I make no secret of the fact that I am glad to live in the 21st century and even in a country with excellent hygiene standards. In our society, parasites only play a minor role as disease carriers, even though they tormented our ancestors in Europe less than a hundred years ago and continue to plague people in many countries around the world with poorer hygiene standards. That’s why I’m initially skeptical when I hear that targeted clinical application of parasites is supposed to solve the major medical questions of our time – as also when reading a recent work in JAMA Neurology on the treatment of multiple sclerosis with hookworms (Tanasescu et al. Hookworm Treatment for Relapsing Multiple Sclerosis: A Randomized Double-Blinded Placebo-Controlled. JAMA Neurol 2020 Jun 15;e201118). Because I know that many MS patients are easily “enthusiastic about naturopathy” and that it certainly won’t be long before headlines about this study appear in the media, proclaiming a “new breakthrough in MS therapy”, I feel obliged to comment on this study.
What was done? At an MS center in England, a total of 71 MS patients, predominantly with relapsing MS and without specific MS therapy at the time of the study, were included in a study in which one half (35 patients) received 25 larvae of the hookworm Necator americanus transcutaneously (through the skin on the arm) and the other half (36 patients) received transcutaneous placebo. After 9 months, it was then looked at which group had more new lesions in the MRI of the head – the cumulative number of new/enlarging T2 lesions/T1 lesions was the so-called primary endpoint of the study (the important one). The number of regulatory T cells in both groups was examined as a secondary endpoint.
Before presenting the results, a few brief words about Necator americanus, a parasite that normally occurs in the tropics. The eggs of the worm can be found in soil contaminated with feces. The third larval stage, which was also used in the study, is capable of penetrating the skin, migrating through the lymph and blood vessels, and reaching the lungs. In the lungs, the larvae penetrate the alveoli and ascend in the trachea to reach the small intestine with the saliva during swallowing. In the small intestine, the larvae grow into adult worms and feed on the host’s blood by attaching themselves to the intestinal villi. The worm’s eggs are then excreted again with the stool. An infestation with Necator americanus can lead to abdominal pain, diarrhea and weight loss. A high parasite load (which was avoided in the study) leads to anemia and iron deficiency – for children in developing countries, this parasitosis can be quite threatening and lead to developmental delay. On the other hand, the infection can be easily eliminated with mebendazole (a worming agent) – which all subjects also received at the end of the study.
Against this background, the question may now arise as to why such a study approach is chosen at all? Well, it is known, and has also been experimentally confirmed in the past, that an infection with parasites leads to a change in the immune response towards a more anti-inflammatory immune response. This mode of action of the immune system is particularly “underrepresented” in autoimmune diseases such as MS. Among other things, this observation has contributed to the formation of the so-called hygiene hypothesis – i.e., the assumption that we in our Western world are “too hygienic” and that by increasingly avoiding infections in childhood, we are setting our immune system “too sharp” and thus have become more susceptible to autoimmune diseases. This is an interesting point of view and also justifies the authors’ approach.
But now to the point – what came out? To put it briefly – very little. The primary endpoint of the study was missed, the number of new/enlarging MRI lesions was almost the same in both study arms. The authors do emphasize that in a subsequent analysis fewer of the “hookworm” patients showed any activity in the MRI at all, but given the small cohort (28 complete MRI datasets), one should be very cautious with a positive interpretation. It is positive to note that the secondary endpoint was reached – the patients exposed to the parasite had a slightly higher proportion of regulatory T cells. However, this result should also be handled very carefully, as it is completely unclear whether and how this laboratory value translates into a clinical effect.
Therefore, I would doubt that the approach has any practical value for the current treatment of MS – even though I acknowledge that the study – especially in the light of the hygiene hypothesis – is interesting. Because even if you look at the study benevolently, at most a moderate effect of the intervention with the parasites can be inferred.
Today we test highly specific and highly effective biologics in MS therapy research, usually against comparative substances that also lead to a highly significant reduction of inflammatory activity in MRI. Against this background, the mild effects that a therapy with hookworms promises seem rather misplaced. The proposal of an add-on concept also makes little sense to me, because I would not like to use a human-pathogenic pathogen like Necator americanus in combination with a highly effective immunotherapy. Therefore, I agree with the assessment of the study made by Daniel Ontaneda and Jeffery Cohen, two renowned American MS experts who wrote the editorial in JAMA Neurology on the above-mentioned article: “Keep the worms in the mud” (let the worms stay in the dirt).
