FMT (Fecal Microbiota Transplantation) Super-donors and Abandoning the “One Stool Fits All” Approach

Not all stools were created equal

There was a comment recently left on this blog posing the question of what makes a good donor for FMT (Fecal Microbiota Transplantation), or a “poop transplant” in plain English.

FMT is actually an approved therapy for Clostridioides difficile infection (CDI). Research has shown  FMT to be more effective than the antibiotic vancomycin. To quote from the research, “The infusion of donor feces was significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin”.

FMT might not be for discussion at the dinner table, but it is highly effective in some instances.

FMT is actually far more widely used than you might imagine.  In one of today’s papers from China they had treated 1,387 people using 20 donors, for a wide variety of conditions.

In the US, autism researchers at Arizona State University showed a benefit that was maintained after a period of two years.

Autism symptoms reduced nearly 50 percent two years after fecal transplant

At two years post-treatment, most of the initial improvements in gut symptoms remained. In addition, parents reported a slow steady reduction of ASD symptoms during treatment and over the next two years. A professional evaluator found a 45% reduction in core ASD symptoms (language, social interaction and behavior) at two years post-treatment compared to before treatment began.

An earlier study with only vancomycin (an antibiotic) had found major temporary improvements in GI and autism symptoms, but the benefits were lost a few weeks after treatment stopped despite use of over-the-counter probiotics.

The obvious question to ask is whether FMT has a potential benefit to people with autism who do not have GI dysfunction.  I think this question is far from being answered.

We have seen in earlier posts that modifying the microbiome has great potential to fine-tune the function of the brain.  Researchers at UCLA showed that the high fat ketogenic diet controls epileptic seizures not through the action of ketones in the brain, but via the high fat intake changing the mix of bacteria in the gut.

The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet

FMT is just one way to modify the microbiome.  The UCLA researchers are developing a medical food to produce similar effects on the microbiome as the ketogenic diet.

Very likely a personalized bacteria transfer, customized to the symptoms of the person, might effectively treat many more conditions than just GI problems.  

It does look likely that for some conditions there may be super-donors, people whose microbiome is particularly effective, when transferred to others.

But the research cautions against what is called the “One Stool Fits All” Approach.  The donor and recipient need to be “compatible”.

The Super-Donor Phenomenon in Fecal Microbiota Transplantation

The microbial diversity of the donor is a good predictor of FMT success in the recipient. However, donor-recipient compatibility also plays an influential role in determining FMT success. Donor-recipient compatibility can stem from genetic factors such as differences in innate immune responses, or environmental factors including diet, xenobiotic exposure, and microbial interactions.

FMT for Inflammatory Bowel Disease (IBD): The Emergence of the FMT Super-Donor

IBD encompasses both Crohn's disease and ulcerative colitis; two debilitating disorders characterized by chronic relapsing inflammation of the intestinal. In contrast to CDI, there is no evidence that IBD results from an overgrowth of one specific pathogen. Rather, the disease is likely brought on by complex interactions involving the host's genetics, immune system, and gut microbiota. Both Crohn's disease and ulcerative colitis are broadly characterized by a reduced diversity of the gut microbiota with lower relative abundances of the Bacteroidetes and Firmicutes phyla and higher proportions of Proteobacteria. A specific reduction in the abundance of butyrate-producing bacterial species, particularly Faecalibacterium prausnitzii, has been observed for both Crohn's disease and ulcerative colitis. Meanwhile, for Crohn's disease, an increase in a pro-inflammatory form of Escherichia coli has also been reported.

The first successful case report of an FMT for the treatment of IBD was published in 1989 when a male with refractory ulcerative colitis achieved clinical remission for 6 months following a retention enema with healthy donor stool. Subsequently, a large number of FMT studies have been conducted on IBD patients with variable clinical outcomes, remission rates, and longevity of effect. Recently, Paramsothy et al. performed a systematic review and meta-analysis of 53 studies (four RCT, 30 cohort, 19 case studies) of FMT in IBD patients. Avoiding publication bias, their analysis of cohort studies revealed FMT was more effective at inducing remission in Crohn's disease patients when compared to patients with ulcerative colitis (52 vs. 33%, respectively). With regard to ulcerative colitis, a larger number of FMT infusions and a lower gastrointestinal tract administration were associated with improved rates of remission.

In contrast to studies of CDI, FMT studies conducted on IBD patients have frequently identified differential recipient responses that have been associated with variability in the donor stool. Currently, the stool used for FMT is not standardized in terms of donor selection (related vs. unrelated), preparation (fresh vs. frozen, aerobic vs. anaerobic), or the dose that is administered (single vs. multiple doses). While inconsistencies in FMT protocols make it difficult to compare different studies, there is a large degree of variability in clinical responses to FMT between recipients who have been subjected to the same study design. It is unfortunate that information on a recipient's genetic background or dietary intake is not yet routinely assessed, particularly given that some instances of IBD have an underlying genetic component. Due to the lack of genetic information, investigators have instead focused on the donor-dependent effect and proposed the existence of so called super-donors to explain the variation in recipient responses.

The first study to record the super-donor effect was a randomized control trial that was investigating the efficacy of FMT for inducing clinical remission in patients with ulcerative colitis. Moayyedi et al. assigned 75 patients with active disease to weekly enemas containing either fecal material or water (placebo) for a period of 6 weeks. FMT was shown to be superior to the placebo, resulting in significantly higher rates of endoscopic and clinical remission, albeit of modest effect (24 vs. 5%, respectively), after 7 weeks. Of the nine patients who entered remission, seven had received FMT from the same donor. Thus, it was argued that FMT success was donor-dependent.

Currently, it is not possible to predict the clinical efficacy of a donor before FMT in IBD patients. It has been suggested that remission rates could be improved by pooling donor's stool together, limiting the chances a patient will receive only ineffective stool. This stool pooling approach was recently investigated on an Australian cohort of 85 mild to moderate ulcerative colitis patients, in the largest randomized control trial of FMT for IBD to date. Rather than receiving FMT from just one donor, patients in the treatment arm were administered a stool mixture that contained contributions from up to seven different donors with the hope that donor-dependent effects could be homogenized. In addition to this, a far more intensive dosing program was adopted with an initial FMT delivered by colonoscopy that was followed by fecal enemas, five times a week for 8 weeks. Despite the multi-donor and intensive dosing approach, Paramsothy et al. achieved post-FMT remission rates (FMT, 27% vs. placebo, 8%, p = 0.02) that were similar to those reported previously. Notably, however, both clinical and endoscopic remission were required for primary outcome achievement in this study, whereas previous studies have mostly focused on either endoscopic or clinical remission rates alone. The pooled stool mixture was demonstrated to have higher microbial diversity than individual stool alone based on OTU count and phylogenetic diversity measures. Subsequent analysis of the different stool batches discovered that one donor appeared to exhibit a super-donor effect. Specifically, patients that received FMT batches that contained stool from this one donor exhibited a higher remission rate than those whose FMT batches did not include the super-donor (37 vs. 18%, respectively).

FMT for Other Disorders: Is There Also a Super-Donor Effect?

Evidence of FMT super-donors in other disorders outside of IBD is currently lacking. Case series and reports limit the capacity to identify super-donor effects because of limited sample sizes. However, despite the lack of large cohort studies, several studies have hinted at the possibility of a donor-dependent effect on FMT outcome. For example, in a short-term FMT pilot trial on 18 middle-aged men with metabolic syndrome, FMTs from lean donors (allogenic FMT) were found to correspond with a 75% increase in insulin sensitivity and a greater diversity of intestinal bacteria in the recipient compared to autologous FMTs (recipient-derived). It was later noted that the patients who experienced a more robust improvement of insulin sensitivity post-FMT had all been in receipt of the same donor. In a subsequent study on 38 Caucasian men with metabolic syndrome, lean donor FMT also resulted in a significant improvement in peripheral insulin sensitivity at 6 weeks. However, this effect was lost by the 18 week follow up. For the allogenic FMT, 11 lean donors were used, seven of which were used for more than one recipient. Whilst donor-dependent effects were not reported, the authors noted that the “multiple fecal donors might explain the transient and variable effects seen in the allogenic group.” As FMT research in this field progresses from small-scale case series to larger-scale randomized placebo controlled clinical trials, it remains to be seen whether the super-donor phenomenon generalizes to other conditions outside of IBD.

Abandoning the “One Stool Fits All” Approach

Microbial dysbiosis is a blanket term for an unhealthy or imbalanced gut community. As such, the population structure that is considered to represent microbial dysbiosis is variable between different disorders. Moreover, the microbiome deficit of one individual may not necessarily mirror that of another individual and therefore it is not surprising that patients respond differently to FMT. As more FMT-related clinical and microbial data are generated, it is becoming clear that “one stool does not fit all” in the context of treating chronic diseases with microbial dysbiosis. Equally so, the selection of donors based solely on clinical screening guidelines provides no guarantee of FMT success. It appears a patient's response to FMT predominantly depends on the capability of the donor's microbiota to restore the specific metabolic disturbances associated with their particular disease phenotype. If this is true, a donor-recipient matching approach, where a patient is screened to identify the functional perturbations specific to their microbiome, may be the best way forward. The patient could then be matched to a specific FMT donor known to be enriched in taxa associated with the metabolic pathway that needs to be restored. Immune tolerance screening would also be beneficial for reducing the impact of donor-recipient incompatibilities stemming from underlying differences in innate immune responses.

Framework for rational donor selection in fecal microbiota transplant clinical trials

Early clinical successes are driving enthusiasm for fecal microbiota transplantation (FMT), the transfer of healthy gut bacteria through whole stool, as emerging research is linking the microbiome to many different diseases. However, preliminary trials have yielded mixed results and suggest that heterogeneity in donor stool may play a role in patient response. Thus, clinical trials may fail because an ineffective donor was chosen rather than because FMT is not appropriate for the indication. Here, we describe a conceptual framework to guide rational donor selection to increase the likelihood that FMT clinical trials will succeed. We argue that the mechanism by which the microbiome is hypothesized to be associated with a given indication should inform how healthy donors are selected for FMT trials, categorizing these mechanisms into four disease models and presenting associated donor selection strategies. We next walk through examples based on previously published FMT trials and ongoing investigations to illustrate how donor selection might occur in practice. Finally, we show that typical FMT trials are not powered to discover individual taxa mediating patient responses, suggesting that clinicians should develop targeted hypotheses for retrospective analyses and design their clinical trials accordingly. Moving forward, developing and applying novel clinical trial design methodologies like rational donor selection will be necessary to ensure that FMT successfully translates into clinical impact.

Association Between the Clinical Efficacy of Fecal Microbiota Transplantation in Recipients and the Choice of Donor

Objective: To examine the association between the clinical efficacy of fecal microbiota transplantation (FMT) in recipients and the choice of donor, and to observe the characteristics of intestinal flora and metabolites among different donors. 

Methods: A retrospective case-control study was conducted. Donor whose feces was administrated for more than 30 recipients was enrolled. Data of 20 FMT donors and corresponding recipients at Intestinal Microecology Diagnosis and Treatment Center of the Tenth People's Hospital from October 2018 to December 2019 were collected retrospectively.

During follow-up, the efficacy of each recipient 8-week after FMT treatment was recorded and analyzed. Based on the efficacy of each donor, the donors were divided into three groups.Association of the efficacy of each donor group with the morbidity of complications, and association of efficacy of recipients with donors were analyzed. The evaluation indicators of FMT efficacy included objective clinical effectiveness and/or subjective effectiveness. Objective effectiveness indicated clinical cure plus clinical improvement, and subjective effectiveness indicated marked effectiveness plus medium effectiveness through questionnaire during follow-up. 

Results: A total of 1387 recipients were treated by 20 donors, including 749 cases of chronic constipation, 141 cases of chronic diarrhea, 107 cases of inflammatory bowel disease (IBD), 121 cases of irritable bowel syndrome (IBS), 83 cases of autism, and 186 cases of other diseases, such as radiation bowel injury, intestinal pseudo-obstruction, paralytic intestinal obstruction, functional bloating and allergic diseases. There were 829 cases, 403 cases, and 155 cases in high efficacy group, moderate efficacy group and low efficacy group respectively. Baseline data among 3 groups were not significantly different (all P> 0.05).

In comparison of bacterial abundance (operational taxonomic unit, OTU) among different effective donor groups, the high efficacy group was the highest (330.68±57.28), the moderate efficacy group was the second (237.79±41.89), and the low efficacy group was the lowest (160.60±49.61), whose difference was statistically significant. 
In comparison of butyric acid content among three groups, the high efficacy group had the highest [(59.20±9.00) μmol/g], followed by middle efficacy group [(46.92±9.48) μmol/g], and the low efficacy group had the lowest [(37.23±5.03) μmol/g], whose difference was statistically significant (F=10.383, P=0.001). The differences of acetic acid and propionic acid among three groups were not statistically significant (all P>0.05). A total of 418 cases developed complications (30.1%). Morbidity of complication in low efficacy group, moderate efficacy group and high efficacy group was 40.6% (63/155), 30.0% (121/403) and 28.2% (243/829) respectively, and the difference was statistically significant (χ(2)=9.568, P=0.008). The incidence of diarrhea in low efficacy group, moderate efficacy group and high efficacy group was 7.1% (11/155), 4.0% (16/403) and 2.8% (23/829) respectively, and the difference was statistically significant (χ(2)=7.239, P=0.027). Comparing the incidences of other types of complications, no statistically significant differences were found (all P>0.05). Follow up began 8 weeks after the FMT treatment. The total follow-up rate was 83.6% (1160/1387). The overall effective rate 58.3% (676/1160). Effective rates of various diseases were as follows: chronic constipation 54.3% (328/604), chronic diarrhea 88.5% (115/130), IBD 56.1% (55/98), IBS 55.1% (59/107), autism 61.6% (45/73), and other diseases 50.0% (74/148). Comparing the effective rate of three groups of donors for different diseases, there was no statistically significant difference in chronic diarrhea (P>0.05); there was a positive correlation trend in IBD, IBS and autism, but the differences were not statistically significant (all P>0.05). For chronic constipation and other diseases, high efficacy group had the highest effective rate [65.0% (243/374) and 63.2% (55/87)], followed by moderate efficacy group [49.4% (86/174) and 38.1% (16/42)], and low efficacy group had the lowest [16.1% (9/56) and 15.8% (3/19)], whose differences were significant (all P

Conclusions: Different donors have different efficacy in different diseases. Chronic constipation, radiation bowel injury, etc. need to choose donors with high efficacy. IBD, IBS and autism may also be related to the effectiveness of donors, while chronic diarrhea is not associated to the donor. The efficiency of the donor is negatively correlated to the morbidity of complications. The abundance and diversity of intestinal flora and the content of butyric acid may affect the efficacy of the donor.

Conclusion

FMT in practice today does look rather primitive, but seems to be beneficial more than half of the time, even in autism in the Chinese study.

As expected, different donors have different efficacy in different diseases.  As FMT becomes more popular you would expect that more super-donors will be stumbled upon and then clinicians will have a better chance to match the donor to the recipient.

For certain GI conditions that do not respond well to current drug therapy, FMT does look a good option to investigate.  The level of success is likely to vary depending on the availability and selection of the donor.

It does seem that orally ingested bacteria in the form of probiotics often do not colonize the gut as hoped for, and just past straight through, with only a limited and transient effect.  The fact that FMT can have a very long-lasting effect is remarkable and likely due to the fact that these bacteria are direct from another human.

Modifying the microbiome is only now emerging as a treatment idea and it will take many decades to fully develop it.

Ingesting a mix of another human’s bacteria is not without risk.  

Massachusetts General Hospital oversaw trial that led to the first death from a fecal transplant, a new paper shows

This spring, a 73-year-old man with a rare blood condition became the first person to die from drug-resistant bacteria found in a fecal transplant. New details about that unprecedented incident emerged on Wednesday.

The man was a participant in a clinical trial run at Massachusetts General Hospital and received fecal transplant capsules made in November with fecal material from one stool donor, according to a paper published Wednesday in the New England Journal of Medicine. Tests after the man’s death revealed that material contained a rare type of E. coli bacteria.

FMT seems to be becoming fashionable, with all kinds of people offering it.  The American Journal of Gastroenterology even published a study on Do-it-Yourself FMT. "Almost all indicated that they would perform DIY FMT again, though many would have preferred to have FMT in a clinical setting."  I would vote for the clinical setting and a carefully selected/screened donor. 

Immune modulatory treatments for autism spectrum disorder

Need a wizard, or your local doctor?

I was intrigued to come across a recent paper on immune modulatory treatments for autism by a couple of doctors from Massachusetts General Hospital for Children.  The lead author has interests in:

·      Autism spectrum disorders

·      Psychopharmacology

·      Developmental Disabilities

·      Williams syndrome

·      Angelman syndrome

·      Down syndrome

Apparently, he is an internationally-recognized expert in the neurobiology and neuropsychopharmacology of childhood-onset neuropsychiatric disorders including autistic disorder.  Sounds promising, hopefully we will learn something new.

The paper is actually a review of existing drugs, with immunomodulatory properties, that have already been suggested to be repurposed for autism. The abstract was not very insightful, so I have highlighted the final conclusions and listed the drugs, by category, that they thought should be investigated further.

All the drugs have already been covered in this blog and have already been researched in autism.

One important point raised in the conclusion relates to when the drugs are used.  Autism is a progressive condition early in life and there are so-called “critical periods” when the developing brain is highly vulnerable.

For example, Pentoxifylline has been found to be most effective in very young children.  This does not mean do not give it to a teenager with autism, it just means the sooner you treat autism the better the result will be.  This is entirely logical.

Some very clever drugs clearly do not work if given too late, for example Rapamycin analogs used in people with TSC-type autism.

Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain

Importantly, each of these developmental abnormalities that are caused by enhanced mTOR pathway has a specific window of opportunity to respond to rapamycin. Namely, dyslamination must be corrected during neurogenesis, and postnatal rapamycin treatment will not correct the cortical malformation. Similarly, exuberant branching of basal dendrites is rectifiable only during the first 2 weeks postnatally while an increase in spine density responds to rapamycin treatment thereafter.  

Back to today’s paper.

Immune modulatory treatments for autism spectrum disorder

The identification of immune dysregulation in at least a subtype ASD has led to the hypothesis that immune modulatory treatments may be effective in treating the core and associated symptoms of ASD. In this article, we discussed how currently FDA-approved medications for ASD have immune modulatory properties.

“Risperidone also inhibited the expression of inflammatory signaling proteins, myelin basic protein isoform 3 (MBP1) and mitogen-activated kinase 1 (MAPK1), in a rat model of MIA. Similarly, aripiprazole has been demonstrated to inhibit expression of IL-6 and TNF-α in cultured primary human peripheral blood mononuclear cells from healthy adult donors.”

We then described emerging treatments for ASD which have been repurposed from nonpsychiatric fields of medicine including metabolic disease, infectious disease, gastroenterology, neurology, and regenerative medicine, all with immune modulatory potential. Although immune modulatory treatments are not currently the standard of care for ASD, remain experimental, and require further research to demonstrate clear safety, tolerability, and efficacy, the early positive results described above warrant further research in the context of IRB-approved clinical trials. Future research is needed to determine whether immune modulatory treatments will affect underlying pathophysiological processes affecting both the behavioral symptoms and the common immune-mediated medical co-morbidities of ASD. Identification of neuroimaging or inflammatory biomarkers that respond to immune modulatory treatment and correlate with treatment response would further support the hypothesis of an immune-mediated subtype of ASD and aid in measuring response to immune modulatory treatments. In addition, it will be important to determine if particular immune modulating treatments are best tolerated and most effective when administered at specific developmental time points across the lifespan of individuals with ASD.

Here are the drugs they listed:-

1.     Metabolic disease

Spironolactone

Pioglitazone

Pentoxifylline

Spironolactone is a cheap potassium sparing diuretic. It has secondary effects that include reducing the level of male hormones and some inflammatory cytokines.

Pioglitazone is drug for type 2 diabetes that improves insulin sensitivity.  It reduces certain inflammatory cytokines making it both an autism therapy and indeed a suggested Covid-19 therapy.

Pentoxifylline is a non-selective phosphodiesterase (PDE) inhibitor, used to treat muscle pain.  PDE inhibitors are very interesting drugs with a great therapeutic potential for the treatment of immune-mediated and inflammatory diseases.  Roflumilast and Ibudilast are PDE4 inhibitors that also may improve some autism.  The limiting side effect can be nausea/vomiting, which can happen with non-selective PDE4 inhibitors.

I did try Spironolactone once; it did not seem to have any effect.  It is a good match for bumetanide because it increases potassium levels.

I do think that Pioglitazone has a helpful effect and there will be another post on that.

PDE inhibitors are used by readers of this blog. Maja is a fan of Pentoxifylline, without any side effects. Roflumilast at a low dose is supposed to raise IQ, but still makes some people want to vomit. The Japanese drug Ibudilast works for some, but nausea is listed as a possible side effect.

2.     Infectious disease

Minocycline

Vancomycin

Suramin

Minocycline is an antibiotic that crosses in to the brain.  It is known to stabilize activated microglia, the brain’s immune cells.  It is also known that tetracycline antibiotics are immunomodulatory.

Vancomycin is an antibiotic used to treat bacterial infections, if taken orally it does not go beyond the gut.  It will reduce the level of certain harmful bacteria including Clostridium difficile.

Suramin is an anti-parasite drug that Dr Naviaux is repurposing for autism, based on his theory of cell danger response.

  

3.     Neurology

Valproic acid

Valproic acid is an anti-epileptic drug.  It also has immunomodulatory and HDAC effects, these effects can both cause autism when taken by a pregnant mother and also improve autism in some people.

Valproic acid can have side effects. Low dose valproic acid seems to work for some people. 

4.     Gastroenterology

Fecal microbiota transplant (FMT)

FMT is currently used to treat recurrent Clostridium difficile infection and may also be of benefit for other GI conditions including IBD, obesity, metabolic syndrome, and functional GI disorders.

Altered gut bacteria (dysbiosis) is a feature of some autism which then impairs brain function.  Reversing the dysbiosis with FMT improves brain function.  

5.     Oncology

Lenalidomide

Romidepsin

  

Lenalidomide is an expensive anti-cancer drug that also has immunomodulatory effects.

Romidepsin is a potent HDAC inhibitor, making it a useful cancer therapy.  HDAC inhibitors are potential autism drugs, but only if given early enough not to miss the critical periods of brain development. 

6.     Pulmonology

N-acetylcysteine

Many people with autism respond well to NAC. You do need a lot of it, because it has a short half-life.

7.     Nutritional medicine and dietary supplements

Omega-3 fatty acids

Vitamin D

Flavonoids

Nutritional supplements can get very expensive.  In hot climates, like Egypt, some dark skinned people cover up and then lack vitamin D.  A lack of vitamin D will make autism worse.

Some people with mild brain disorders do seem to benefit from some omega-3 therapies.

Flavonoids are very good for general health, but seem to lack potency for treating brain disorders.  Quercetin and luteolin do have some benefits. 

8.     Rheumatology

Celecoxib

Corticosteroids

Intravenous immunoglobulin (IVIG)

Celecoxib is a common NSAID that is particularly well tolerated (it affects COX-2 and only marginally COX-1, hence its reduced GI side effects).

NSAIDS are used by many people with autism.

Steroids do improve some people’s autism, but are unsuitable for long term use.  A short course of steroids reduces Covid-19 deaths – a very cost effective therapy.

IVIG is extremely expensive, but it does provide a benefit in some cases. IVIG is used quite often to treat autism in the US, but rarely elsewhere other than for PANS/PANDAS that might occur with autism.

9.     Regenerative medicine

Stem cell therapy

I was surprised they gave stem cell therapy a mention. I think it is still early days for stem cell therapy.

Conclusion

I have observed the ongoing Covid-19 situation with interest and in particular what use has been made of the scientific literature.

There are all sorts of interesting snippets of data. You do not want to be deficient in Zinc or vitamin D, having high cholesterol will make it easier for the virus to enter your cells.  Potassium levels may plummet and blood becomes sticky, so may form dangerous clots. A long list of drugs may be at least partially effective, meaning they speed up recovery and reduce death rates. Polytherapy, meaning taking multiple drugs, is likely to be the best choice for Covid-19.

Potential side effects of some drugs have been grossly exaggerated, as with drugs repurposed for autism.  Even in published research, people cheat and falsify the data. In the case of hydroxychloroquine, the falsified papers were quickly retracted.

The media twist the facts, to suit their narrative, as with autism.  This happens even with Covid-19. Anti-Trump media (CNN, BBC etc) is automatically anti-hydroxychloroquine, and ignores all the published research and the results achieved in countries that widely use it (small countries like China and India). 

Shutting down entire economies when only 5-10% of the population have been infected and hopefully got some immunity, does not look so smart if you are then going to reopen and let young people loose.  They will inevitably catch the virus and then infect everyone else. Permanent lockdown restrictions, if followed by everyone, until a vaccine which everyone actually agreed to take, makes sense and living with the virus makes sense, but anything in between is not going to work. After 3 months without any broad lockdown, and allowing young people to socialize, most people would have had the virus and then those people choosing to shield could safely reemerge. The death rate with the current optimal, inexpensive treatment, as used in India or South Africa is very low, in people who are not frail to start with. Time to make a choice.  Poor people in poor countries cannot afford to keep going into lockdown, they need to eat.

What hope is there for treating a highly heterogeneous condition like autism, if it is not approached entirely rationally and without preconceptions and preconditions?  In a pandemic we see that science does not drive policy and translating science into therapy is highly variable.  The science is there for those who choose to read it.

I frequently see comments from parents who have seen some of the research showing that autism has an inflammatory/auto-immune component.  They ask why this has not been followed up on in the research.  It has been followed up on.  It just has not been acted upon.

Why has it not been acted on?

This missing stage is called “translation”.  Why don’t doctors translate scientific findings into therapy for their patients?

What is common sense to some, is “experimental” to others. “Experimental” is frowned upon in modern medicine, but innovation requires experimentation.

Many people’s severe autism is unique and experimental polytherapy/polypharmacy is their only hope.

The cookie cutter approach is not going to work for autism. 

Thankfully, for many common diseases the cookie cutter approach works just fine.

Do the authors of today’s paper, Dr McDougle and Dr Thom, actually prescribe to their young patients many of the drugs that they have written about?  I doubt it and therein lies the problem.  

Time for that wizard, perhaps? 

A few years ago I did add the following tag line, under the big Epiphany at the top of the page. 

An Alternative Reality for Classic Autism - Based on Today's Science

You can choose a different Autism reality, if you do not like your current one.  I am glad I did. I didn't even need a wizard.  

There are many immuno-modulatory therapies for autism that the Massachusetts doctor duo did not mention, but it is good that they made a start.