic – Approach clearly described nd

approach – Repeatedly examined by a nd
test or two different tests
– Re-examined by a senior nd
laboratory technician
Study design Cohort study Case control study or cross –
sectional study
No. of case ≥100 50–100 ≤50
subjects
Source of Community-based ≥2 hospitals 1 hospital
population or from two or more
countries
Matching of Age and sex Age or sex nd
case and control FIGURE 1 | Data search and selection.
subjects

nd, no data available.

two in French (Maiga et al., 2001; Gamba et al., 2013), and one
each in Spanish (Gongora-Biachi et al., 1998) and in Croatian
analysis was performed by modification of the inclusion criteria
(Dakovic-Rode et al., 2010). There were 6 papers whose raw data
of this meta-analysis. The analysis was conducted using Stata
were extracted from the abstract (Ryan et al., 1993; Gongora-
software version 12.0 (Stata Corporation, College Station, TX,
Biachi et al., 1998; Sukthana et al., 2000; Uneke et al., 2005;
USA). The publication bias was considered significant when
Akanmu et al., 2010; Manouchehri Naeini et al., 2015). The oldest
p-value of Begg’s test and Egger’s test was <0.05.
study was conducted in 1987 (Quinn et al., 1987). Totally, 40
datasets investigated T. gondii infection in HIV/AIDS patients,
RESULTS and 29 datasets examined T. gondii infection in cancer patients,
whereas only six datasets studied T. gondii infection in transplant
Literature Search recipients.
As shown in Figure 1, the literature search yielded 11,799 According to our criteria, eight publications were of high
relevant studies, which included 2,434 duplicates. After a quality (>6 points), 43 publications had quality scores of 4–6
careful examination of each article’s title and abstract, 493 were points indicating moderate quality, whereas the remaining 21
considered as having potential value, and the full texts were publications were of low quality (<4 points).
retrieved for detailed evaluation. A total of 422 potentially
relevant articles were excluded from this meta-analysis after
Pooled Prevalence of T. gondii Infection
consulting the full text. Of these, 273 articles did not present
sufficient data that required, or not conform with the included (IgG) in Immunocomprised Patients
criteria; 135 had prevalence without raw data; 9 had unmatched The estimated pooled prevalence of T. gondii infection in the
control populations; the sample size in three articles was <30; HIV/AIDS patients and control population was 42.1% (95%
there were two publications whose full texts were not retrieved. CI, 34.0–50.2%) and 32.0% (95% CI, 24.0–40.1%), respectively
One additional publication regarding T. gondii infection in HIV (p < 0.05); the prevalence in cancer patients and control was
patients was identified through the second search on Feb, 29, 26.0% (95% CI, 20.5–31.5%) and 12.1% (95% CI, 9.5–14.8%),
2016. Finally, a total of 72 publications were included for our respectively (p < 0.001); and the prevalence in transplant
meta-analyses. recipients and its control was 42.1% (95% CI, 27.1–57.2%) and
34.5% (95% CI, 17.1–51.9%), respectively (p = 0.59). The results
Characteristics of Included Studies are shown in Supplementary Figures 1–6.
Characteristics of the included publications are listed in
Tables 2–4. In brief, 38 publications described T. gondii infection Association of Immunocomprised Patients
in HIV/AIDS patients, 28 articles investigated T. gondii infection with T. gondii Infection
in cancer patients, whereas 6 studies reported T. gondii Forest plots on the association of immunosuppressed
infection in transplant patients. The identified studies were populations with T. gondii infection are presented in Figures 3–5.
conducted worldwide (Figure 2). In terms of epidemiological The estimated pooled random effects ORs of HIV/AIDS, cancer,
design, 51 of the included publications were case-control studies, and transplant patients compared with their controls were
17 were cross-sectional studies, and four were cohort studies. 1.92 (95% CI, 1.44–2.55), 2.89 (95% CI, 2.36–3.55), and 1.51
Thirty-nine papers were written in English, 29 were in Chinese, (95% CI, 1.16–1.95) for infection with T. gondii. However, the

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Wang et al. Toxoplasma gondii Infection in Immunocompromised Patients

TABLE 2 | Characteristics of the included studies forT. gondii infection TABLE 2 | Continued
(IgG) in HIV/AIDS patients.
References Study Country Study Method Score
References Study Country Study Method Score design population
design population
Walle et al., 2013 C-S Ethiopia NA ELISA 5
Quinn et al., 1987 C-C DR Congo NA IFA 3 Endris et al., 2014 C-S Ethiopia NA ELISA 2
Quinn et al., 1987 C-C USA Homosexual IFA 4 Pang et al., 2015 C-S China NA ELISA 3
men
Uppal et al., 2015 C-S India NA ELISA 4
Zumla et al., 1991 C-C Uganda NA DT, LAT 6
Shen et al., 2016 C-C China NA ELISA 3
Zumla et al., 1991 C-C Zambia NA DT, LAT 6
Meisheri et al., 1997 C-C India NA ELISA 2 HIV, human immunodeficiency virus; AIDS, acquired immune deficiency syndrome; C-
C, case control study; C-S, cross-sectional study; NA, not applicable because the
Wongkamchai et al., C-C Thailand NA ELISA 1
reference does not provide this parameter; IFA, indirect fluorescent antibody test; MEIA,
1995 microparticle enzyme immunoassay; DT, dye test; LAT, latex agglutination test; ELISA,
Gongora-Biachi C-C Mexico NA MEIA 4 enzyme-linked immunosbsorbent assay.
et al., 1998
Chaves-Borges C-S India NA ELISA 4
et al., 1999
heterogeneity analysis showed that there was a relatively high-
Sukthana et al., C-C Thailand NA NA 3
2000
level heterogeneity in our meta-analysis of HIV/AID patients
Praharaj et al., 2001 C-C India NA ELISA 7
(Q = 401.6, I 2 = 90.3%, p = 0.000) and cancer individuals
Wanachiwanawin C-C Thailand Pregnant ELISA 4
(Q = 76.4, I 2 = 63.4%, p = 0.000), and no heterogeneity
et al., 2001 women was found in transplant recipients (Q = 8.0, I 2 = 37.3%,
Maiga et al., 2001 C-C Mali NA ELISA 5 p = 0.157).
Zhou and Huang, C-C China NA MEIA 3 We also analyzed all the data, showing that the estimated
2001 pooled prevalence of T. gondii infection in immunocompromised
Falusi et al., 2002 C-S USA NA DT 5 patients and the controls was 35.9% (95% CI, 31.0–40.8%) and
Nissapatorn et al., C-S Malaysia NA ELISA 4 24.7% (95% CI, 20.5–28.8%, p < 0.001), with an OR of 2.24 (95%
2002 CI, 1.87–2.69).
Uneke et al., 2005 C-C Nigeria NA ELISA 4
Simpore et al., 2006 C-S Burkina Pregnant ELISA 3 Subgroup Analysis
Faso women All subgroup analysis, including those of geographical
Jin et al., 2006 C-S China Drug user ELISA 3 distribution, country income, published years, sample size,
Shimelis et al., 2009 C-C Ethiopia NA ELISA 5 detection methods, study design, and population, did not
Ouermi et al., 2009 C-C Burkina Pregnant ELISA 5 show any significant differences between the respective groups,
Faso women as indicated by overlapping 95% CIs, with the exception of
Hua et al., 2009 C-C China NA ELISA 3 subgroups based on geographical distribution and income level
Lago et al., 2009 C-S Brazil Pregnant ELFA 4 (Supplementary Table 1). For example, the odd of T. gondii
women infection in HIV/AIDS patients in Asia (OR = 2.77, 95% CI,
Akanmu et al., 2010 C-C Nigeria NA ELISA 4 1.58–4.87) was significantly higher as comparison with that in
Li et al., 2010 C-S China Drug ELISA 3 Latin America (OR = 1.19, 95% CI, 0.90–1.56) and in Europe
users
(OR = 0.97, 95% CI, 0.65–1.46); the odd of T. gondii infection
Sitoe et al., 2010 C-C Mozambique Pregnant ELISA 4
in cancer patients in Asia (OR = 3.07, 95% CI, 2.51–3.76) was
women
significantly higher, compared with that in Oceania (OR = 1.42,
Tian et al., 2010 C-C China NA ELISA 6
95% CI, 0.80–2.54). Additionally, higher odds of T. gondii
Dakovic-Rode et al., C-C Croatia NA ELISA 4
2010
infection in both HIV/AIDS and cancer patients were found in
Daryani et al., 2011 C-S Iran NA ELISA 4
middle-income and low-income countries, compared with that
Fernandes et al., C-C Brazil Pregnant ELFA 3
of high-income countries.
2012 women
Song, 2012 C-S China NA ELISA 5 Publication Bias and Sensitivity Analysis
John et al., 2012 C-C Papua NA ELISA 7 Begg and Egger tests were used to evaluate the publication bias.
New Guinea No significant bias was revealed in HIV/AIDS- or transplant-
Alavi et al., 2013 C-C Iran Drug user ELISA 2 related publications, but significant bias was observed in cancer-
Gamba et al., 2013 C-C Central Pregnant ELISA 5 associated publications (p < 0.05, Supplementary Table 1,
Africa women Supplementary Figure 7).
You, 2013 C-C China NA ELISA 7 A sensitivity analysis was conducted by excluding one single
Ogoina et al., 2013 C-S Nigeria NA ELISA 3 study each time to find out whether modification of the inclusion
criteria of this meta-analysis had an effect on the final results. All
(Continued) the results were not materially altered (data not shown).

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Wang et al. Toxoplasma gondii Infection in Immunocompromised Patients

TABLE 3 | Characteristics of the included studies for cancer patients. TABLE 4 | Characteristics of the included studies for transplant recipients.

References Study Country Cancer Control Method Score References Study Country Control Transplanted Method Score
design design population organ

Wei et al., 1991 C-C China Mixed NP IHA, 4 Sluiters et al., 1989 C Netherland Donor Heart ELISA 5
ELISA Gan et al., 1991 C-C China Self-control Kidney IHA 4

Zhao et al., 1992 C-C China Mixed NP ELISA 2 Arora et al., 2007 C Norway Donor Heart ELISA 5
Caner et al., 2008 C Turkey Donor Liver DT 5
Ryan et al., 1993 C-C Australia Glioma NP ELISA 4
Gharavi et al., 2011 C Iran Self-control Kidney ELFA, 9
Ryan et al., 1993 C-C Australia Meningioma NP ELISA 4 ELISA
Peng et al., 1994 C-C China Mixed NP IHA 4 Gharavi et al., 2011 C Iran Self-control Kidney ELISA 9
Wu et al., 1994 C-C China Mixed NP IHA 5 Soltani et al., 2013 C-S Iran Healthy Kidney ELISA 4
Lai et al., 1998 C-C China Mixed NP ELISA 5 subjects

Liu and Li, 1998 C-C China Mixed NP IHA 3 C, cohort study; C-C, case-control study; C-S, cross-sectional study; IHA, indirect
Zhang et al., C-S China Mixed NP IHA 5 hemagglutination; DT, dye test; LAT, latex agglutination test; ELFA, enzyme-linked
1998 flourescence assay; ELISA, enzyme-linked immunosorbent assay.
Wang et al., 2000 C-C China Mixed NP ELISA 6
Huang et al., C-C China Cervical Other ELISA 3
2000 cancer diseases different genotype (Sharma et al., 1983; Dzitko et al., 2006).
Wu et al., 2000 C-C China Mixed NP IHA, 5 During extraction of data in this study, the IgM antibodies
ELISA
against T. gondii in immunocompromised patients were also
Wei and Zhu, C-C China Mixed NP ELISA 3
2000
collected (Supplementary Tables 2–4). Due to insufficient data
Yang et al., 2001 C-C China Mixed NP ELISA 4
on HIV/AIDS and transplant patients, we only analyzed T. gondii
Zhang et al., C-C China Mixed NP ELISA 3
IgM in cancer patients and the control, showing a prevalence of
2003 11.4% (95% CI, 8.1–14.7%) in cancer patients and 2.7% (95%
Yazar et al., 2004 C-C Turkey Mixed NP ELISA 7 CI, 1.5–4.0%, p < 0.01) in its control group and OR of 2.65
Huang et al., C-C China Mixed NP IHA 5 (95% CI, 2.04–3.45, Supplementary Figures 8–10). The results
2005 also confirmed that the immunocompromised patients were
Ma et al., 2006 C-C China Mixed NP ELISA 3 associated with significantly higher odds of recently acquired
Zheng et al., C-C China Lung NP ELISA 5 T. gondii infection.
2006 cancer
Yuan et al., 2007 C-C China Mixed NP ELISA 4
DISCUSSION
Ghasemian et al., C-S Iran Mixed NP ELISA 7
2007
T. gondii has been suggested as an important opportunistic
Sun et al., 2008 C-C China Mixed NP ELISA 4
pathogen in immunocompromised patients (Walker and Zunt,
Li et al., 2008 C-C China Mixed NP ICT 4
2005). The infection in healthy (immunocompetent) people
Zhang et al., C-C China Mixed NP ELISA 3
is usually self-limited and asymptomatic, resulting in chronic
2009
infection of tissue cysts that can lie dormant, probably for the
Lian et al., 2010 C-C China Mixed NP ELISA 4
entire lifetime of the hosts. However, immunocompromised
Cong et al., 2015 C-C China Mixed NP ELISA 8
individuals, such as HIV/ADIS patients, cancer patients
Tian et al., 2015 C-C China Leukemia NP ELISA 3
and
with chemotherapy, and transplant recipients, are at risk
Lymphoma of developing Toxoplasma encephalitis, myocarditis, or
Manouchehri C-C Iran Mixed NP ELISA 7 pneumonitis, due to reactivation of the chronic infection.
Naeini et al., 2015 For example, approximately 30–40% of HIV co-infected
Kalantari et al., C-S Iran Breast Healthy ELISA 6 immunocompromised individuals with T. gondii develop
2015 cancer women encephalitis (Walker and Zunt, 2005).
C-C, case-control study; C-S, cross-sectional study; IHA, indirect hemagglutination;
The associations of HIV and seroprevalence of T. gondii
ELISA, enzyme-linked immunosbsorbent assay; ICT, immunochromatographic test; NP, infection are varied in the world (Grant et al., 1990). Some
normal population. reports showed higher prevalence of T. gondii infection in HIV-
infected patients compared to non-infected individuals, whereas
others did not find any differences between the two groups
(Sukthana et al., 2000; Galvan-Ramirez Mde et al., 2012). This
Pooled Prevalence of T. gondii Infection global systematic review and meta-analyses were conducted
(IgM) in Immunocomprised Patients to quantify the prevalence and ORs of T. gondii infection
Our meta-analysis focused on T. gondii IgG antibodies, which in immunocompromised individuals compared with those in
are a marker of lifetime exposure to toxoplasmosis, whereas control individuals.
IgM antibodies are a marker of acute or recent infection, Subgroup analyses comparing published year, sample size,
or also potentially persistent infection or reinfection with a detection method, study design, country income, and population

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Wang et al. Toxoplasma gondii Infection in Immunocompromised Patients

FIGURE 2 | Geographical distribution of the included studies. The map was created using MapInfo Professional software version 9.5. Pooled odds ratio and
95% confidence interval are shown for each country.

FIGURE 3 | Meta-analysis of the association of HIV/AIDS patients and T. gondii infection (IgG) with random-effects analysis. CI, confidence interval; OR,
odds ratio.

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Wang et al. Toxoplasma gondii Infection in Immunocompromised Patients

FIGURE 4 | Meta-analysis of the association of cancer patients and T. gondii infection (IgG) with random-effects analysis. CI, confidence interval; OR,
odds ratio.

FIGURE 5 | Meta-analysis of the association of transplant recipients and T. gondii infection (IgG) with fixed-effects analysis. CI, confidence interval; OR,
odds ratio.

revealed non-significant differences, but high odds were found T. gondii infection in these regions. Thus, no meta-analysis could
for T. gondii infection in HIV/AIDS patients in Asia and be done and no firm conclusion should be drawn. Most studies
Africa as comparison with that of America and Europe, and were conducted in the countries of Asia. Our analyses further
in cancer patients in Asia compared to that in Oceania demonstrated that the studies are geographically clustered,
(Supplementary Table 1). However, only one or two studies with few studies in Latin America, Europe, and Oceania
examined the association of immunocompromised patients with (Figure 2).

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Wang et al. Toxoplasma gondii Infection in Immunocompromised Patients

The presence of heterogeneity was observed in HIV/AIDS and contribute to the difference of T. gondii infection between the
cancer patients, but subgroup analyses did not explain the specific patient and control groups (Minbaeva et al., 2013; Walle et al.,
causes of heterogeneity, which may come from various sources, 2013; Wang et al., 2015). The cluster randomized controlled trial
including geographical distribution, published years, sample size, would provide high-quality data, but their implementation is
detection methods, study design, or populations. Without meta- more difficult. An alternative way to generate high-quality data
regression or additional subgroup analysis that requires a large would be using a time-series approach as a study design (Speich
number of studies, it is difficult to investigate the causes of et al., 2016).
heterogeneity. The presence of heterogeneity shows that pooled Third, diagnosis of T. gondii infection in
results are averaging multiple related, but different effects (Strunz immunocompromised patients is difficult. Though detection
et al., 2014). of the parasite by microscopy and bioassays is considered as
In fact, higher prevalence of T. gondii infection in HIV/AIDS the gold standard for diagnosis of toxoplasmosis, its clinical
patients has been reported in many countries, such as Nigeria, diagnosis more likely relies on serological methods (Liu et al.,
Mali, Ethopia, India, China, and Thailand (Maiga et al., 2001; 2015). However, the serological methods may be unreliable in
Wanachiwanawin et al., 2001; Akanmu et al., 2010; Daryani the immunocompromised individuals, whose immune system
et al., 2011; Uppal et al., 2015; Shen et al., 2016). The present has been impaired, and cannot produce enough antibodies
study provided robust evidence that support the conclusion, and (Lewis et al., 2015). In the identified studies, all the detection
demonstrated that HIV/AIDS patients are associated risk factors methods were serological, including indirect hemagglutination
(OR = 1.92, 95% CI 1.44–2.55) for T. gondii infection. The data (IHA), dye test (DT), immunochromatographic test (ICT), and
were derived from 38 publications from 20 countries, which enzyme-linked immunosorbent assay (ELISA) (Tables 2–4).
included 10,028 HIV/AIDS patients and 12,334 control people Thus, by the reason of lack of specific antibody, the
(Table 2). detected results would be lower than the actual prevalence
A recent study reported T. gondii infection in Chinese cancer in immunocompromised patients, including HIV/AIDS patients,
population, with a prevalence of 20.6% in cancer patients and cancer patients, and transplant recipients (Saadatnia and Golkar,
6.3% in the control (OR = 3.9) (Jiang et al., 2015). Our meta- 2012).
analysis also included the data of other countries, such as Fourth, insufficient data about further relevant factors on
Australia, Iran, and Turkey (Table 3), which involved 7,011 T. gondii infection (e.g., age, cancer type, transplanted organ)
cancer patients and 9,254 control people, therefore, the results were available for subgroup analysis.
would be more reliable. However, of the included 28 publications, In summary, our global meta-analysis shows a higher
21 were written in Chinese, resulting in significant publication prevalence of T. gondii infection in immunocompromised
bias. patients, and demonstrates that the immunocompromised
There are many case reports of toxoplasmosis in transplant individuals, including HIV/AIDS patients, cancer patients, and
recipients, including haematopoietic cell (Barcan et al., 2002), transplant recipients, were associated with higher odds of
heart (Gajurel et al., 2015), liver (Hamza et al., 2015), and T. gondii infection. Therefore, a routine serological screening
kidney (Petty et al., 2015) transplant patients. A previous test for T. gondii infection is suggested to be conducted in
study reported a higher prevalence of T. gondii infection immunocompromised patients in endemic area, or patients with
in renal transplant recipients (Soltani et al., 2013). In the no proper chemoprophylaxis and/or HAART. Patients with
present study, we analyzed T. gondii infection in 671 transplant a positive result are at risk of reactivation of the infection,
patients (heart, kidney, and liver) and 628 control people from while patients with a negative result should be informed to
five countries (Table 4), revealing no significant difference of prevent primary infection. Health education, particularly toward
T. gondii infection between the two groups, but showing that avoiding eating raw and undercooked meat, and avoiding contact
transplant population is an risk factor (OR = 1.51, 95% CI, 1.16– with cats’ feces should also be considered.
1.95) for T. gondii infection. Interestingly, it was found that 14.3%
of renal transplant recipients were detected positive for T. gondii
infection in the first year of transplantation, and the prevalence AUTHOR CONTRIBUTIONS
increased to 85.7% in 1 year post-transplantation (Aufy et al.,
QL was responsible for the idea and concept of the paper.
2009).
ZW and QL analyzed the results. HL, ZM, HM, ZL, FW, ZY,
There are several limitations in this meta-analysis, which may
and BX collected and analyzed the data. QL and XZ wrote the
affect the results. First, a number of potentially relevant studies
manuscript. All authors contributed to the manuscript editing
were identified through our systematic review, but not all the
and approved the final manuscript.
underlying data were available. Therefore, though most of these
studies might not have relevant data, there is a certain risk to miss
some eligible data. FUNDING
Second, based on our scoring system, most studies were of
moderate or even relatively low quality. This finding is mainly This work was supported by the National Natural Science
due to the epidemiological design of the studies; most were cross- Foundation of China (31672542, 31472183, 31372430 and
sectional in nature. The differences between the study groups also 31230073) and the Special Fund for Agro-scientific Research in
included ages, lifestyles, and geographical conditions, which all the Public Interest in China (201303042).

Frontiers in Microbiology | www.frontiersin.org 8 March 2017 | Volume 8 | Article 389

Wang et al. Toxoplasma gondii Infection in Immunocompromised Patients

SUPPLEMENTARY MATERIAL Supplementary Figure 7 | Funnel plots to assess publication bias in the
meta-analysis. (A) Funnel plot for experimental studies. (B) Funnel plot for
The Supplementary Material for this article can be found observational studies.
online at: http://journal.frontiersin.org/article/10.3389/fmicb. Supplementary Figure 8 | Meta-analysis of the association of cancer
2017.00389/full#supplementary-material patients and T. gondii infection (IgM).
Supplementary Figure 1 | Forest plot of estimated pooled prevalence (IgG) Supplementary Figure 9 | Forest plot of estimated pooled prevalence (IgM)
of T. gondii infection in HIV/AIDS patients. of T. gondii infection in cancer patients.
Supplementary Figure 2 | Forest plot of estimated pooled prevalence (IgG) Supplementary Figure 10 | Forest plot of estimated pooled prevalence
of T. gondii infection in HIV/AIDS-negative population. (IgM) of T. gondii infection in cancer-negative population.
Supplementary Figure 3 | Forest plot of estimated pooled prevalence (IgG) Supplementary Table 1 | Results of the subgroup analyses examining the
of T. gondii infection in cancer patients. association of immunosuppressed individuals with T. gondii infection∗
Supplementary Figure 4 | Forest plot of estimated pooled prevalence (IgG) Supplementary Table 2 | Characteristics of the included studies for
of T. gondii infection in cancer-negative patients. T. gondii infection (IgM) in HIV/AIDS patients.
Supplementary Figure 5 | Forest plot of estimated pooled prevalence (IgG) Supplementary Table 3 | Characteristics of the included studies for
of T. gondii infection in transplant patients. T. gondii infection (IgM) in cancer patients.
Supplementary Figure 6 | Forest plot of estimated pooled prevalence (IgG) Supplementary Table 4 | Characteristics of the included studies for
of T. gondii infection in non-transplant population. T. gondii infection (IgM) in transplant patients.

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