Table 2. Studies implicating and those not supporting helminth co-infection as affecting the diagnosis and outcome of Mtb infections.

S/N	Location of Study/Study type	Helminth(s)	Findings	References
1	*Asia (India) Human Study	Filaria	The investigators revealed that coincident filarial infection exerted a profound inhibitory effect on protective mycobacteria-specific Th1 and Th17 responses in latent tuberculosis, suggesting a mechanism by which concomitant filarial (and other systemic helminth) infections predispose to the development of active TB in humans. They further reported that IFNγ and IL-12 were significantly down-regulated in patients in the PPD+Fil+ group, suggesting that the IL-12/INF- γ pathway in patients with coincident lymphatic filariasis and latent TB was compromised.	[59]
2	**North (USA)	Filaria	The authors indicated that chronic filarial infection does not exacerbate Mtb infection in cotton rat model. They showed that PPD-specific cellular proliferation and IFNγ production were not suppressed in coinfected animals.	[64]
3	*Africa (Ethiopia) Human Study	Trichuris trichiura, Ascaris lumbricoides, Hookworm, Tenia spp, Hymenolepis nana, and Enterobius vermicularis	Elias and colleagues reported that helminth infections reduced BCG immunogenicity in humans by inducing the production of elevated TGF-β instead of the usual Th2 induced cytokines (IL-4 and IL-5).	[75]
4	*Africa (Ethiopia) Human Study	Ascaris lumbricoides, Hookworm, Strongyloides stercoralis, hymenolepis nana, Tenia spp, Entamoeba histolytica&Giardia lamblia	Elias and colleagues revealed that helminth infections impaired BCG vaccination immunogenicity. However, antihelminthic treatment resulted in enhancement of T-cell proliferation and IFN-γ proliferation with improved BCG efficacy among college students.	[84]
5	*Africa (Kenya) Human Study	Filaria and Schistosoma	Malhotra and colleagues reported that helminth-specific immune responses acquired during gestation persisted into childhood and that this prenatal sensitization biased T-cell immunity induced by BCG vaccination away from Th1 and IFN-γ responses associated with protection against mycobacterial infection.	[85]
6	*Europe (UK)	Fasciola hepatica	The authors indicated that F. hepatica was an additional environmental risk factor for BTB and, importantly, was negatively associated with the odds of BTB being diagnosed on a farm. They suggested that, in the presence of F. hepatica infection, the SICCT test was less effective.	[98]
7	*Africa (Ethiopia) Human study	Ascaris lumbricoides	They found that concomitant asymptomatic helminth infection profoundly affected the immune phenotype of TB patients with a strong leaning towards Th2 types of immune response such as increased regulatory T cells as well as IL-5 and IL-10 secreting cells. Furthermore, helminth co-infection was associated with a significantly lower ratio of sputum smear positivity, which correlated to the egg load in helminth positive TB patients.	[101]
8	*South America (Venezuela) Human Study	Trichuria trichiura and Ascaris lumbricoides	Here, the authors confirmed that helminth together with low Th1 were associated with TST positivity in pediatric TB contacts.	[110]
9	**Asia (India)	Filaria and Hookworm	Lipner and colleagues showed that neither hookworm nor filarial significantly influenced the delayed-type hypersensitivity response to tuberculin. They reported that BCG vaccination had a protective effect, even in the presence of hookworm and filarial infection.	[109]
10	***Europe (Sweden)	Hymenolepis diminuta, Trichuris muris, and Schistosoma mansoni	Findings revealed that antigens from different species of helminths directly affected macrophage responses to Mtb. Antigens from the tapeworm Hymenolepis diminuta and the nematode Trichuris muris caused an anti-inflammatory response with M2-type polarization and reduced macrophage phagosome maturation and ability to activate T cells, along with increased Mtb burden, especially in T. muris exposed cells, which also induced the highest IL-10 production upon co-infection. However, antigens from the trematode Schistosoma mansoni had the opposite effect causing a decrease in IL-10 production, M1-type polarization, and increased control of Mtb.	[111]
11	**North America (New Jersey, USA) Experimental Study	Nippostrongylus brasiliensis	Here, Potian and colleagues identified an AAM which was induced via the IL-4Rα signaling pathway in Nippostrongylus brasiliensis mouse model. Th2 response in the coinfected mice did not impair the onset and development of the protective Mtb-specific Th1 cellular immune responses. However, the helminth-induced Th2 environment resulted in the accumulation of AAMs in the lung.	[116]
12	* Experimental	Schistosoma mansoni	Using a pulmonary mouse model of Mtb infection, the authors demonstrated that S. mansoni co-infection or immunization with S. mansoni egg antigens can reversibly impair Mtb-specific T cell responses without affecting macrophage-mediated Mtb control. Instead, S. mansoni infection resulted in accumulation of high arginase-1–expressing macrophages in the lung, which formed type 2 granulomas and exacerbated inflammation in Mtb-infected mice. Treatment of coinfected animals with an antihelminthic improved Mtb-specific Th1 responses and reduced disease severity.	[117]
13	**New Jersey, USA	Heligmosomoides polygyrus, a murine enteric nematode	Rafi and others indicated that prior infection with Heligmosomoides polygyrus a murine enteric nematode, did not affect the outcome of primary Mtb infection or challenged infection in vaccinated hosts. Despite the presence of helminth-induced Tregs, resistance to primary Mtb infection was not compromised in coinfected mice.	[120]
14	*Europe (UK) Human study	Strongyloides and Schistosoma	Helminth infection was associated with a lower frequency of CD4+IFN-γ + T cells, which increased following treatment. Patients with helminth infection showed a significant increase in CD4+FoxP3+ T cells (Treg) compared to those without helminth infection. There was a decrease in the frequency of Treg cells and an associated increase in CD4+IFN-γ + T cells after the anthelmintic treatment. Here, they showed a potential role of Treg cells in reducing the frequency and function of antimycobacterial CD4+IFN-γ + T cells and that these effects were reversed after anthelmintic treatment.	[121]
15	*Asia (India) Human Study	Wuchereria bancrofti and Strongyloides stercoralis	The authors confirmed that co-existent helminth infection was associated with an IL-10–mediated (for filarial infection) profound inhibition of antigen-specific CD4+ T cell (Th1 &Th17) responses as well as protective systemic cytokine responses in active pulmonary TB. Their study therefore revealed significant alterations in the baseline frequencies of mono—and multifunctional CD4+ and CD8 + Th1 and Th17 cells in TB-infected individuals with active helminth infection.	[122]
16	*Asia (India)	Hookworm	The authors revealed that coincident hookworm infection exerted a profound inhibitory effect on protective Th1 and Th17 responses in latent TB and therefore predisposed toward the development of active TB in humans.	[123]
17	*Europe (Sweden) Experimental	Schistosoma mansoni	Elias and others confirmed that S. mansoni infection reduced the protective efficacy of BCG vaccination against Mtb possibly by attenuation of protective immune responses to mycobacterial antigens and/or by polarizing the general immune responses to the Th2 profile in mice.	[124]
18	*South America (Brazil)	Toxocara canis and Schistosoma mansoni,	Frantz and colleagues demonstrated that the therapeutic effects of DNAhsp65 (a DNA vaccine that codifies heat shock protein Hsp65 from M. leprae, which is used in therapy during experimental TB) in experimental TB infection was persistent in the presence of an unrelated Th2 immune response induced by helminth infections in mice.	[125]
19	*Europe (Sweden)	Schistosoma mansoni	The authors indicated that S. mansoni coinfected mice had significantly higher levels of BCG bacilli in their organs and sustained greater lung pathology compared to Schistosoma uninfected controls.	[126]
20	*Europe (Ireland)	Fasciola hepatica	Flynn and colleagues demonstrated that F. hepatica altered irresponsiveness (delayed-type hypersensitivity reaction and cytokine responses) to virulent M. bovis, thus inducing the reduction of IFN-γ responsiveness in coinfected animals.	[127]
21	*Europe (Ireland)	Fasciola hepatica	Flynn and colleagues found the predictive capacity of tests (SCITT and the IFN-γ) to be compromised in coinfected animals and that F. hepatica infection altered macrophage function. IL-4 and IFN-γ expression in whole-blood lymphocytes restimulated in vitro with M. bovis antigen was also altered in coinfected animals. These results raised the question of whether F. hepatica infection can affect the predictive capacity of tests for the diagnosis of BTB and possibly also influence susceptibility to BTB and other bacterial diseases.	[128]

AAM, alternatively activated macrophage; BCG, Bacille Calmette Guerin; BTB, bovine tuberculosis; CD, cluster of differentiation; IFN-γ, interferon gamma; Mtb, Mycobacterium tuberculosis; PPD, purified protein derivative; SCITT, single cervical intradermal tuberculin test; TB, tuberculosis; TGF-β, transforming growth factor β; Th1, T-helper type 1; Treg, regulatory t cells; TST, tuberculin skin test

*In agreement

** Not in agreement

*** Indicated both agreement and not in agreement