Are intestinal helminths playing a positive role in tuberculosis risk? A systematic review and meta-analysis.

BACKGROUND: Co-infection of intestinal helminthic infections (IHIs) and tuberculosis (TB) has appeared as a public health issue, especially in developing countries. Some recent studies have been carried out on the possible relevance of IHIs to TB. The current systematic review and meta-analysis was conducted to assess the prevalence and odds ratio (OR) of IHIs among TB patients and clarify the relationship between IHIs and TB disease. METHODS: For the purpose of the study, five English databases including PubMed, Science Direct, Scopus, Web of Science (ISI), and Google scholar were searched (up to January 30, 2019) in order to find the related studies. Random-effects meta-analysis model was used to estimate the pooled prevalence, odds ratio (OR), and 95% confidence interval (CI). Inclusion and exclusion criteria were applied. RESULTS: A total of 20 studies including 10 studies with case-control design (2217 patients and 2520 controls) and 10 studies with cross-sectional design (a total of 2415 participants) met the eligibility criteria. As shown by the random-effects model, the pooled prevalence of IHIs in TB patients was estimated to be 26% (95% CI, 17-35%; 1249/4632). The risk of IHI was higher in TB patients compared to controls but this was not statistically significant. However, according to genus/species, the pooled OR of Strongyloides stercoralis (S. stercoralis) (OR, 2.68; 95% CI, 1.59-4.54) had a significantly higher risk in TB patients compared to controls. Nevertheless, the results of random effects model showed no statistically significant association between overall pooled OR of IHIs in TB patients compared to controls in case-control studies (OR, 1; 95% CI, 0-1). CONCLUSIONS: It is highly recommended that more precise studies should be carried out by researchers in order to better understand this association. Also, it is of great importance to include the periodic screenings for IHIs in the routine clinical care of these patients.

Blastocystis subtype 1 (allele 4); Predominant subtype among tuberculosis patients in Iran.

BACKGROUND: Blastocystis and tuberculosis are two public health issues that are frequently reported in regions with low level of hygiene. Therefore, the current study aimed to investigate Blastocystis subtype and allele distribution in TB patients. METHODS: Totally, 161 stool samples were taken from TB patients who were undergoing anti-MTB treatment. Stool samples were concentrated using conventional formalin-ether technique and examined using Lugol's iodine staining under light microscopy. DNA extraction was carried out and discriminative fragment was amplified and sequenced. With comparison in GenBank database, relevant subtypes and alleles were characterized and phylogenetically analyzed using MEGA v.7 and Tamura 3-parameter model. RESULTS: In total, from 161 stool samples, 19 samples were suspected to be Blastocystis-positive. The expected fragment was amplified in 13 (8.07%) of samples. Accordingly, 11/13 (84.62%) of Blastocystis cases settled in urban and 2/13 (15.38%) were villagers. Close-contact with animals was also seen among 7/13 (53.84%) of samples. Subtype 1 (7/13; 53.84%) was the most prevalent followed by subtype 2 (5/13; 38.46%) and subtype 3 (1/13, 7.69%). All ST1 were allele 4, while alleles 9, 11 and 12 were seen in ST2 and allele 34 was the only allele observed in ST3. All three subtypes were clearly separated, while there was no separation between sequences from TB and non-TB patients. CONCLUSION: Blastocystis ST1 was the most prevalent subtype in TB patients and there was no difference between Blastocystis isolates from TB and non-TB human subjects.

Distinct clinical characteristics and helminth co-infections in adult tuberculosis patients from urban compared to rural Tanzania.

BACKGROUND: Differences in rural and urban settings could account for distinct characteristics in the epidemiology of tuberculosis (TB). We comparatively studied epidemiological features of TB and helminth co-infections in adult patients from rural and urban settings of Tanzania. METHODS: Adult patients (≥ 18 years) with microbiologically confirmed pulmonary TB were consecutively enrolled into two cohorts in Dar es Salaam, with ~ 4.4 million inhabitants (urban), and Ifakara in the sparsely populated Kilombero District with ~ 400 000 inhabitants (rural). Clinical data were obtained at recruitment. Stool and urine samples were subjected to diagnose helminthiases using Kato-Katz, Baermann, urine filtration, and circulating cathodic antigen tests. Differences between groups were assessed by χ2, Fisher's exact, and Wilcoxon rank sum tests. Logistic regression models were used to determine associations. RESULTS: Between August 2015 and February 2017, 668 patients were enrolled, 460 (68.9%) at the urban and 208 (31.1%) at the rural site. Median patient age was 35 years (interquartile range [IQR]: 27-41.5 years), and 454 (68%) were males. Patients from the rural setting were older (median age 37 years vs. 34 years, P = 0.003), had a lower median body mass index (17.5 kg/m2 vs. 18.5 kg/m2, P <  0.001), a higher proportion of recurrent TB cases (9% vs. 1%, P <  0.001), and in HIV/TB co-infected patients a lower median CD4 cell counts (147 cells/µl vs. 249 cells/µl, P = 0.02) compared to those from urban Tanzania. There was no significant difference in frequencies of HIV infection, diabetes mellitus, and haemoglobin concentration levels between the two settings. The overall prevalence of helminth co-infections was 22.9% (95% confidence interval [CI]: 20.4-27.0%). The significantly higher prevalence of helminth infections at the urban site (25.7% vs. 17.3%, P = 0.018) was predominantly driven by Strongyloides stercoralis (17.0% vs. 4.8%, P <  0.001) and Schistosoma mansoni infection (4.1% vs. 16.4%, P <  0.001). Recurrent TB was associated with living in a rural setting (adjusted odds ratio [aOR]: 3.97, 95% CI: 1.16-13.67) and increasing age (aOR: 1.06, 95% CI: 1.02-1.10). CONCLUSIONS: Clinical characteristics and helminth co-infections pattern differ in TB patients in urban and rural Tanzania. The differences underline the need for setting-specific, tailored public health interventions to improve clinical management of TB and comorbidities.

Association between the Human Development Index and Millennium Development Goals 6 Indicators in Sub-Saharan Africa from 2000 to 2014: Implications for the New Sustainable Development Goals.

It is important to assess whether regional progress toward achieving the millennium development goals (MDGs) has contributed to human development and whether this has had an effect on the triple burden of disease in the continent. This analysis investigates the association between the human development index (HDI) and co-occurrence of HIV/AIDS, tuberculosis (TB), and malaria as measured by MDG 6 indicators in 35 selected sub-Saharan African countries from 2000 to 2014. The analysis used secondary data from the United Nations Development Programme data repository for HDI and disease data from WHO Global Health observatory data repository. Generalized Linear Regression Models were used to analyze relationships between HDI and MDG 6 indicators. HDI was observed to improve from 2001 to 2014, and this varied across the selected sub-regions. There was a significant positive relationship between HDI and HIV prevalence in East Africa (ß = 0.048 [95% CI: 0.040-0.056], p < 0.001) and Southern Africa (ß = 0.032 [95% CI: 0.002-0.062], p = 0.034). A significant positive relationship was observed with TB incidence (ß = 0.009 [95% CI: 0.003-0.015], p = 0.002) and a significant negative relationship was observed with malaria incidence (ß = -0.020 (95% CI: -0.029 to -0.010, p < 0.001) in East Africa. Observed improvements in HDI from the year 2000 to 2014 did not translate into commensurate progress in MDG 6 goals.

Tubercular infection of hydatid cyst.

Tubercular infection of hydatid cyst of the chest wall in an immunocompetent individual is rare. Immune modulation for symbiosis between host cells and the parasite - Echinococcus granulosus favors tubercular infection. In this case report, we describe a case of both these chronic diseases coexisting together, to present as chest wall mass.

Tuberculosis arthritis of the sternoclavicular joint after uncomplicated falciparum malaria: a case report.

BACKGROUND: Malaria and tuberculosis are co-endemic in many developing countries. However their associations are rarely reported. Yet, it has been suggested that a pathological process may link the two diseases. CASE PRESENTATION: A 20-year-old female patient was admitted in the internal medicine service of Aristide Le Dantec Hospital for uncomplicated malaria. She was previously treated for autoimmune hemolytic anaemia using prednisone at 5 mg per day. Clinical examination showed swelling in front of the sternoclavicular joint. She presented with fever and headache. Thick smear from blood revealed trophozoites of P. falciparum at parasite density of 52,300 parasites/µl. The Ziehl-Neelsen stained smear showed the presence of acid-fast bacilli from the fluid puncture of the swelling. Mycobacterium tuberculosis was further isolated in culture. The diagnosis of falciparum malaria co-infection with sternoclavicular tuberculosis was posed. The patient was treated successfully using antimalarial drugs subsequently followed by multidrug antitubercular therapy. CONCLUSION: Interactions between malaria and tuberculosis need to be largely and prospectively investigated and appropriate treatment should be undertaken.

Differential proteomics approach to identify putative protective antigens of Mycobacterium tuberculosis presented during early stages of macrophage infection and their evaluation as DNA vaccines.

Unsatisfactory performance of the existing BCG vaccines, especially against the adult pulmonary disease, has urged the need for an effective vaccine against tuberculosis (TB). In this study, we employed differential proteomics to obtain a list of antigens as potential vaccine candidates. Bacterial epitopes being presented at early stages on MHC class I and class II molecules of macrophages infected with Mycobacterium tuberculosis (M. tb) were identified using iTRAQ labelling and reverse phase LC-MS/MS. The putative vaccine candidates, thus identified, were tested as plasmid DNA vaccines in mice to ascertain their protective efficacy against the aerosolized M. tb challenge, based on their ability to reduce the bacterial load in the lungs of infected mice. Here, we observed that 4 out of the 17 selected antigens imparted significant protection against the challenge of M. tb. The four shortlisted antigens were further assessed in a more stringent guinea pig model, where too, they demonstrated.significant protection. It concludes that combining a proteomics approach with the in vivo assessment of vaccine candidates in animal models can be valuable in identifying new potential candidates to expand the antigenic repertoire for novel vaccines against TB.

An experimental model to study tuberculosis-malaria coinfection upon natural transmission of Mycobacterium tuberculosis and Plasmodium berghei.

Coinfections naturally occur due to the geographic overlap of distinct types of pathogenic organisms. Concurrent infections most likely modulate the respective immune response to each single pathogen and may thereby affect pathogenesis and disease outcome. Coinfected patients may also respond differentially to anti-infective interventions. Coinfection between tuberculosis as caused by mycobacteria and the malaria parasite Plasmodium, both of which are coendemic in many parts of sub-Saharan Africa, has not been studied in detail. In order to approach the challenging but scientifically and clinically highly relevant question how malaria-tuberculosis coinfection modulate host immunity and the course of each disease, we established an experimental mouse model that allows us to dissect the elicited immune responses to both pathogens in the coinfected host. Of note, in order to most precisely mimic naturally acquired human infections, we perform experimental infections of mice with both pathogens by their natural routes of infection, i.e. aerosol and mosquito bite, respectively.

Parasite infection and tuberculosis disease among children: a case-control study.

We conducted a case-control study to examine associations between parasite infection, including protozoa infection, and tuberculosis (TB) in children in Lima, Peru. We enrolled 189 matched-pairs. In multivariable conditional logistic regression analyses, Blastocystis hominis infection (rate ratio = 0.30, 95% confidence interval = 0.14-0.64, P = 0.002) was strongly associated with a lower risk of TB. We observed a statistically significant inverse linear dose-response relationship between Blastocystis hominis infection and TB. These findings should be confirmed in future prospective studies.

Development of Mycobacterium tuberculosis whole cell screening hits as potential antituberculosis agents.

The global pandemic of drug sensitive tuberculosis (TB) as well as the increasing threat from various multidrug resistant forms of TB drives the quest for newer, safer, more effective TB treatment options. The general lack of success in progressing novel chemical matter from high throughput screens of Mycobacterium tuberculosis (M.tb) biochemical targets has prompted resurgence in interest and efforts in prosecuting mycobacterial phenotypic screens. Whole cell active compounds identified from such screens offer significant intrinsic advantages over biochemical screening hits, and derivatives of many of these have proven invaluable in helping to fill the current TB drug development pipeline. Modern techniques for "de-orphaning" such screening hits (i.e., determining their specific biological mechanism of action) offer the possibility of ultimately identifying improved next-generation chemical series by screening these essential, pharmacologically validated biochemical targets as well.

Pleuropulmonary paragonimiasis: mimicker of tuberculosis.

Infection caused by the lung fluke is endemic in north eastern parts of India. Paragonimus westermani and Paragonimus heterotremus are known to be endemic in eastern Indian states of Manipur and Nagaland. The infection is related to eating habits of the locals and is acquired by ingestion of raw, inadequately cooked crabs or crayfish containing encysted metacercariae which act as second intermediate hosts during the life cycle of the lung fluke. Diagnosis is generally delayed due to lack of suspicion and presentation similar to tuberculosis which is endemic in the population. We report pleuropulmonary paragonimiasis in a soldier from eastern India who presented with chest pain, haemoptysis, and eosinophilia. He gave history of consumption of raw crabs while on leave at his native village in Nagaland. Ova morphologically resembling Paragonimus heterotremus were detected in sputum and bronchoalveolar lavage specimen. Symptoms resolved with praziquantel treatment.

Rv2190c, an NlpC/P60 family protein, is required for full virulence of Mycobacterium tuberculosis.

Mycobacterium tuberculosis, the etiologic agent of tuberculosis (TB) possesses at least five genes predicted to encode proteins with NlpC/P60 hydrolase domains, including the relatively uncharacterized Rv2190c. As NlpC/P60 domain-containing proteins are associated with diverse roles in bacterial physiology, our objective was to characterize Rv2190c in M. tuberculosis growth and virulence. Our data indicate that lack of Rv2190c is associated with impaired growth, both in vitro and during an in vivo mouse model of TB. These growth defects are associated with altered colony morphology and phthiocerol dimycocerosate levels, indicating that Rv2190c is involved in cell wall maintenance and composition. In addition, we have demonstrated that Rv2190c is expressed during active growth phase and that its protein product is immunogenic during infection. Our findings have significant implications, both for better understanding the role of Rv2190c in M. tuberculosis biology and also for translational developments.

From host immunity to pathogen invasion: the effects of helminth coinfection on the dynamics of microparasites.

Concurrent infections with multiple parasites are ubiquitous in nature. Coinfecting parasites can interact with one another in a variety of ways, including through the host's immune system via mechanisms such as immune trade-offs and immunosuppression. These within-host immune processes mediating interactions among parasites have been described in detail, but how they scale up to determine disease dynamic patterns at the population level is only beginning to be explored. In this review, we use helminth-microparasite coinfection as a model for examining how within-host immunological effects may influence the ecological outcome of microparasitic diseases, with a specific focus on disease invasion. The current literature on coinfection between helminths and major microparasitic diseases includes many studies documenting the effects of helminths on individual host responses to microparasites. In many cases, the observed host responses map directly onto parameters relevant for quantifying disease dynamics; however, there have been few attempts at integrating data on individual-level effects into theoretical models to extrapolate from the individual to the population level. Moreover, there is considerable variability in the particular combination of disease parameters affected by helminths across different microparasite systems. We develop a conceptual framework identifying some potential sources of such variability: Pathogen persistence and severity, and resource availability to hosts. We also generate testable hypotheses regarding diseases and the environmental contexts when the effects of helminths on microparasite dynamics should be most pronounced. Finally, we use a case study of helminth and mycobacterial coinfection in the African buffalo to illustrate both progress and challenges in understanding the population-level consequences of within-host immunological interactions, and conclude with suggestions for future research that will help improve our understanding of the effects of coinfection on dynamics of infectious diseases.

Hidden consequences of living in a wormy world: nematode­induced immune suppression facilitates tuberculosis invasion in African buffalo.

Most hosts are infected with multiple parasites, and responses of the immune system to co-occurring parasites may influence disease spread. Helminth infection can bias the host immune response toward a T-helper type 2 (Th2) over a type 1 (Th1) response, impairing the host's ability to control concurrent intracellular microparasite infections and potentially modifying disease dynamics. In humans, immune-mediated interactions between helminths and microparasites can alter host susceptibility to diseases such as HIV, tuberculosis (TB), and malaria. However, the extent to which similar processes operate in natural animal populations and influence disease spread remains unknown. We used cross-sectional, experimental, and genetic studies to show that gastrointestinal nematode infection alters immunity to intracellular microparasites in free-ranging African buffalo (Syncerus caffer). Buffalo that were more resistant to nematode infection had weaker Th1 responses, there was significant genotypic variation in nematode resistance, and anthelminthic treatment enhanced Th1 immunity. Using a disease dynamic model parameterized with empirical data, we found that nematode-induced immune suppression can facilitate the invasion of bovine TB in buffalo. In the absence of nematodes, TB failed to invade the system, illustrating the critical role nematodes may play in disease establishment. Our results suggest that helminths, by influencing the likelihood of microparasite invasion, may influence patterns of disease emergence in the wild.

Helminth coinfection does not affect therapeutic effect of a DNA vaccine in mice harboring tuberculosis.

BACKGROUND: Helminthiasis and tuberculosis (TB) coincide geographically and there is much interest in exploring how concurrent worm infections might alter immune responses against bacilli and might necessitate altered therapeutic approaches. A DNA vaccine that codifies heat shock protein Hsp65 from M. leprae (DNAhsp65) has been used in therapy during experimental tuberculosis. This study focused on the impact of the co-existence of worms and TB on the therapeutic effects of DNAhsp65. METHODOLOGY/PRINCIPAL FINDINGS: Mice were infected with Toxocara canis or with Schistosoma mansoni, followed by coinfection with M. tuberculosis and treatment with DNAhsp65. While T. canis infection did not increase vulnerability to pulmonary TB, S. mansoni enhanced susceptibility to TB as shown by higher numbers of bacteria in the lungs and spleen, which was associated with an increase in Th2 and regulatory cytokines. However, in coinfected mice, the therapeutic effect of DNAhsp65 was not abrogated, as indicated by colony forming units and analysis of histopathological changes. In vitro studies indicated that Hsp65-specific IFN-gamma production was correlated with vaccine-induced protection in coinfected mice. Moreover, in S. mansoni-coinfected mice, DNA treatment inhibited in vivo TGF-beta and IL-10 production, which could be associated with long-term protection. CONCLUSIONS/SIGNIFICANCE: We have demonstrated that the therapeutic effects of DNAhsp65 in experimental TB infection are persistent in the presence of an unrelated Th2 immune response induced by helminth infections.

Regulation of type 1 diabetes, tuberculosis, and asthma by parasites.

Helminth infection is a worldwide health problem. In addition to directly causing disease, helminthic infection also affects the incidence and progression of other diseases by exerting immune modulatory effects. In animal models, infection with helminthic parasites can prevent autoimmune diseases and allergic inflammatory diseases, but worsens protective immunity to certain infectious pathogens. In this review, we summarize current findings regarding the effects of helminth infection on type 1 diabetes, tuberculosis, and asthma and discuss possible mechanisms through which helminthic parasites modulate host immunity. Investigating these mechanisms could lead to treatment strategies that specifically modulate the immune response as well as address fundamental questions in immunobiology.

Infection with Mycobacterium tuberculosis Beijing genotype strains is associated with polymorphisms in SLC11A1/NRAMP1 in Indonesian patients with tuberculosis.

Differences in host immune genes may predispose to tuberculosis caused by particular Mycobacterium tuberculosis genotypes. We examined this hypothesis in Indonesia by spoligotyping M. tuberculosis isolates recovered from 336 patients with pulmonary tuberculosis and typing the patients' SLC11A1 gene (formerly known as "NRAMP1"), which is involved in susceptibility to tuberculosis. The M. tuberculosis Beijing genotype, which comprised 29.8% of all isolates, was strongly associated with 2 polymorphisms in SLC11A1: the D543N G allele (odds ratio [OR], 2.15; P=.005) and the 3' untranslated region (3'UTR) insertion/insertion genotype (OR, 2.5; P=.001). This finding supports the hypothesis of coevolution of M. tuberculosis and the human immune system.

Fatal relapse of disseminated strongyloidiasis in an HIV-positive patient, despite ivermectin treatment.

There are no established guidelines for the treatment of disseminated strongyloidiasis in immunosuppressed patients, and many different treatment regimens have been used. Here, the case of a 48-year-old, HIV-positive, Congolese man, who was hospitalized for disseminated tuberculosis but developed life-threatening disseminated strongyloidiasis, is described. This patient died, with relapsing disseminated strongyloidiasis, 3 months after being treated with ivermectin. The reasons for this poor outcome and the various treatment options for strongyloidiasis in HIV-infected patients are discussed.

The immune response to toxocariasis does not modify susceptibility to Mycobacterium tuberculosis infection in BALB/c mice.

Mycobacterium tuberculosis and helminth infections coincide geographically and are classically described as TH1 and TH2 pathologies. There is much interest in exploring how concurrent worm infections might alter immune responses to mycobacterial infection. To explore this issue, mice were infected with Toxocara canis and co-infected with M. tuberculosis. Mice infected with M. tuberculosis had high numbers of neutrophils and mononuclear cells within the alveolar spaces, with increased parenchymal interferon (IFN)-gamma levels. However, in Toxocara-infected mice we detected increased eosinophil numbers in bronchoalveolar lavage fluid (BALF) and increased parenchymal levels of interleukin (IL)-5. In co-infected mice the BALF demonstrated enhanced eosinophil influx with decreased neutrophil and mononuclear cell accumulation. However, co-infected mice had similar mycobacterial proliferation in their lungs accompanied by similar histopathological changes and similar cytokine/nitric oxide production compared with Mycobacterium-only-infected mice. Our results suggest that T. canis infection does not necessarily lead to increased susceptibility to pulmonary tuberculosis.

Intestinal helminth co-infection has a negative impact on both anti-Mycobacterium tuberculosis immunity and clinical response to tuberculosis therapy.

The impact of intestinal helminth infection on Mycobacterium tuberculosis (MTB)-specific immune responses during active tuberculosis (TB) is not known. We investigated the role of intestinal helminth infection in anti-MTB immunity by evaluating both cellular phenotype and cytokine profiles in patients with TB and patients with concomitant TB and intestinal helminth infection (TB + Helm) during TB therapy. Twenty-seven per cent of TB patients enrolled for the study were co-infected with at least one intestinal helminth. At baseline, absolute frequencies of leucocytes, monocytes and eosinophils from TB and TB + Helm patients differed from healthy subjects. Concomitant intestinal helminth infection in TB + Helm patients had a negative impact (P < 0.05) on absolute frequencies of CD3(+), CD4(+), CD8(+), natural killer (NK) T and CD4(+) CD25(high) T cell subsets when compared to either TB patients or healthy controls. Differences in CD4(+) T cell frequencies were accompanied by lower interferon (IFN)-gamma and elevated and sustained interleukin (IL)-10 levels in whole blood (WB) cultures from TB + Helm compared to TB patients. In addition to a depressed anti-MTB immunity, TB + Helm patients also presented with more severe radiological pulmonary disease, with a significant difference (P = 0.013) in the number of involved lung zones at the end of TB treatment. The above data may indicate that concomitant intestinal helminth infection in patients with newly diagnosed TB skews their cytokine profile toward a T helper 2 response, which could favour persistent MTB infection and a more protracted clinical course of the disease.