Helminthic Trichuris Suis Ova vs. placebo for repetitive behaviours in adult autism

The trial results published by Eric Hollander and colleagues [1] were not entirely unexpected. I had previously mentioned their study on the "use of the immunomodulator Trichuris Suis Ova (TSO)" with autism in mind in another post (see here) but, at that time, still awaited the peer-reviewed publication version to appear. I wait no longer.

OK, Trichuris suis (T. suis) is a parasite. It makes its home in the deepest, darkest recesses of other creatures, apparently also having the rather important evolutionary advantage of being able to stay in egg form for quite a long time 'awaiting ingestion'. But just before you turn away John Hurt style (no, I'm not going to link to the 'chest-buster' scene), this particular parasite might not be 'all bad'. I'm specifically talking about some preliminary data suggesting that T. suis *might* have some important immunological effects [2] when ingested in a controlled manner under certain clinical circumstances.

Hollander et al took things one stage further by their insinuation of a link between use of an "immunomodulator" such as T. suis and their study to determine "the effect sizes for TSO vs. placebo on repetitive behaviors, irritability and global functioning in adults with ASD [autism spectrum disorder]." And just before you question the idea that immune function might be something important to some overt behaviour(s), there is other research out there discussing the possibility of such an effect (see here and see here) specifically with autism in mind.

"A 28-week double-blind, randomized two-period crossover study of TSO vs. placebo in 10 ASD adults, ages 17 to 35, was completed, with a 4-week washout between each 12-week period." This was a 'gold-standard' trial design albeit with a very, very small participant group who represented only a specific 'part' of the autism spectrum [3]. The trial was also registered for all to see the proposed hows-and-whys (see here) including the detail: "Have a personal or family history of allergies" as part of the inclusion criteria.

Results: "Differences between treatment groups did not reach statistical significance." This is an important point highlighting how use of T. suis ("the eggs of intestinal helminthes (trichuris suis ova) administered as 2500 ova doses every two weeks") did not translate into statistically significant group differences across measures looking at the social communication aspects of autism for example. I say this bearing in mind that the Hollander study was a cross-over trial too.

But... "Large effect sizes for improvement in repetitive behaviors (d = 1.0), restricted interests (d = 0.82), rigidity (d = 0.79), and irritability (d = 0.78) were observed after 12 weeks of treatment." What this means is that when comparing participants using T. suis vs. their baseline measurements, they seemed to do better on the T. suis portion of the trial across various different types of behaviour. Importantly too we are told that "TSO had only minimal, non-serious side effects" bearing in mind this included various gastrointestinal (GI) side-effects (and knowing that GI issues are already 'a thing' when it comes to autism).

So, there we have it. The results of the first (small scale) clinical trial using Trichuris Suis Ova (TSO) helminthic style with autism in mind. Obviously a lot more research is required before this type of intervention goes anything like 'mainstream'. Alongside there is also the 'acceptability' factor to consider: how many people would actually want to ingest a parasite such as T. suis? Indeed, one of the next courses of study is perhaps to see 'why' such helminthic therapy has the effect that it has on behaviour, and whether such an effect can be replicated in a medicine or other formulation rather than ingesting a parasite?

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[1] Hollander E. et al. Randomized Crossover Feasibility Trial of Helminthic Trichuris Suis Ova vs. Placebo for Repetitive Behaviors in Adult Autism Spectrum Disorder. World J Biol Psychiatry. 2018 Sep 19:1-25.

[2] Jouvin MH. & Kinet JP. Trichuris suis ova: testing a helminth-based therapy as an extension of the hygiene hypothesis. J Allergy Clin Immunol. 2012 Jul;130(1):3-10.

[3] Hollander E. et al. Trichuris Suis Ova (TSO) as an immune-inflammatory treatment for repetitive behaviors in ASD. European Neuropsychopharmacology. 2016; 26: 891.

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'Self-treatment' with helminths and autism?

At the end of 2013 there was some media interest in the presentation of interim data at the 2013 Annual Meeting of the American College of Neuropsychopharmacology from a couple of studies being run by Prof. Eric Hollander.

It's life Jim but not as we know it... @ CDC

The abstracts for the studies 'Trichuris Suis Ova (TSO) as an Immune-inflammatory Treatment for Repetitive Behaviors in ASD' and 'Hyperthermia and the Improvement of ASD Symptoms' can be found here (look under abstracts T177 and T231).

Whilst the media headlines citing 'worms and hot baths' as potential intervention approaches for autism generated quite a nice soundbite and are probably enough for most people to click on the story to read more, I personally did not think they did justice to how potentially important these areas might be to at least some cases of autism. Indeed hot baths as a way of mimicking fever took me back to the article by Curran and colleagues [1] who "documented behavior change among children with autism spectrum disorders during fever."

Sweeping generalisations about hot baths, fever and autism aside, today I'm discussing the paper by Liu and colleagues [2] who, following a review of "the practices and experiences of individuals 'self-treating' with helminths through the eyes of their physicians" reported that over half of those 'self-treating' had a diagnosis of autism. Helminths by the way, are parasitic worms, and whilst some are rather unpleasant in terms of their detrimental effects to health, others have been used in a more therapeutic capacity. Insofar as the idea of 'self-treatment', well, let's just say that this may not be unusual...

Liu et al describe how: "Five physicians monitoring more than 700 self-treating patients were interviewed" and how: "These observations point toward potential starting points for clinical trials, and provide further support for the importance of such trials and for concerted efforts aimed at probing the potential of helminths, and perhaps other biologicals, for therapeutic use." Although one has to be slightly cautious about this type of 'clinical experiences' methodology ('the plural of anecdote is not data' and all that) adopted in the study, it was interesting to note that: "Physicians reported that the majority of patients with autism and inflammation-associated co-morbidities responded favourably to therapy with either of the two most popular organisms currently used by self-treaters, Hymenolepis diminuta and Trichuris suis." We are also importantly told that about 1% of paediatric patients using H. diminuta "experienced severe gastrointestinal pains" suggesting that any future studies should also be observant for side-effects.

I am still in two minds about this area of study and the 'palatability' of the proposed intervention. I note the full trial by Hollander and colleagues looking at the use of Trichuris Suis Ova in the context of autism has kinda fallen off the radar a little bit judging by the status of the trial entry in ClinicalTrials.gov at the time of writing. Aside from that proposed trial and some other speculations about the use of helminthic therapy potentially applied to autism [3] there is little else in the peer-reviewed research literature on this topic in terms of effects or some further details about any proposed mode of action. With my speculating hat on, one could perhaps see the logic around helminthic therapy with regards to the suggested augmentation of an abnormal immune response thought to involve the Th1/Th2 response (see here [4] for more details about this). With autism in mind, certainly there has been some research chatter about this immunological balancing act being potential important for some [5].

I'm sure also that some readers who've encountered this post are either (a) thinking WTF (apologies for my bad language) or (b) potentially thinking about how unethical this study and intervention sounds. Worms after all, are not generally regarded as a great therapy for anything, particularly when people are talking about eradication of such parasites rather than supplementing with them (see here). I'm certainly not going to stand up and suggest helminthic therapy is the be-all-and-end-all for autism intervention by any means even in the context of inflammatory process being potentially involved in many behaviourally-defined conditions [6]

The thing is though, that our prejudice against all parasites is similar to our prejudice against all bacteria. Not all parasitic worms are the same, just as not all bacteria are the same (he says drinking from his probiotic yoghurt). Indeed, helminthic therapy has found a place in medicine, particularly when it comes to various conditions with an immune system element to them as exemplified by papers such as this one [7]. The review article by Wammes and colleagues [8] kinda summarises the mixed feelings that science has about such intervention and how "a paradox exists between efforts to deworm populations with helminth-associated morbidities, and initiatives to test helminthic therapy on patients with hyperinflammatory diseases". If I remember correctly, I think Dr Michael Mosley also had something to say about swallowing parasites...

Added also to the words of caution about proposed side-effects from helminthic therapy, I will draw your attention to the paper by Bager and colleagues [9] who reported that "gastrointestinal reactions" were quite significantly elevated during the early days of quite a long administration period (every 21 days for 168 days) of pig whipworm in their particular trial and cohort. With all that science now knows about gastrointestinal (GI) issues in relation to autism, one probably doesn't want to compound any existing problems in that particular area of comorbidity.

Palatability aside, there is however more science to do in this area including looking further at potential mechanisms [10] and specifically, how swallowing worm eggs might one day be replaced by swallowing pills with a similar mode of biological action...

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[1] Curran LK. et al. Behaviors associated with fever in children with autism spectrum disorders. Pediatrics. 2007 Dec;120(6):e1386-92.

[2] Liu J. et al. Practices and outcomes of self-treatment with helminths based on physicians' observations. J Helminthol. 2016 May 31:1-11.

[3] Siniscalco D. & Antonucci N. Possible use of Trichuris suis ova in autism spectrum disorders therapy. Med Hypotheses. 2013 Jul;81(1):1-4.

[4] Kidd P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev. 2003 Aug;8(3):223-46.

[5] Gupta S. et al. Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism. J Neuroimmunol. 1998 May 1;85(1):106-9.

[6] Friedrich MJ. Research on Psychiatric Disorders Targets Inflammation. JAMA. 2014. July 23.

[7] Elliott DE. & Weinstock JV. Helminthic therapy: using worms to treat immune-mediated disease. Adv Exp Med Biol. 2009;666:157-66.

[8] Wammes LJ. et al. Helminth therapy or elimination: epidemiological, immunological, and clinical considerations. Lancet Infect Dis. 2014 Jun 26. pii: S1473-3099(14)70771-6.

[9] Bager P. et al. Symptoms after ingestion of pig whipworm Trichuris suis eggs in a randomized placebo-controlled double-blind clinical trial. PLoS One. 2011;6(8):e22346.

[10] Chhabra S. et al. Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases. FASEB J. 2014 Jun 2. pii: fj.14-251967

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Liu J, Morey RA, Wilson JK, & Parker W (2016). Practices and outcomes of self-treatment with helminths based on physicians' observations. Journal of helminthology, 1-11 PMID: 27240605

Hookworm infection and microchallenge for coeliac disease?

I'm getting rather baffled by some of the literature appearing with the autoimmune condition coeliac (celiac) disease in mind. The paper by Kalliokoski and colleagues [1] started the bafflement ball rolling with their suggestion that: "administration of IgA-deficient celiac disease patient serum or total IgG induces both deterioration of the intestinal mucosa and clinical features of celiac disease in mice". Then came the paper from Namatovu and colleagues [2] who concluded that: "Neighborhood composition influences CD [coeliac disease] risk". Such discussions were based on a condition which science seemed to be getting a handle on in terms of the genetic and biological processes involved... or maybe not.

"Klaatu Barada N... Necktie... Neckturn... Nickel"

Enter also the findings reported by John Croese and colleages [3] observing that: "Necator americanus and gluten microchallenge promoted tolerance and stabilized or improved all tested indices of gluten toxicity in CeD [coeliac disease] subjects" and the bafflement ball starts to roll away yet faster and further.

A few points from the Croese paper are worth noting:

• This was a year long study looking at a small number of adults with "diet-managed" CD (N=12). In case you might not know, the diet in question is a gluten-free diet.
• Said participants were "inoculated" with 20 hookworm larvae (see here for a picture if you really wish) and subsequently fed increasing doses of gluten - consumed as pasta - ranging from micrograms to grams over the course of some weeks. 
• "Symptomatic, serologic, and histological outcomes evaluated gluten toxicity. Regulatory and inflammatory T cell populations in blood and mucosa were examined".
• Results: Not all the participants went the distance with the gluten challenge; two of which were labelled 'gluten intolerant' (which is a little odd because intolerance of gluten is I presume a hallmark of all CD). That being said, there were some interesting findings observed such as: "the mean IgA-tissue transglutaminase titers declined". I'm not an expert on CD but elevated IgA-tissue transglutaminase is closely associated with CD and I believe levels should fall when a person adopts a gluten-free diet [4]. The fact that levels declined when a gluten challenge (ingesting gluten) was in place was, in the words of the authors, "contrary to the predicted rise".
• Researchers also described how: "Intestinal T cells expressing IFNγ were reduced following hookworm infection". Again with my non-expert hat on, these are some interesting results. The interferons have been previously discussed on this blog with autism in mind (see here) but with CD in focus, are thought to be part of the destructive immune system processes which describe the condition (see here). The suggestion that hookworm infection might be somehow placating such immune processes is intriguing.

Obviously, there is a lot more to do in this area before anyone decides that hookworm infection is a panacea for CD. I've already mentioned the small participant number and attrition rate but given also that CD is usually described as a lifelong condition, one year of experimental study is not nearly enough to discuss any long-term effects. That other studies from the authors have reported less eventful results [5] is also worth mentioning.

But, I'm also minded to discuss another paper from this research group [6] which was covered on a sister blog (see here). On that occasion, authors talked about how hookworm infection seemed to influence production of the TH-17 cytokine, IL-17A too: "Hookworm infection suppressed basal production of the inflammatory cytokines IFN-γ and IL-17A". I've become quite interested in IL-17 over the years, again with the autism research connection in mind (see here) and a possible link with autoimmunity. The fact that IL-17 might also represent one way of distinguishing subgroups with CD [7] is likewise intriguing and offer something in the way of a variable on response to such helminthic therapy...

Music to close. How about some bluegrass... The Grascals and Bugle Call Rag?

And since, I have your attention, here's a link to my latest paper [8] on the potential use of gluten and casein-free diets for autism (shameless self-publicity I know).

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[1] Kalliokoski S. et al. Injection of celiac disease patient sera or immunoglobulins to mice reproduces a condition mimicking early developing celiac disease. J Mol Med (Berl). 2014 Sep 12.

[2] Namatovu F. et al. Neighborhood conditions and celiac disease risk among children in Sweden. Scand J Public Health. 2014 Sep 23. pii: 1403494814550173.

[3] Croese J. et al. Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease. J Allergy Clin Immunol. 2014 Aug 29. pii: S0091-6749(14)01010-0.

[4] Dahele AV. et al. Serum IgA tissue transglutaminase antibodies in coeliac disease and other gastrointestinal diseases. QJM. 2001 Apr;94(4):195-205.

[5] Daveson AJ. et al. Effect of hookworm infection on wheat challenge in celiac disease--a randomised double-blinded placebo controlled trial. PLoS One. 2011 Mar 8;6(3):e17366.

[6] McSorley HJ. et al. Suppression of inflammatory immune responses in celiac disease by experimental hookworm infection. PLoS One. 2011;6(9):e24092.

[7] Sapone A. et al. Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease. Int Arch Allergy Immunol. 2010;152(1):75-80.

[8] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2014 Oct 14:1-6.

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Croese J, Giacomin P, Navarro S, Clouston A, McCann L, Dougall A, Ferreira I, Susianto A, O'Rourke P, Howlett M, McCarthy J, Engwerda C, Jones D, & Loukas A (2014). Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease. The Journal of allergy and clinical immunology PMID: 25248819