Rapidly progressive respiratory failure after helminth larvae ingestion.

BACKGROUND: Self-administration of helminths has gained attention among patients as a potential but unproven therapy for autoimmune disease. We present a case of rapidly progressive respiratory failure in a patient with systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH) as a result of self-administration of parasitic organisms. CASE: A 45-year-old woman with a history of interstitial lung disease and PAH due to limited cutaneous SSc presented to pulmonary clinic with worsening dyspnea, cough, and new onset hypoxemia. Three months prior to presentation she started oral helminth therapy with Necator americanus as an alternative treatment for SSc. Laboratory evaluation revelaed eosinophilia and elevated IgE levels. IgG antibodies to Strongyloides were detected. High resolution computed tomography of the chest revealed progressive ILD and new diffuse ground glass opacities. Transthoracic echocardiogram and right heart catheterization illustrated worsening PAH and right heart failure. The patient was admitted to the hospital and emergently evaluated for lung transplantation but was not a candidate for transplantation due to comorbidities. Despite aggressive treatment for PAH and right heart failure, her respiratory status deteriorated, and the patient transitioned to comfort-focused care. CONCLUSION: Although ingestion of helminths poses a risk of infection, helminth therapy has been investigated as a potential treatment for autoimmune diseases. In this case, self-prescribed helminth ingestion precipitated fatal acute worsening of lung inflammation, hypoxemia, and right heart dysfunction, highlighting the risk of experimental helminth therapy in patients, especially those with underlying respiratory disease.

Immunomodulatory potential of nematodes against dendritic cells is dependent on intestinal inflamation.

The mouse intestinal parasite Heligmosomoides polygyrus demonstrates adaptation to the inflammatory milieu as a result of colitis induced by dextran sulphate sodium (DSS). Nematodes from mice with colitis had different effects on dendritic cells than nematodes from mice without colitis. Immature JAWSII cells pre-exposed to L4 stage H. polygyrus from DSS-treated mice were adoptively transferred to mice with induced colitis. After two days, a higher disease activity index, macroscopic damage score and colon histology score were observed. MLN T cells isolated nine days after transfer demonstrated proinflammatory IFN-γ and IL-17 production. Transfer of JAWSII stimulated with male or female L4 larvae from a control invasion resulted in a slight improvement of colitis; in addition, dendritic cells exposed to H. polygyrus female L4 larvae, provoked migration of CD8+CD25+ T cells from MLN to the colon. Nematodes from an inflammatory environment changed cytokine production by dendritic cells. Inflammatory milieu changing nematode immunomodulatory activity affects dendritic cell functions, which offers new insight into the helminth-host relationship.

Clinical Use of Schistosoma mansoni Antigens as Novel Immunotherapies for Autoimmune Disorders.

The hygiene hypothesis states that improved hygiene and the resulting disappearance of once endemic diseases is at the origin of the enormous increase in immune related disorders such as autoimmune diseases seen in the industrialized world. Helminths, such as Schistosoma mansoni, are thought to provide protection against the development of autoimmune diseases by regulating the host's immune response. This modulation primarily involves induction of regulatory immune responses, such as generation of tolerogenic dendritic cells and alternatively activated macrophages. This points toward the potential of employing helminths or their products/metabolites as therapeutics for autoimmune diseases that are characterized by an excessive inflammatory state, such as multiple sclerosis (MS), type I diabetes (T1D) and inflammatory bowel disease (IBD). In this review, we examine the known mechanisms of immune modulation by S. mansoni, explore preclinical and clinical studies that investigated the use of an array helminthic products in these diseases, and propose that helminthic therapy opens opportunities in the treatment of chronic inflammatory disorders.

Effectiveness of Helminth Therapy in the Prevention of Allograft Rejection: A Systematic Review of Allogeneic Transplantation.

Background: The unique immunomodulatory capacity of helminth parasites has been investigated as a novel strategy in the prevention of allograft rejection after transplantation. This review was conducted to fully evaluate the specific effects of helminth therapy on allograft survival reported in published studies of animal models of allogeneic transplantation. Method: Following PRISMA protocol guidelines, a literature search was conducted using PubMed, MEDLINE via OvidSP, along with additional manual searches of selected reference lists. Publications describing helminth intervention within allograft transplantation models were screened for relevance to eligibility criteria. Primary and secondary outcomes were extracted using standardized data collection tables. The SYRCLE risk of bias assessment tool was used for quality assessment. Due to heterogeneity of study designs, meta-analysis could not be performed; rather outcomes are presented as a narrative synthesis with concept mapping. This review was registered in PROSPERO with ID: CRD42018097175. Results: The literature search generated 1,443 publications, which after screening for relevance to the eligibility criteria yielded 15 publications for qualitative analysis. All 15 publications reported improvement to allograft survival as a result of helminth therapy. This prolonged allograft survival was not significantly different when helminth-derived products were used compared to live infection. However, the extent of positive impact on allograft survival was noted to be dependent on study design factors, such as the chronicity of the live helminth infection, allograft type and the species/genus of helminth selected. Conclusion: Both live and product-based helminth therapy have potential applications as novel immune regulators or adjuncts for the prevention of allograft rejection. However, there were differences in efficacy between different worms and preparations of worm-derived products. Therefore, further studies are required to determine the most appropriate worm for a specific allograft, to elucidate the optimal dose and route of administration, and to better understand the modulation of immune responses that can mediate tolerance.

Randomized, Placebo Controlled Trial of Experimental Hookworm Infection for Improving Gluten Tolerance in Celiac Disease.

INTRODUCTION: Celiac disease is an autoimmune disorder where intestinal immunopathology arises after gluten consumption. Previous studies suggested that hookworm infection restores gluten tolerance; however, these studies were small (n = 12) and not placebo controlled. METHODS: We undertook a randomized, placebo-controlled trial of hookworm infection in 54 people with celiac disease. The 94-week study involved treatment with either 20 or 40 Necator americanus third-stage larvae (L3-20 or L3-40) or placebo, followed by escalating gluten consumption (50 mg/d for 12 weeks, 1 g intermittent twice weekly for 12 weeks, 2 g/d sustained for 6 weeks, liberal diet for 1 year). RESULTS: Successful study completion rates at week 42 (primary outcome) were similar in each group (placebo: 57%, L3-20: 37%, and L3-40: 44%; P = 0.61), however gluten-related adverse events were significantly reduced in hookworm-treated participants: Median (range) adverse events/participant were as follows: placebo, 4 (1-9); L3-20, 1 (0-9); and L3-40, 0 (0-3) (P = 0.019). Duodenal villous height:crypt depth deteriorated similarly compared with their enrolment values in each group (mean change [95% confidence interval]: placebo, -0.6 [-1.3 to 0.2]; L3-20, -0.5 [-0.8 to 0.2]; and L3-40, -1.1 [-1.8 to 0.4]; P = 0.12). A retrospective analysis revealed that 9 of the 40 L3-treated participants failed to establish hookworm infections. Although week 42 completion rates were similar in hookworm-positive vs hookworm-negative participants (48% vs 44%, P = 0.43), quality of life symptom scores were lower in hookworm-positive participants after intermittent gluten challenge (mean [95% confidence interval]: 38.9 [33.9-44] vs 45.9 [39.2-52.6]). DISCUSSION: Hookworm infection does not restore tolerance to sustained moderate consumption of gluten (2 g/d) but was associated with improved symptom scores after intermittent consumption of lower, intermittent gluten doses.

Potential application of helminth therapy for resolution of neuroinflammation in neuropsychiatric disorders.

Neuropsychiatric disorders (NPDs) are among the major debilitating disorders worldwide with multiple etiological factors. However, in recent years, psychoneuroimmunology uncovered the role of inflammatory condition and autoimmune disorders in the etiopathogenesis of different NPDs. Hence, resolution of inflammation is a new therapeutic target of NPDs. On the other hand, Helminth infections are among the most prevalent infectious diseases in underdeveloped countries, which usually caused chronic infections with minor clinical symptoms. Remarkably, helminths are among the master regulator of inflammatory reactions and epidemiological studies have shown an inverse association between prevalence of autoimmune disorders with these infections. As such, changes of intestinal microbiota are known to be associated with inflammatory conditions in various NPDs. Conversely, helminth colonization alters the intestinal microbiota composition that leads to suppression of intestinal inflammation. In animal models and human studies, helminths or their antigens have shown to be protected against severe autoimmune and allergic disorders, decline the intensity of inflammatory reactions and improved clinical symptoms of the patients. Therefore, "helminthic therapy" have been used for modulation of immune disturbances in different autoimmunity illnesses, such as Multiple Sclerosis (MS) and Inflammatory Bowel Disease (IBD). Here, it is proposed that "helminthic therapy" is able to ameliorate neuroinflammation of NPDs through immunomodulation of inflammatory reactions and alteration of microbiota composition. This review discusses the potential application of "helminthic therapy" for resolution of neuroinflammation in NPDs.

Safety and tolerability of experimental hookworm infection in humans with metabolic disease: study protocol for a phase 1b randomised controlled clinical trial.

BACKGROUND: Abdominal obesity and presence of the metabolic syndrome (MetS) significantly increase the risk of developing diseases such as Type 2 diabetes mellitus (T2DM) with escalating emergence of MetS and T2DM constituting a significant public health crisis worldwide. Lower prevalence of inflammatory and metabolic diseases such as T2DM in countries with higher incidences of helminth infections suggested a potential role for these parasites in the prevention and management of certain diseases. Recent studies confirmed the potential protective nature of helminth infection against MetS and T2DM via immunomodulation or, potentially, alteration of the intestinal microbiota. This Phase 1b safety and tolerability trial aims to assess the effect of inoculation with helminths on physical and metabolic parameters, immune responses, and the microbiome in otherwise healthy women and men. METHODS: Participants eligible for inclusion are adults aged 18-50 with central obesity and a minimum of one additional feature of MetS recruited from the local community with a recruitment target of 54. In a randomised, double-blind, placebo-controlled design, three groups will receive either 20 or 40 stage three larvae of the human hookworm Necator americanus or a placebo. Eligible participants will provide blood and faecal samples at their baseline and 6-monthly assessment visits for a total of 24 months with an optional extension to 36 months. During each scheduled visit, participants will also undergo a full physical examination and complete diet (PREDIMED), physical activity, and patient health (PHQ-9) questionnaires. Outcome measurements include tolerability and safety of infection with Necator americanus, changes in metabolic and immunological parameters, and changes in the composition of the faecal microbiome. DISCUSSION: Rising cost of healthcare associated with obesity-induced metabolic diseases urgently calls for new approaches in disease prevention. Findings from this trial will provide valuable information regarding the potential mechanisms by which hookworms, potentially via alterations in the microbiota, may positively influence metabolic health. TRIAL REGISTRATION: The protocol was registered on ANZCTR.org.au on 05 June 2017 with identifier ACTRN12617000818336. Alternatively, a Google search using the above trial registration number will yield a direct link to the trial protocol within the ANZCTR website.

Helminths products directly modulate T cells that mediate experimental autoimmune encephalomyelitis.

Infection with helminths can protect against the development of autoimmune diseases and this has been associated with induction of anti-inflammatory innate immune responses and Tregs. Here, we demonstrate that helminth-derived products can directly target T cells, especially IL-17-secreting γδ T cells that play a key pathogenic role in CNS autoimmune disease.

Helminth therapy for autism under gut-brain axis- hypothesis.

Autism is a neurodevelopmental disease included within Autism Syndrome Disorder (ASD) spectrum. ASD has been linked to a series of genes that play a role in immune response function and patients with autism, commonly suffer from immune-related comorbidities. Despite the complex pathophysiology of autism, Gut-brain axis is gaining strength in the understanding of several neurological disorders. In addition, recent publications have shown the correlation between immune dysfunctions, gut microbiota and brain with the behavioral alterations and comorbid symptoms found in autism. Gut-brain axis acts as the "second brain", in a communication network established between neural, endocrine and the immunological systems. On the other hand, Hygiene Hypothesis suggests that the increase in the incidence of autoimmune diseases in the modern world can be attributed to the decrease of exposure to infectious agents, as parasitic nematodes. Helminths induce modulatory and protective effects against several inflammatory disorders, maintaining gastrointestinal homeostasis and modulating brain functions. Helminthic therapy has been previously performed in diseases such as ulcerative colitis, Crohn's disease, diabetes, multiple sclerosis, asthma, rheumatoid arthritis, and food allergies. Considering gut-brain axis, Hygiene Hypothesis, and the modulatory effects of helminths I hypothesized that a treatment with Trichuris suis soluble products represents a feasible holistic treatment for autism, and the key for the development of novel treatments. Preclinical studies are required to test this hypothesis.

Trichuris suis ova therapy in inflammatory bowel disease: A meta-analysis.

BACKGROUND: In recent years, Trichuris suis ova (TSO) therapy in inflammatory bowel disease (IBD) has attracted much attention. However, efficacy and safety of TSO therapy are still not well described. The aim of the study was to perform a meta-analysis to assess the effectiveness of TSO therapy in IBD. METHODS: PubMed, Embase, Web of Science, ClinicalTrials.gov, and Cochrane Library were searched from inception to August 2017. Only randomized, double-blind, placebo-controlled trials (RCTs) were included. The pooled estimate rates were performed by meta-analysis and reported according to the standard Cochrane guidelines and the PRISMA statement. RESULTS: In ulcerative colitis study (3 RCTs, n = 74), the induced rates of clinical remission and clinical response were 10.8% (4/37) and 53.8% (21/39) in TSO group, while 6.7% (2/30) and 29.0% (9/31) in placebo group (all P > .26). Twenty-two (9/41) percent of patients in TSO group experienced at least 1 adverse event compared with 27.3% (9/33) of placebo [relative ratio (RR) 0.75, 95% confidence interval (95% CI) 0.17-3.27]. In Crohn disease study (3 RCTs, n = 538), 40.7% (74/182) of patients in TSO group achieved clinical remission compared with 42.9% (90/210) of placebo (RR 0.95, 95% CI 0.75-1.20); 45.9% (141/307) of patients in TSO group entered clinical response compared with 45.1% (151/335) of placebo (RR 1.02, 95% CI 0.86-1.21). There were sparse data of adverse events reporting both TSO and placebo group (RR 1.00, 95% CI 0.88-1.13). CONCLUSION: TSO therapy showed no statistical benefit for IBD patients, so it suggested clinicians consider its value carefully before putting into clinical practice. Perhaps continued investigations of larger sample size are necessary due to the previous results with lack of power.

Helmintosis y autoinmunidad / Helminth infections and autoimmunity

Las evidencias epidemiológicas, clínicas e inmunológicas de estudios en humanos y los datos obtenidos de experimentos en modelos animales ofrecen un soporte creciente al criterio de que las infecciones por helmintos tienen un efecto protector contra entidades patológicas que transcurren con desregulación del sistema inmunitario, tales como enfermedades autoinmunes y algunas alteraciones inflamatorias idiopáticas. A partir de este precedente, el objetivo de este trabajo fue revisar y analizar lo publicado sobre helmintosis, regulación de las respuestas inmunitarias y eventos autoinmunes e inflamatorios. Los análisis realizados permiten concluir que la regulación de las respuestas inmunitarias del hospedero por los helmintos repercute en la frecuencia e intensidad de eventos autoinmunes e inflamatorios. En aras de una práctica médica de mejor calidad, las consecuencias clínicas y terapéuticas de esas repercusiones deben ser conocidas por los profesionales relacionados con el diagnóstico y tratamiento de enfermedades autoinmunes y alteraciones inflamatorias idiopáticas(AU)

Epidemiological, clinical and immunological evidence from human studies and data obtained from experiments in animal models offer increased support to the view that helminth infections have a protective effect against pathological entities that run with deregulation of the immune system, such as illness idiopathic autoimmune and inflammatory changes some. From this precedent, the objective of this study was to review and analyze the literature on helminth infections, regulation of immune responses and autoimmune and inflammatory events. Studies support the conclusion that regulation of immune responses by helminth hosts affects frequency and intensity of autoimmune and inflammatory events. In order to better quality medical practice, clinical and therapeutic implications of these impacts should be known by professionals in diagnosis and treatment of idiopathic autoimmune diseases and inflammatory disorders(AU)

Opening (and Swallowing) A Can of Worms to Treat My Crohn's Disease.

Editor's Note: This article discusses the experience, ingenuity, and determination of Sean Ahrens, a young patient with Crohn's disease who took it upon himself to treat his longstanding, symptomatic Crohn's disease with pig whipworm eggs. Reading this story will make some of you uncomfortable. You might question whether this work belongs in a medical journal or sends the wrong message to readers. However, we recognize that this topic is controversial and that N=1 reports cannot and should not change practice. The purpose of this story is not to encourage the use of pig whipworm or to demonstrate its efficacy (or lack thereof). We firmly believe that patients are uniquely qualified to provide insights into how they view their illnesses, weigh risks and benefits, and ultimately achieve self-efficacy. Stories like this are important for us to acknowledge and understand, even if they do not change our practice.

Diplomatic Assistance: Can Helminth-Modulated Macrophages Act as Treatment for Inflammatory Disease?

Helminths have evolved numerous pathways to prevent their expulsion or elimination from the host to ensure long-term survival. During infection, they target numerous host cells, including macrophages, to induce an alternatively activated phenotype, which aids elimination of infection, tissue repair, and wound healing. Multiple animal-based studies have demonstrated a significant reduction or complete reversal of disease by helminth infection, treatment with helminth products, or helminth-modulated macrophages in models of allergy, autoimmunity, and sepsis. Experimental studies of macrophage and helminth therapies are being translated into clinical benefits for patients undergoing transplantation and those with multiple sclerosis. Thus, helminths or helminth-modulated macrophages present great possibilities as therapeutic applications for inflammatory diseases in humans. Macrophage-based helminth therapies and the underlying mechanisms of their therapeutic or curative effects represent an under-researched area with the potential to open new avenues of treatment. This review explores the application of helminth-modulated macrophages as a new therapy for inflammatory diseases.

Mast cells: new therapeutic target in helminth immune modulation.

Helminth infection and their secreted antigens have a protective role in many immune-mediated inflammatory disorders such as inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. However, studies have focused primarily on identifying immune protective mechanisms of helminth infection and their secreted molecules on dendritic cells and macrophages. Given that mast cells have been shown to be implicated in the pathogenesis and progression of many inflammatory disorders, their role should also be examined and considered as cellular target for helminth-based therapies. As there is a dearth of studies examining the interaction of helminth-derived antigens and mast cells, this review will focus on the role of mast cells during helminth infection and examine our current understanding of the involvement of mast cells in TH 1/TH 17-mediated immune disorders. In this context, potential mechanisms by which helminths could target the TH 1/TH 17 promoting properties of mast cells can be identified to unveil novel therapeutic mast cell driven targets in combating these inflammatory disorders.

[Of worms and men--Administration of helminth products as an innovative approach to treatment of autoimmune diseases].

In areas where helminth infections are common, there is a low prevalence of autoimmune diseases. This observation gave rise to the hygiene hypothesis, claiming that certain organisms which were abundant in the human microenvironment hold an immunoregulatory and immunosuppressive effect, therefore, their eradication led to an increase in immune mediated diseases. This hypothesis laid the foundation for several directions of research which demonstrated an immunosuppressive and immunoregulatory effect of helminths on both the acquired and the innate immune systems. These studies led to the examination of the therapeutic potential of helminths and their components in treating different autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus. The administration of helminth products in murine models of these diseases exhibited a positive effect on disease expression, morbidity and mortality, as well as the ability to prevent the onset of disease to some extent (when given in a preventive protocol). Recently, a synthetic molecule composed of phosphorylcholine (a product of the nematode a. vitae) combined with the protein tuftsin, which is produced by human splenocytes, was shown to exert the aforementioned positive effects on a murine model of systemic lupus erythematosus (SLE). These discoveries point to a new direction in research for developing helminth-based therapies for autoimmune diseases.