Prevalence and Clinical Relevance of Schistosoma mansoni Co-Infection with Mycobacterium tuberculosis: A Systematic Literature Review

Bocar Baya^1,2*, Bourahima Kone¹, Amadou Somboro¹, Ousmane Kodio¹, Anou Moise Somboro¹, Bassirou Diarra¹, Fah Gaoussou Traore¹, Drissa Kone³, Mama Adama Traore³, Mahamadou Kone¹, Antieme Georges Togo¹, Yeya Sadio Sarro¹, Almoustapha Maiga¹, Mamoudou Maiga^3,4, Yacouba Toloba², Souleymane Diallo¹, Robert L. Murphy⁴, Seydou Doumbia¹

¹University Clinical Research Center (UCRC) of the University of Sciences, Techniques and Technologies of Bamako (USTTB), Bamako, Mali.
²Service of Pneumopthisiology of the University Teaching Hospital of Point G, Bamako, Mali.
³Clinical Laboratory of the University Teaching Hospital of Point G, Bamako, Mali.
⁴Havey Institute for Global Health (Havey IGH), Northwestern University (NU), Chicago, USA.

DOI: 10.4236/ojepi.2023.131008                

Abstract

Tuberculosis disease stands for the second leading cause of death worldwide after COVID-19, most active tuberculosis cases result from the reactivation of latent TB infection through impairment of immune response. Several factors are known to sustain that process.Schistosoma mansoni, a parasite of the helminth genus that possesses switching power from an immune profile type Th1 to Th2 that favors reactivation of latent TB bacteria. The aim of the study was to assess the prevalence of the co-infection between the two endemic infections. Systematic literature was contacted at the University Clinical Research Center at the University of Sciences, Techniques, and Technologies of Bamako in Mali. Original articles were included, and full texts were reviewed to assess the prevalence and better understand the immunological changes that occur during the co-infection. In total, 3530 original articles were retrieved through database search, 53 were included in the qualitative analysis, and data from 10 were included in the meta-analysis. Prevalence of the co-infection ranged from 4% to 34% in the literature. Most of the articles reported that immunity against infection with helminth parasite and more specifically Schistosoma mansoni infection enhances latent TB reactivation through Th1/Th2. In sum, the impact of Schistosoma mansoni co-infection with Mycobacterium tuberculosis is under-investigated. Understanding the role of this endemic tropical parasite as a contributing factor to TB epidemiology and burden could help integrate its elimination as one of the strategies to achieve the END-TB objectives by the year 2035.

Keywords

Schistosoma mansoni, Tuberculosis, Co-Infections, LTBI, Reactivation

1. Introduction

Before the COVID-19 pandemic, Mycobacterium tuberculosis (M. tb) represented the deadliest infectious agent, killing more than 4000 people per day, exceeding the human immunodeficiency virus (HIV) and malaria two times each [1] [2] [3] . Despite, that tuberculosis (TB) incidence is slowly decreasing but still not sufficient enough to meet the World Health Organization’s (WHO) Ending TB objectives by the year 2035 [1] [4] . Latent TB infection (LTBI) is defined as an immunologically controlled M. tb infection with no apparent clinical and radiological sign of active TB. LTBI control involves the establishment of T helper 1 (type-1) inflammatory granuloma to block M. tb bacteria replication and spread. Several immune cells and cytokines are involved in this mechanism, such as T-cells lymphocytes, macrophages, monocytes, interleukin (IL)-1, 2, 6, 10, 12, IFN-γ, and TNF-α [5] [6] [7] . In immunocompetent individuals, LTBI can remain harmless throughout their entire lifetime. Reactivation or progression to active TB is defined as a transition from the latency stage to a symptomatic disease due to the escape and replication of the bacteria throughout a breach in the immune system induced by a new infection or failure to control an existing condition [5] [7] [8] [9] . Several health conditions can impair immune response leading to a possible reactivation of LTBI, they are classified from high-risk such as HIV, organ transplants, chronic hemodialysis, and alcohol abuse to low-risk factors including smoking, diabetes, and use of corticosteroids [10] [11] .

Schistosoma mansoni (Sch. m) is one of the sub-species of Schistosoma spp, a parasite of the helminth family and trematode genus encountered in sleeping water and causing schistosomiasis, one of the neglected tropical infectious diseases (NTDs) still endemic in more than 78 resource-limited countries in Africa, South America, and Asia. Its prevalence in Sub-Saharan Africa represents 93% of all cases worldwide [12] [13] .

Recent studies have shown that chronic infection with Schistosoma mansoni (Sch. m) impairs the host immune response and affects the formation and maintenance of type-1 granuloma by inducing T helper 2 (type-2) inflammatory granuloma. The process enhances a switch from the host’s existing type-1 immune response profile to a type-2 that weakens the strength of type-1 granuloma [14] . Cytokines produced during Sch. m chronic infection such as IL-5, 9, 10, and 13 were found to be significantly associated with liver fibrosis [15] . A decrease in CD4+ T cell response was observed in LTBI patients co-infected with helminth parasites which increased after treatment [16] . Similarly, a lower protective effect of the Bacilli Calumet-Guerin (BCG) vaccine in people with Sch. m infection which may lead to M. tb reactivation in case of LTBI co-infection [17] . Hematological and biochemical parameters were found to be altered in patients with Sch. m infection compared to healthy individuals who were improved after praziquantel treatment [18] . Several clinical studies reported statistically significant associations between the two infections and have also strengthened the hypothesis that Sch. m infection enhances LTBI reactivation to active TB through the reduction of the host’s protective immune response. A study in Uganda (2006) assessed the incidence of active TB in HIV patients co-infected with Sch. m versus HIV mono-infected and found an increased risk of developing active TB in HIV and Sch. m co-infected patients compared to those without Sch. m co-infection [19] . A case-control study in Tanzania (2017) also observed similar findings, patients with active TB had significantly higher odds of being Sch. m co-infected compared to their household healthy controls [20] . Based on pulled observation data from the WHO Global TB reports, there is a trend between Schistosomiasis endemic areas and TB burden. Active TB incidence is found to be higher in geographic regions where the prevalence of Schistosomiasis infection is important in sustaining the possible relationship between the two endemic infectious agents (Figure 1). The treatment of Schistosoma mansoni

Figure 1. (a) Prevalence in percentage of Schistosomiasis in 11 Sub-Saharan African countries; (b) Incidence of Tuberculosis per 100,000 population in the same countries. Comparing the two figures, there is a trend between Schistosomiasis prevalence and Tuberculosis incidence.

consists of a single oral dose of Praziquantel (PZQ) 40 mg/Kg repeated after 2 - 4 weeks. The first dose will kill adult worms present in the intestines and the second will target new parasites from egg hatch [21] . The treatment regimen recommended by WHO for people with drug-susceptible TB is a 6-month duration [22] including 2-month of isoniazid (H), rifampicin (R), ethambutol (E), and pyrazinamide (Z) followed by 4-month of isoniazid, rifampicin (2RHZE/4RH). Several regimens are proposed for LTBI treatment, from monotherapy with Rifampicin daily dose for 4-month or Isoniazid 6 or 9-month to bi-therapy with Isoniazid and Rifapentine weekly for 3-month or Isoniazid and Rifampin daily for 3-month [23] . Some works have been conducted on the immunological harm of the co-infection between tuberculosis and Schistosoma mansoni but still, there is more to be investigated for clinical evidence. The treatment of LTBI is confronted with several issues; insufficient investigations to differentiate active from latent TB and poor treatment adherence. The aim of this systematic literature review was to assess the effects of Sch. m infection on LTBI reactivation to active disease and existing data on the frequency of co-infections between M. tb and Sch. m.

2. Materials and Methods

2.1. Study Design and Setting

This study was designed to evaluate the clinical relevance of TB/Sch. m co-infection in the disease progression and active tuberculosis epidemiology dynamic. Therefore, published original research articles that reported the immunological interaction, and clinical frequencies of Mycobacterium tuberculosis and Schistosoma mansoni co-infections were searched and reviewed.

2.2. Article Search

Relevant research articles were searched using two search terms from two different databases, (Google Scholar, Embase, Scopus, PubMed, and Web All of Science) detailed as follow:

“Mycobacterium tuberculosis” [MeSH Terms] OR (“mycobacterium” [All Fields] AND “tuberculosis” [All Fields]) OR “mycobacterium tuberculosis” [All Fields] OR (“tuberculosis” [All Fields] AND “mycobacterium” [All Fields]) OR “tuberculosis mycobacterium” [All Fields]) AND (“tuberculosis” [All Fields] OR “tuberculosis” [MeSH Terms] OR “tuberculosis” [All Fields] OR “tuberculoses” [All Fields] OR “tuberculosis” [All Fields]) AND (“Schistosoma mansoni” [MeSH Terms] OR (“schistosoma” [All Fields] AND “mansoni” [All Fields]) OR “Schistosoma mansoni” [All Fields]) AND (“co-infect” [All Fields] OR “co-infected” [All Fields] OR “co-infecting” [All Fields] OR “co-infection” [MeS Terms] OR “co-infection” [All Fields] OR “co-infections” [All Fields] OR “co-infects” [All Fields]).

All full-text articles found throughout this database search were assessed and all those eligible with an abstract in English were included in this study regardless of the language of the full article.

2.3. Inclusion and Exclusion Criteria

All full-text research articles from the search result of the study using the two search terms built from the words “Tuberculosis and Schistosoma mansoni” were included in the study. All studies that full text or abstract have not been found in the search and studies that do not include results of one of the two infections were excluded from the study.

2.4. Data Collection and Interpretation

Each included article was reviewed to retrieve information about TB and Schistosoma mansoni co-infections. Article on immune response interactions between the two-infection found in the literature was also described and analyzed in this literature review. Case reports, case series, case control, and cohort studies were summarized in different tables (Table 1 & Table 2).

Table 1. Case reports of co-infection between TB and Schistosoma mansoni.

Table 2. Frequency of Mycobacterium tuberculosis and Schistosoma mansoni co-infections.

Tanzania*: Schistosoma mansoni was 16.4% in the rural area vs. 4.13% in the Urban. Kenya ꝉ: HIV/TB co-infected patients.

2.5. Ethical Approval

The conduct of this systematic review was approved through a current project on the prevalence of Schistosoma mansoni among pulmonary TB patients in Mali by the Ethics committee of the Faculties of Medicine and Odonto-Stomatology, and Pharmacy of the University of Sciences, Techniques, and Technologies of Bamako (USTTB) in Point-G, Bamako, Postal Box: 1805; Mali.

3. Results and Discussion

3.1. Search Results

In total five (5) search engines were explored using the same term, three thousand five hundred ninety-one (3591) articles were found in the databases, including Google Scholar (3530), Embase (23), Scopus (14), PubMed (12) and Web of Science (12) (Figure 2). After removing duplicates and those not fulfilling

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Figure 2. Data search flow chart.

TB and Schistosoma mansoni co-infection criteria, one hundred twenty-three (123) articles were eligible among those, fifty-three (53) were used for qualitative discussion and ten (10) for the quantitative analysis and data discussion.

3.2. Mycobacterium tuberculosis and Helminth Co-Infections: Expression of Th2 Immune Response Profile

The immunological disturbances occurring during M. tb and helminth co-infections have been reported in animal but also human studies. Since the beginning of the 20^th century, Kullberg et al. (1992) observed that Sch. m infection downregulates the host’s Th-1 immune response, and induces an exaggerated Th-2 response that alters existing protective immune response against other infectious agents; the findings were later supported by observations of Rafi et al. (2012), that helminth infection diminishes immune protection against LTBI [24] [25] [26] . In vaccinology, helminth chronic infection has also been found to affect immunization conferred by vaccines; Kondĕlková et al. (2010) & Méndez-Samperio et al. (2014), found in their investigation that Treg cells modulate immune reaction by suppressing cell’s multiplication and production of cytokines, implying that the presence of helminth infection confers a buffer medium that neutralizes the effect of ongoing immune responses [27] [28] . McArdle et al. (2018) reported that reactivation of latent TB infection (LTBI) in the presence of helminth infection comes from a switch from Th1 to Th2 cytokine production [29] . Abate et al. (2015) observed that the simple presence of helminth infection without any clinical manifestation in patients with active TB could downregulate host immune response similar to that seen in patients with immunodepression. The co-infection creates a coexistence of T-Regulatory Cells (Treg cells), and type-1 cytokines (IL-10) but also the secretion of type-2 expressing cytokines (IL-5) conferring an immunodeficiency status to the patient. Thereby, the low bacteria load in sputum observed in TB and Sch. m co-infected patients was already reported as a common finding in TB and HIV co-infection [30] [31] . Babu et al. (2016) also brought evidence from the animal model and human studies that helminth infections affect the host immune control of TB infection, thereby increasing the risk of TB bacteria reactivation in an organism with both infections [32] . Rajamanickam et al. (2019 & 2020) found that helminth and LTBI co-infection exposes LTBI control failure by inducing low-production chemokines and alteration of their function. They also observed an alteration of monocyte cells’ function through inadequate activation and polarization during the co-infection [33] [34] . Cadmus et al. (2020) reported in a literature review that helminth infection negatively impacts the strength of vaccination response, thereby immunization programs should consider helminth endemic areas regarding the protection level of vaccines [13] Kiflie et al. (2021) found that helminth co-infection in active TB patients had a positive correlation between TB disease severity and an increase of helminth-specific TGF-β+ Tregs that was restored after anti-helminth treatment [35] . Resende et al. observed that TB and helminth co-infection leads to a decrease in T-cells and natural killers number, cytokine production, and severe lung damage compared to TB mono-infected patients and healthy controls [36] [37] . A similar observation was reported by Bogdan et al. (1991); Gong et al. (1996); Abate et al. (2015) and Aira et al. showed that IL-10 production down-regulates Th1-driven immune response against TB infection [38] [39] [40] [41] . These observations demonstrate that in the presence of helminth infection, the expression of the Th2 immune profile involves Treg cell proliferation and certain types of cytokines that down-regulate existing Th1 immune inflammatory response against other types of infections and particularly in the case of LTBI.

3.3. Schistosoma mansoni Impairs Immune Response to Mycobacterium tuberculosis Leading to Latent Tuberculosis Infection Reactivation

In more than four past decades, Olds et al. (1981) reported that Sch. m co-infection impairs immune response in active TB patients, and a decrease in killer monocyte cell rate was observed in Sch. m co-infected and TB patients [42] . Several other studies supported the hypothesis that in the presence of Sch. m infection, the host immune response undergoes a modulation process leading to a poor immune response quality against a new or an existing infection. Elias et al. (2006) reported a low protective effect of the BCG vaccine in children infected with Sch. m [17] . The observation was further supported by Musaigwa et al. (2022) that Sch. m infection affects vaccine response again TB infection by inducing deaths of plasmablast and plasma cells in the bone marrow [43] . Among the diverse helminth, Sch. m one of the Schistosoma subspecies, has been identified to possess specific proteins that lead to failure of maintaining type1 granuloma formation by promoting a strong type 2 inflammatory immune response. Monin et al. (2015) were pioneers of that observation by describing that during M. tb and Sch. m co-infection, Sch. m increases susceptibility to TB reactivation but also the disease severity by increasing the level of inflammatory response with the accumulation of arginine-1 expressing macrophages [44] . Pearce et al. also demonstrated that the presence of soluble Sch. m egg antigen inhibits IL-12 cytokine production by dendritic cells and induces a Th2 inflammatory immune response profile promoting T-cell regulatory (Treg) responses that inhibits the establishment of type Th1 response [45] . Giera et al. have also identified lipids such as prostaglandins (rich in Sch. m eggs) to be specifically driving expression of type Th2 immune response profile during Sch. m infection [46] . Meurs et al. in Senegal investigated cytokine production during schistosomiasis infection and observed that Sch. m induces the production of Th2 profile cytokines but is not as stronger compared to Schistosoma haematobium (Sch. h). This implies that Sch. m can induce a switch of immune response profile from Th1 to Th2 but does not induce such a stronger response to limit damages from other infections [47] . Schramm et al. (2018) investigated the immune modulatory effect of Sch. m and observed that using Sch. m egg-specific antigens can significantly decrease the immune response against Salmonella infection [48] . Dinardo et al. (2016) observed that M. tb-specific CD4+ T-cell functions are altered in presence of soluble schistosome antigen and block the maturation of macrophage phagolysosome [49] . However, McLaughlin et al. (2020) reported a contradictory finding that Th1 immune functions are still maintained by TCD4 cells during TB and Sch. m co-infection [50] .

Lessons learned from this step are that Sch. m infection induces a buffered media in the immune response pattern and plays an important role in TB infection control. In the presence of Sch. m antigens, the host immune system fails to establish an appropriate defense against other infections. This immunological disaster happens when the host immune system is facing an acute infection and knocking it down to a latency phase or when Sch. m infection occurs in an individual with an immunologically well-controlled latent TB infection (Figure 3).

3.4. Prevalence of Schistosoma mansoni and Tuberculosis Coinfections across Clinical Studies

Schistosoma mansoni and Mycobacterium tuberculosis co-infections have gained increasing interest over the last two decades. Observations started with single case reports; Cristina et al. (2006), in Brazil reported a case of hepatic TB co-infected with Sch. m [51] . Basile et al. (2007) published one of the first cases of Sch. m and M. tb tuberculosis co-infection in a 32-year-old, male, living in France but of Sub-Saharan African origin [52] . Gobbi et al. (2014), further support a case of Schistosoma mansoni and Mycobacterium tuberculosis co-infection mimicking a single infection of Schistosoma mansoni in the lung [53] . Range et al. (2007) in Tanzania found more than one-third (35.5%) of Schistosoma mansoni co-infection among confirmed pulmonary TB patients and also HIV co-infection was 43.6% [54] Ten years later, structured case series started to report remarkable frequencies, and clinical characteristics of patients with the co-infection. Earlier in 2012, Abate et al. (2012) conducted another study in Ethiopia, the frequency of Sch. m co-infection among TB patients was 19% [55] . Li & Zhou (2013) conducted a systematic review on TB and parasite co-infections, they observed a prevalence of 5.4% of Sch. m among TB patients [56] . McLaughlin et al., in a recent study in Kenya, it has been observed a 4% increase in TB incidence in HIV-Negative people infected with Sch. m (19.7%) compared to Sch. m-uninfected cases (15.8%) whereas a 14% increase was observed in TB incidence in HIV-Positive patients co-infected with Sch. m (27.3%) compared to HIV-Positive Sch. m-uninfected patients (41.2%) [57] . Tegegne et al. (2018) conducted a study in Gondar (Ethiopia) that reported a prevalence of 0.4% of Sch. m in patients suspected of pulmonary tuberculosis [58] . Gashaw et al. (2019) reported a prevalence of 4.3% of Sch. m in active TB patients with under-nutritional status in Northeastern Ethiopia [59] . Mhimbira et al. (2017) found 5.7% of Sch. m co-infection in TB patients compared to their household control individuals. There was a 2.15-fold higher risk of Sch. m co-infection in TB patients compared to their household controls. Sch. m and M. tb co-infected patients had a

Figure 3. TB Infection Transmission and reactivation through Schistosoma mansoni infection.Th1/Th2 immune impairment during Schistosoma mansoni Latent TB co-infection.

2.63-fold risk of being in the group of TB patients with lower sputum bacterial load, and also 0.41-fold less chance of having pulmonary cavitations [20] . Sikalengo et al. (2018) in Tanzania found 16.4% of Sch. m co-infection among active TB patients living in the rural area of Dar Salam [60] . From the findings of this review, there is evidence of an association between the two infections that Sch. m infection increases active TB incidence in individuals with LTBI regardless of their immunological status and there is a clear pathway explaining the mechanism of switching Th1 immune response to a predominant Th2 cytokines production creating a buffer media that drive out the immune control of TB latent bacteria.

4. Conclusions

This Systematic Literature Review has narrowed down findings from different investigational studies on the harms of Sch. m infection on the acquired immune response that controls M. tb infection during the latency stage.

Th2-driven immune response expressed in Sch. m infection down-regulates Th1-induced immune reaction which disrupts immunological cascades against other infectious agents, particularly in patients with LTBI where cell-based immune reaction is predominantly needed to lockdown the TB bacteria in a latent stage when failing its elimination.

Based on this review, we speculate that strategies for TB elimination must consider Schistosoma mansoni eradication actions where both infections are endemic. Large sample sizes and multicentric cohort studies are needed to deeply investigate the epidemiological and clinical implications of Sch. m infection on the global active TB burden, especially in endemic settings.

Acknowledgements

The study team sincerely thanks Mr. Soumaila Traore for his role in the grant that provided support in the literature review.

Funding Support

Research reported in this publication was supported by the Fogarty International Center of the National Institutes of Health under Award Number D43TW010350. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflicts of Interest

The authors declare no conflicts of interest regarding the publication of this paper.

References

[1]	World Health Organization (2021) Global Tuberculosis Report 2021. Geneva.
[2]	F.S.J.U.N.P.o.H.A. (2021) Global HIV & AIDS Statistics—2021.
[3]	World Health Organization (2021) World Malaria Report 2021. Geneva.
[4]	Raviglione, M. and Sulis, G. (2016) Tuberculosis 2015: Burden, Challenges and Strategy for Control and Elimination. Infectious Disease Reports, 8, 6570. https://doi.org/10.4081/idr.2016.6570
[5]	Huynh, K.K., Joshi, S.A. and Brown, E.J. (2011) A Delicate Dance: Host Response to Mycobacteria. Current Opinion in Immunology, 23, 464-472. https://doi.org/10.1016/j.coi.2011.06.002
[6]	Munk, M.E. (1995) Functions of T-Cell Subsets and Cytokines in Mycobacterial Infections. The European Respiratory Journal. Supplement, 20, 668s-675s.
[7]	Ahmad, S. (2011) Pathogenesis, Immunology, and Diagnosis of Latent Mycobacterium tuberculosis Infection. Clinical and Developmental Immunology, 2011, Article ID: 814943. https://doi.org/10.1155/2011/814943
[8]	Kiazyk, S. and Ball, T.B. (2017) Latent Tuberculosis Infection: An Overview. Canada Communicable Disease Report, 43, 62-66. https://doi.org/10.14745/ccdr.v43i34a01
[9]	Spellberg, B. and Edwards, J.E. (2001) Type 1/Type 2 Immunity in Infectious Diseases. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 32, 76-102. https://doi.org/10.1086/317537
[10]	Ai, J.W., et al. (2016) Updates on the Risk Factors for Latent Tuberculosis Reactivation and Their Managements. Emerging Microbes & Infections, 5, e10. https://doi.org/10.1038/emi.2016.10
[11]	Williams, B.G., Dye, C., et al. (2009) Drivers of Tuberculosis Epidemics: The Role of Risk Factors and Social Determinants. Social Science & Medicine, 68, 2240-2246. https://doi.org/10.1016/j.socscimed.2009.03.041
[12]	Karunamoorthi, K., Almalki, M. and Ghailan, K. (2018) Schistosomiasis: A Neglected Tropical Disease of Poverty: A Call for Intersectoral Mitigation Strategies for Better Health. Journal of Health Research and Reviews, 5, 1-12. https://doi.org/10.4103/jhrr.jhrr_92_17
[13]	Cadmus, S.I., et al. (2020) Interactions between Helminths and Tuberculosis Infections: Implications for Tuberculosis Diagnosis and Vaccination in Africa. PLOS Neglected Tropical Diseases, 14, e0008069. https://doi.org/10.1371/journal.pntd.0008069
[14]	Chiu, B.C., et al. (2003) Cytokine-Chemokine Networks in Experimental Mycobacterial and Schistosomal Pulmonary Granuloma Formation. The American Journal of Respiratory Cell and Molecular Biology, 29, 106-116. https://doi.org/10.1165/rcmb.2002-0241OC
[15]	Magalhães, A., et al. (2004) Cytokine Profile Associated with Human Chronic Schistosomiasis mansoni. Memórias do Instituto Oswaldo Cruz, 99, 21-26. https://doi.org/10.1590/S0074-02762004000900004
[16]	Toulza, F., et al. (2016) Mycobacterium tuberculosis-Specific CD4+ T-Cell Response Is Increased, and Treg Cells Decreased, in Anthelmintic-Treated Patients with Latent TB. European Journal of Immunology, 46, 752-761. https://doi.org/10.1002/eji.201545843
[17]	Elias, D., et al. (2001) Effect of Deworming on Human T Cell Responses to Mycobacterial Antigens in Helminth-Exposed Individuals before and after Bacille Calmette-Guérin (BCG) Vaccination. Clinical & Experimental Immunology, 123, 219-225. https://doi.org/10.1046/j.1365-2249.2001.01446.x
[18]	Dessie, N., Lema, W. and Aemero, M. (2020) Hematological and Biochemical Profile of Patients Infected with Schistosoma mansoni in Comparison with Apparently Healthy Individuals at Sanja Town, Northwest Ethiopia: A Cross-Sectional Study. Journal of Tropical Medicine, 2020, Article ID: 4083252. https://doi.org/10.1155/2020/4083252
[19]	Brown, M., et al. (2006) Schistosoma mansoni, Nematode Infections, and Progression to Active Tuberculosis among HIV-1-Infected Ugandans. American Journal of Tropical Medicine and Hygiene, 74, 819-825. https://doi.org/10.4269/ajtmh.2006.74.819
[20]	Mhimbira, F., et al. (2017) Prevalence and Clinical Relevance of Helminth Co-Infections among Tuberculosis Patients in Urban Tanzania. PLOS Neglected Tropical Diseases, 11, e0005342. https://doi.org/10.1371/journal.pntd.0005342
[21]	Montgomery, S. (2020) Health Information for International Travel. Centers for Disease Control and Prevention (CDC) Yellow Book, Atlanta, Chapter 4.
[22]	World Health Organization (2022) Global Tuberculosis Report 2022. Geneva, 68.
[23]	Division of Tuberculosis Elimination, N.C.f.H., Viral Hepatitis, STD, and TB Prevention (2020) Treatment Regimens for Latent TB Infection. Centers for Disease Control and Prevention (CDC), Atlanta.
[24]	Kullberg, M.C., et al. (1992) Infection with Schistosoma mansoni Alters Th1/Th2 Cytokine Responses to a Non-Parasite Antigen. Journal of Immunology, 148, 3264-3270. https://doi.org/10.4049/jimmunol.148.10.3264
[25]	Rafi, W., et al. (2012) Coinfection-Helminthes and Tuberculosis. Current Opinion in HIV and AIDS, 7, 239-244. https://doi.org/10.1097/COH.0b013e3283524dc5
[26]	Salgame, P., Yap, G.S. and Gause, W.C. (2013) Effect of Helminth-Induced Immunity on Infections with Microbial Pathogens. Nature Immunology, 14, 1118-1126. https://doi.org/10.1038/ni.2736
[27]	Kondělková, K., et al. (2010) Regulatory T Cells (Treg) and Their Roles in Immune System with Respect to Immunopathological Disorders. Acta Medica (Hradec Králové), 53, 73-77. https://doi.org/10.14712/18059694.2016.63
[28]	Méndez-Samperio, P. (2014) Modulation of Tuberculosis-Related Immune Responses by Helminths. Journal of the Egyptian Society of Parasitology, 44, 141-144. https://doi.org/10.12816/0006453
[29]	McArdle, A.J., Turkova, A. and Cunnington, A.J. (2018) When Do Co-Infections Matter? Current Opinion in Infectious Diseases, 31, 209-215. https://doi.org/10.1097/QCO.0000000000000447
[30]	Abate, E., et al. (2015) Asymptomatic Helminth Infection in Active Tuberculosis Is Associated with Increased Regulatory and Th-2 Responses and a Lower Sputum Smear Positivity. PLOS Neglected Tropical Diseases, 9, e0003994. https://doi.org/10.1371/journal.pntd.0003994
[31]	Mendelson, M. (2007) Diagnosing Tuberculosis in HIV-Infected Patients: Challenges and Future Prospects. British Medical Bulletin, 81-82, 149-165. https://doi.org/10.1093/bmb/ldm009
[32]	Babu, S. and Nutman, T.B. (2016) Helminth-Tuberculosis Co-Infection: An Immunologic Perspective. Trends in Immunology, 37, 597-607. https://doi.org/10.1016/j.it.2016.07.005
[33]	Rajamanickam, A., et al. (2019) Coexistent Helminth Infection-Mediated Modulation of Chemokine Responses in Latent Tuberculosis. The Journal of Immunology, 202, 1494-1500. https://doi.org/10.4049/jimmunol.1801190
[34]	Rajamanickam, A., et al. (2020) Helminth Coinfection Alters Monocyte Activation, Polarization, and Function in Latent Mycobacterium tuberculosis Infection. The Journal of Immunology, 204, 1274-1286. https://doi.org/10.4049/jimmunol.1901127
[35]	Kiflie, A., et al. (2021) Differential Effects of Asymptomatic Ascaris lumbricoides, Schistosoma mansoni or Hook Worm Infection on the Frequency and TGF-Beta-Producing Capacity of Regulatory T Cells during Active Tuberculosis. Tuberculosis (Edinb), 131, Article ID: 102126. https://doi.org/10.1016/j.tube.2021.102126
[36]	Resende Co, T., et al. (2007) Intestinal Helminth Co-Infection Has a Negative Impact on both Anti-Mycobacterium tuberculosis Immunity and Clinical Response to Tuberculosis Therapy. Clinical & Experimental Immunology, 147, 45-52. https://doi.org/10.1111/j.1365-2249.2006.03247.x
[37]	Méndez-Samperio, P. (2012) Immunological Mechanisms by Which Concomitant Helminth Infections Predispose to the Development of Human Tuberculosis. The Korean Journal of Parasitology, 50, 281-286. https://doi.org/10.3347/kjp.2012.50.4.281
[38]	Bogdan, C., Vodovotz, Y. and Nathan, C. (1991) Macrophage Deactivation by Interleukin 10. Journal of Experimental Medicine, 174, 1549-1555. https://doi.org/10.1084/jem.174.6.1549
[39]	Gong, J.H., et al. (1996) Interleukin-10 Downregulates Mycobacterium tuberculosis-Induced Th1 Responses and CTLA-4 Expression. Infection and Immunity, 64, 913-918. https://doi.org/10.1128/iai.64.3.913-918.1996
[40]	Abate, E., et al. (2015) Effects of Albendazole on the Clinical Outcome and Immunological Responses in Helminth Co-Infected Tuberculosis Patients: A Double Blind Randomised Clinical Trial. International Journal for Parasitology, 45, 133-140. https://doi.org/10.1016/j.ijpara.2014.09.006
[41]	Aira, N., et al. (2017) Species Dependent Impact of Helminth-Derived Antigens on Human Macrophages Infected with Mycobacterium tuberculosis: Direct Effect on the Innate Anti-Mycobacterial Response. PLOS Neglected Tropical Diseases, 11, e0005390. https://doi.org/10.1371/journal.pntd.0005390
[42]	Olds, G.R., et al. (1981) Monocyte-Mediated Killing of Schistosomula of Schistosoma mansoni: Alterations in Human Schistosomiasis mansoni and Tuberculosis. The Journal of Immunology, 127, 1538-1542. https://doi.org/10.4049/jimmunol.127.4.1538
[43]	Musaigwa, F., et al. (2022) Schistosoma mansoni Infection Induces Plasmablast and Plasma Cell Death in the Bone Marrow and Accelerates the Decline of Host Vaccine Responses. PLOS Pathogens, 18, e1010327. https://doi.org/10.1371/journal.ppat.1010327
[44]	Monin, L., et al. (2015) Helminth-Induced Arginase-1 Exacerbates Lung Inflammation and Disease Severity in Tuberculosis. Journal of Clinical Investigation, 125, 4699-4713. https://doi.org/10.1172/JCI77378
[45]	Cervi, E. (2004) Th2 Response Polarization during Infection with the Helminth Parasite Schistosoma mansoni. Immunological Reviews, 201, 117-126. https://doi.org/10.1111/j.0105-2896.2004.00187.x
[46]	Giera, M., et al. (2018) The Schistosoma mansoni Lipidome: Leads for Immunomodulation. Analytica Chimica Acta, 1037, 107-118. https://doi.org/10.1016/j.aca.2017.11.058
[47]	Meurs, L., et al. (2014) Cytokine Responses to Schistosoma mansoni and Schistosoma haematobium in Relation to Infection in a Co-Endemic Focus in Northern Senegal. PLOS Neglected Tropical Diseases, 8, e3080. https://doi.org/10.1371/journal.pntd.0003080
[48]	Schramm, G., et al. (2018) Schistosome Eggs Impair Protective Th1/Th17 Immune Responses against Salmonella Infection. Frontiers in Immunology, 9, 2614. https://doi.org/10.3389/fimmu.2018.02614
[49]	DiNardo, A.R., et al. (2016) Schistosome Soluble Egg Antigen Decreases Mycobacterium tuberculosis-Specific CD4+ T-Cell Effector Function with Concomitant Arrest of Macrophage Phago-Lysosome Maturation. The Journal of Infectious Diseases, 214, 479-488. https://doi.org/10.1093/infdis/jiw156
[50]	McLaughlin, T.A., et al. (2020) CD4 T Cells in Mycobacterium tuberculosis and Schistosoma mansoni Co-Infected Individuals Maintain Functional TH1 Responses. Frontiers in Immunology, 11, 127. https://doi.org/10.3389/fimmu.2020.00127
[51]	Ferrari, T.C.A., et al. (2006) Localized Hepatic Tuberculosis Presenting as Fever of Unknown Origin. The Brazilian Journal of Infectious Diseases, 10, 364-367. https://doi.org/10.1590/S1413-86702006000500013
[52]	Basile, D., et al. (2007) Co-Infection Schistosoma mansonii and Mycobacterium tuberculosis, about a Case and Literature Review. Travel Medicine and Infectious Disease, 5, 412-413. https://doi.org/10.1016/j.tmaid.2007.09.038
[53]	Gobbi, F., et al. (2015) Schistosoma mansoni Eggs in Spleen and Lungs, Mimicking Other Diseases. PLOS Neglected Tropical Diseases, 9, 6. https://doi.org/10.1371/journal.pntd.0003860
[54]	Range, N., et al. (2007) HIV and Parasitic Co-Infections in Tuberculosis Patients: A Cross-Sectional Study in Mwanza, Tanzania. Annals of Tropical Medicine & Parasitology, 101, 343-351. https://doi.org/10.1179/136485907X176373
[55]	Abate, E., et al. (2012) The Impact of Asymptomatic Helminth Co-Infection in Patients with Newly Diagnosed Tuberculosis in North-West Ethiopia. PLOS ONE, 7, e42901. https://doi.org/10.1371/journal.pone.0042901
[56]	Li, X.X. and Zhou, X.N. (2013) Co-Infection of Tuberculosis and Parasitic Diseases in Humans: A Systematic Review. Parasites & Vectors, 6, 79. https://doi.org/10.1186/1756-3305-6-79
[57]	McLaughlin, T.A., et al. (2021) Schistosoma mansoni Infection Is Associated with a Higher Probability of Tuberculosis Disease in HIV-Infected Adults in Kenya. JAIDS Journal of Acquired Immune Deficiency Syndromes, 86, 157-163. https://doi.org/10.1097/QAI.0000000000002536
[58]	Tegegne, Y., Wondmagegn, T. and Worku, L. (2018) Prevalence of Intestinal Parasites and Associated Factors among Pulmonary Tuberculosis Suspected Patients Attending University of Gondar Hospital, Gondar, Northwest Ethiopia. Journal of Parasitology Research, 2018, Article ID: 9372145. https://doi.org/10.1155/2018/9372145
[59]	Gashaw, F., et al. (2019) High Helminthic Co-Infection in Tuberculosis Patients with Undernutritional Status in Northeastern Ethiopia. Infectious Diseases of Poverty, 8, 88. https://doi.org/10.1186/s40249-019-0600-2
[60]	Sikalengo, G., Mhimbira, F., Rutaihwa, L.K., et al. (2018) Distinct Clinical Characteristics and Helminth Co-Infections in Adult Tuberculosis Patients from Urban Compared to Rural Tanzania. Infectious Diseases of Poverty, 7, Article No. 24. https://doi.org/10.1186/s40249-018-0404-9
[61]	Torresi, J. and Sievert, W. (2001) Hepatosplenic Schistosomiasis Presenting as Granulomatous Hepatitis in an Immigrant from the Philippines with Pulmonary Tuberculosis, Tuberculous Lymphadenitis, and a History of Alcohol Abuse. Journal of Travel Medicine, 8, 216-218. https://doi.org/10.2310/7060.2001.22142