One of the great theological writers of our time was C.S. Lewis,--a true "Thinking Man's Theologian".  One of his greatest works was "The ScrewTape Letters", and it was largely because of this work (and others) that he eventually made the cover of Time Magazine.  The Screwtape Letters" is a Christian Satire, first published in book form in 1942. The story takes the form of a series of letters from a senior demon, Screwtape, to his nephew, a junior tempter named Wormwood, so as to advise him on methods of securing the damnation of an earthly man, known only as "the Patient.  It's a truly great work...and as I was reading it again, I couldn't help but think...

                   What if there was a Screwtape Letter...                               for Allergists?   

Well, read on...

                                                                                     My dear Wormwood,

I have been informed of a most dire circumstance in your patient--namely, that he wants to become an Allergist.  This is very worrisome, and bears extreme concern and attention--for Allergists have the capacity to help many people (30% of humankind, so I'm told), and offer relief from suffering in the human condition--something that obviously we want to perpetuate whenever possible and The Enemy weeps to see.  However, we must make the best of the situation, and there is no need to despair, provided you work hard on certain things. At best, we can render him a frustrated, ineffectual healer who misses the true Potential of what Allergy care and treatment is, and lives out his life in a dull, monotonous manner, helping as few people as possible.  How do we do this?  It's not hard:  

First, if you notice, infectious disease specialists never have forgotten that they have to deal with bacteria, viruses, all the time.  Their starting point is the organisms that affect humans.  They seem to have the nasty habit of dealing with all organ systems affected by viral and bacterial particles.  The Allergist has exactly the same relationship with the environment--except with allergens instead of bacteria.  Therefore, it is extremely important that you do everything possible to help your patient forget that allergens are the focus of his work, and that they can effect multiple organ systems, just like viruses and bacteria.  There is fortunately, much you can do in helping him along this pathway of amnesia.  For one thing, make him think of himself as a one-organ doctor.  "Asthma, not allergens", should be the mantra whispered in his ear whenever you get the chance.  Get him enamored with the various colored inhalers that humans so like to use.  Make him lose site of his focus.  Remember--loving asthma (as if "love" is a word that we even approve of down here!) is not enough--we prefer to have him passionately obsessed (there it is!  a much more favorable word!) with it.   This will help immensely in limiting his potential to help all people who suffer from allergy.  Because It's true that all mucous membranes (and the skin!) can have allergic manifestations--but don't let your budding allergist realize that!  And remember--one of our great Allies in this effort are the many medical societies now-in-days that seem to focus on asthma, to the exclusion of the "bigger picture".  Remember, we want him to see Allergy as Asthma, and Asthma as Allergy. Period.   It's that simple!  

Secondly, stifle his sense of curiosity whenever possible. The most dangerous characteristic an allergist can have is curiosity.  You can do this in several ways.  By all means, encourage him wherever possible to view lab tests and prick tests as Gods themselves.  He should "stop thinking and start pricking" whenver he sees a new patient. Believe me, this works!  If a patient has a curious story that doesn't "fit" with a few negative tests, encourage him to--and I repeat myself--stop thinking.  Another good phrase to whisper in his ear when he can't come up with an easy answer to a human's problems is, "you do not have IgE mediated allergy".  That will make him superficially satisfied, and the human can continue to suffer!  Get him solely--completely--interested in IgE mediated issues.  The discovery of IgE was the best thing--and the worst thing--to happen in allergy.  Let's concentrate on the "worst" part whenver possible.  It will pay rich dividends for us!  

Thirdly, whenver possible, your future Allergist should not be encouraged to use immunotherapy for his patients.  For it's the only disease-modifying therapy at his disposal, and it carries the grave risk of helping patients to the greatest degree.  How do we keep the allergist from dealing with allergens, and using immunotherapy?  It's not really that hard--especially with the number and amount of symptom relieving medications at his disposal.  Help him get disoriented--to think he is helping the most when he merely controls an allergic process symptomatically.  Human Allergists love the word control.  They talk about controlling asthma.  Controlling allergic disease, etc. etc. etc.  Get him to love the word control. But better yet--get him to be (and here's one of my favorfite words used once again!) obsessed with it.  Avoid the word "cause" wherever possible.  You will have magnificently and completely failed if he becomes a curious allergist trying to find a cause for his patients illness! He should not be thinking of "causes" for his patients ills--just control.  The irony is that when he is thinking he is "controlling" asthma with his fancy inhalers and monitoring peak flow charts, all the while the "allergic march" they talk about continues!  The irony is he really isn't "controlllng" anything at all!  

But now I have to mention one more item...of gravest consequence and concern.  There is currently a movement in Europe espousing a newer form of immunotherapy.  As I mentioned earlier, your young allergist should not even be thinking about immunotherapy.  But I'm afraid it's to no avail in this case...he'll hear about sublingual immmunotherapy (SLIT) no matter what--and be thinking about it.  A dangerous development, to be sure.  But I'm confident we can make the most of it, if we're careful.  First, remember what I told you earlier about curiosity--you must stifle it in this regard.  Keep him happy with his old ways.  Bring up the emotions of fear and uncertainty and confusion to nullify any temporary excitement he might have for this new business of treatment.  Above all, make him think in a defensive manner when it comes to change in his field.  Again, our great Allies in this area will be his professional societies, so encourage him to dutifully follow their dictums, rather than thinking for himself.  Rather than embracing newer forms of immunotherapy it, he should be fighting them!  Remember, it's dangerous for the Allergist to think about allergens.  He could help somebody.  

I'm confident if you follow my advice above, you'll get the desired result, and we'll have one more unhappy, frustrated allergist brought into the fold!  

Your affectionate uncle, 

ScrewTape

It was a cold day on January 31st when I opened the exam room door, and looked into her eyes.  They revealed a look I've seen before on new patients---a mixture of apprehension, anxiety, and fear. It's a look common to all new patients, even physician's assistants (which she was).  

"Please help me stop my episodes of hives", she said.  "I live in fear of another bad attack." 

"Two months ago, on October 10th.  She replied.  But I've had similar episodes before---they began in June last year, and I've had repeated attacks of generalized hives in August, and again in Septemeber.  But the last one in October was particularly frightening, because I also had wheezing for the first time along with the hives." 

"Well, they've given me the usual Emergency room medications--epinepherine, Solu-Medrol, and antihistamines.  And now I'm on Doxepin 10 mg, Allegra 180 mg bid, and and Zantac 150 mg bid, but I still don't know what causes them or if they will return." 

"Yes, she replied, I've known I've been allergic to shrimp for years, and in fact my prior testing showed some reaction to it.  If I eat shrimp, I get generalized hives. So I don't eat any shellfish.  period.  I haven't had another attack of hives for years--until I began having them starting last June.  It's been a nightmare since then..."

"Do you have the results of your prior tests with you?"  I asked. 

"Yes, here they are", she said

She produced a stack of medical tests, done by a famous midwest clinic noted for its diagnostic expertise. I looked over the medical reports.  They revealed (among the many test results) the following:  normal ESR, tryptase level, peripheral eosinophils, and a host of other normal results.  Interestingly, she had IgE RAST positivity to the following:

IgE shrimp:  8.37

IgE lobster   2.18

IgE Crab      1.71

Normal levels are < 0.35 kU/L.  Obviously, with her prior history, these results didn't surprise me.  But my eyebrows rose when I came across the following test results 

IgE Mite:      6.12

IgE wheat   2.75

IgE  rye        0.72

IgE barley   1.04

She was negative to multiple other foods tests.  And believe me, they tested alot of them...Suspecting she had a low grade "smouldering" food sensitivity going on, I asked about chronic GI problems.  It's an axiom that atopic patients with GERD have a hidden food sensitivity until proven otherwise...

"Oh, yes, I have GERD and some IBS issues...and I'm on Prilosec for them" she replied. 

"How old is your mattress and pillow?" I asked, trying to get a rough handle on her dust exposure.

"Older than dirt" she replied.

I also noted that no basic inhalant tests for pollens or mold had been done, and that her episodes of generalized urticaria (recently accompanied by wheezing) occured from June thru October.  So I asked a very general question:

"Are you involved in alot of outdoor activities during the summer months?"  I asked.

"Well, I garden alot during the summer.  Although I practice medicine in a small town clinic, we actually live on a small acreage and when I bale hay this causes some runny nose and itching, but nothing bad" she said.  I'm exposed outdoors to horses, chickens, and dogs in the barn." 

Initial (pretesting) comments:  Up to this point, I had just interviewed the patient, and had done no testing myself.  But I had a pretty good idea of what was going on.  In my experience, when someone comes in with intermittent severe systemic allergic symptoms, there are usually just two possibilities:  (1)  They are getting intermittent, hidden exposure to an allergen that they are severely allergic to, or (2), they have multiple moderate allergens that cause a "critical mass" effect at certain times, and cause a severe allergic reaction.  In my experience, possibility #2 is much, much more common than possibility number 1.  My working hpothesis was that she had day to day low grade--but clinically significant-- constant exposures to dust mite and wheat, which fluctuated in nature.  She probably had seasonal allergic exposures to mold or pollen which "put her over the top" in terms of having a critical mass or "total load" effect.  Animal dander sensitivity could play a mild role too.  The Total Load Theory is operant in possibility #2 above.  The total load theory is like the theory of evolution--it can't be strictly proven, but it sure makes sense and explains alot of puzzling situations.  I was thinking along the lines of the slide shown below, which is from my powerpoint lecture on the management of the complex allergy patient (available for download).  Every day, her wheat load (the green box), mold load (the yellow box) and the dust mite load (the red box) vary in nature, and sometimes reach a critical mass.  The "allergic threshold" can be lowered by stress.  I wasn't sure about all the boxes in the stack (how many boxes there were and how big each one was) but I was pretty sure these 3 boxes existed, and we were on the right track.  So we did some testing in our own clinic.  Here's what we bound: 

Tests:

intradermal tests:

dust mite:          dilution 5                 10 mm

ragweed            dilution 3                  9 mm

alternaria           dilution 3                10 mm

aspergillus       dilution 2                 11  mm

penicillium        dilution 2                 11 mm

histamine         dilution 2                  11 mm

grass                dilution 2                     neg

tree polllen      dilution 2                     neg

dog                    dilution 2                   10 mm

horse                dilution 3                   10 mm

RAST tests:

antigen                   IgE                         IgG

dust mite              III

egg                        I                             III

pork                       0                            neg

milk                       II                            II                      

wheat                   II                            II

Gluten                   I                            neg

Assessment:

1.  Episodes of generalized urticaria & wheezing secondary to "total load" effect. 

2.  Systemic shellfish sensitivity

3.  Low grade food sensitivities contributing to GERD & IBS and urticarial prediliction

4.  Dust mite sensitivity contributing to urticarial prediliction

5.  Seasonal mold & ragweed sensitivity contributing to urticarial prediliction June--October

One piece of the puzzle remained?  Why did she start to have the problem NOW, at this point in her midlife?  "Well, the clinic has been going thru a huge upheaval recently, and I'm working more hours and am stressed to the max", she said.  The stress load probably increased her susceptibility (or, putting it another way, lowered her threshold) towards having clinically significant allergy problems. 

So, in a patient predisposed in her family to get allergies (like her father & sister before her), she's working long hard hours, getting plenty of dust and mold exposures on her small farm acreage, eating too much wheat, and the critical mass effect...happens.  

So, like a wise old allergist once taught me:  "The 3 basic principles of treatment for the patient consist of---diagnosis, diagnosis, and diagnosis.  In short, her treatment approach was to remember the basic equation for all allergic reactions:

allergic reaction = sensitivity x allergic load

So I simultaneously began her on a SLIT program to reduce sensitivity, while also reducing her allergic load:

1.  Begin SLIT to dust mite, mold, ragweed, wheat, egg, milk

2.  Reduce wheat ingestion by 50%--i.e., avoid snacking on "extra wheat" and use it for essential purposes only.

3.  Cover old mattress and pillows with dust mite barrier encasings

4.  Continue antihistamine coverage. 

Clinical progress:  One episode of generalized urticaria immediately after starting treatment, occuring at 10:55 AM on the morning of March 5th 31 days into Rx.    When I spoke with her, the reason was obvious---she had been vacuuming up a dead plant that had fallen over in her home, and then changed the vacuum bag and got a large dose of combined dust and mold together.  She immediately started with hives on her neck and wheezing.  Prednisone, epipen, and benadryl were used with resolution of symptoms.  I spent time discussing the Total Load Effect with her, and since then she has been asymptomatic this summer and fall, and has stopped zantac, eliminated one of her two daily allegra, and will probably go off of the last one soon.  Her GI tract--surprise!--has been excellent, and she can do more farming work without low grade rhinitis and pruritis. 

Important points

 Nearly everything needed to explain the patient's problems had been found through prior  tests at the other clinic.  The problem with this patient's management was twofold:

1.  No one had "put the pieces" together and looked at her from a "Total Load" standpoint.  Allergists like to deal with one allergen at a time.  Failure to address multiple allergens and their interactions is a common mistake. 

2.  No one had offered her immunotherapy, and that's where SLIT shines.  It can be begun rapidly and broadly to              every component of her total load. 

Will these common mistakes by allergists continue to be made in the future?  That, my friends, is an itch that can't be scratched.....

Later, Dude 

As allergists, we must not only be expert in our requisite field of technical immunological knowledge, but also in applying it in the context of the patient whom we carefully observe and listen to.   It is the fusion of expert technical knowledge and expert practical observational and listeniing skills that makes us expert allergy clinicians.  It's been my experience that certain signs seen in day-to-day allergy practice haven't been given enough emphasis, or reported in the literature.  It was in this spirit that (In my last post), I had discussed what I had termed "Eaton's Sign"--the curious phenomenon of "recall" activity at prior skin test sites  when an allergy patient subsequently is re-exposed to his/her allergen.  But wait!  There's more!  In a sense, Eaton's sign is part of a bigger picture--the allergic "target organ" phenomenon.  Here's the story:

When an allergy patient is exposed to an allergen (either by inhaling it or ingesting it), he/she may be principally/preferentially affected at a sight of prior trauma.  The site of prior trauma may be accidental (an injury or infection) or deliberate (a prior surgery).   Here are some examples:

  Case 1:  A patient comes to see me.  He was aware that previously he would ingest milk and have problems with immediate sinus congestion and posterior nasal drainage.  Then he had a car accident and suffered serious whiplash.  Now when he ingests milk, he develops not only sinus congestion and drainage, but his neck aches terribly...

Case 2:  A patient comes to see me with episodic urticaria and pruritis.  When she ingests the wrong food or breathes an allergen, the first site that reacts is a small area on her abdomen....on exam, this is the exact site of a surgical scar where she had a laparoscopy years earlier.

Case 3:  A patient comes to see me.  He states that he is seeing me for knee pain.  He has been scoped three times previously, and only old, degenerative knee disease is seen.  Nothing new.  His orthopedist is mystified that the patient has more kinee pain in the fall season, precisely when he has more sinus and mucous drainage.

Case 4: A patient comes to see me, with a history of a prior scabies episode adequately treated.  But she continues to suffer from periodic episodes of intense pruritis at former sites of infection.  When her corn allergy is diagnosed and treated, the residual pruritis resolves.   

As might be expected, the permutations on this principle are endless.  Among others, sites of prior herpes zoster are particularly vulnerable to subsequent allergic reactions. In short, sites of prior trauma--whether accidental, surgical, or infectious--are all fertile areas for subsequent allergic reactions.  Presumably, cytokine release during allergy reactions preferentially "targets" these vulnerable areas that have preexisting prior trauma, damage, and residual inflammation.  

In short, as good allergy clinicians, we must keep our "eye on the target" at all times.  

Later, Dude

 Clinical medicine--including the specialty of allergy-- is about sight, touch, smell, and hearing--not just about the latest medical article we've read in the Annals of Allergy or JACI.  One thing we've tended to underemphasize  in our profession is late-phase skin test reactions--something we can see and touch hours after the test has been applied--if we just look for them.  But there is another  item that I've never seen described or documented in the lilterature--and that is the curious phenomenon of intradermal skin test "recall" days or even months after intradermal skin testing was done.  Under certain occasions, it seems as if the site where a skin test was formerly applied  retains a "memory" for furher reaction  when a similar antigen is encountered in our environment many days later. 

What do I mean?  For example, I've seen patients receive intradermal skin tests for molds, and end up with strong delayed rections to them.  Upon getting a subsequent  airborne mold exposure many days later, (for example, mowing the lawn), the patient may note pruritis and swelling at the site of his former tests.  If you ask patients about this phenomenon, they will frequently volunteer that it does indeed occur.  Interestingly, I had a chance to examine this phenomenon first-hand in my office one day, in  a patient who I had previously tested for mold allergy.  She had had strong delayed reactions to mold when I initially tested her. .  When she saw me, she had just had a major symptomatic mold exposure the day before.  On her arm, there were faint areas of erythematous swelling and puriritis where I had previously tested her to mold on an earlier occasion.   

I'd like to call this phenomenon "Eaton's Sign", named in memory of the late Dr. Keith Eaton, M.D. 

I remember meeting Dr. Eaton in Manchester, England, when he excitedly came up to me and asked if I thought that heavy mold exposure could trigger depression in susceptible individuals.  He was one of the earliest members of the BSACI (British Society for Allergy and Clinical Immunology), and a student of Professor Jack Pepys. He was a prolific writer, publishing some 80 papers, and specifically wrote about the delayed reaction to molds on intradermal testing,  and described it thoroughly in his publications.  He felt the delayed mold reaction, although obscure in cause, was "not without biological significance".  In retrospect, his interest in mold was probably stimulated by his wife Susan's serious illness from mold, and a serious case of "dry rot" in his house!  He was a consumate clinician and researcher, who tragically passed away with pancreatic cancer.  Dr. David J Freed has this to say about him in his memorium:  

Throughout our lives, allergists listen to tales...and in the end, we become a storytellers, full of fascinating clinical viginettes from our experiences in caring for allergy patients.  A recently article, entitled "The tale of the Allergists life:  A series of interesting case reports" by Ray Slavin, M.D.  in Allergy Asthma Proc. 2008 Jul-Aug;29(4):417-20, emphasizes this fact.  A few quotes from the article are worth noting:

"I want help with my neuropathy", he said.  "I've been to the University of XX and after a detailed workup, they diagnosed idiopatic neuropathy.  I began gabapentin in 2005.  I continued with my symptoms and saw another neurologist for a second opinion, and after a further series of tests, I was given Lyrica to counteract the pain in my feet and legs in 2006.  However, Dr. X is questioning the diagnosis of peripheral neuropathy, because I have tingling in my face, neck and back as well as my feet and legs, and he prefers to call it an immune or inflammatory neuropathy."  

"I began weekly infusions of one gram of methylprednisolone in April of last year (2007), and these were changed to every other week in June of this year (2008).  I immediately noticed benefits--dramatic lessening of need to take Gabapentin for pain, I had better balance, and a return of skin sensitivity where I was previously numb." 

"Tell me about your current symptoms", I said.

He looked at me sadly, then began:

"I have a real struggle with my balance for the last couple of years, but the big thing is that I have terrible numbness and  tingling in the legs and feet, below the knees.  There is tingling, and some pain however, in all areas above the knees, including the face, neck, back, hands, and arms. The feet and lower leg pain and numbness is present most of the time, but can be reduced by the steroid infusions, which reduce the need for pain meds consideratly.  I take the infusions on Monday and initially get good relief, but by Thursday, the pain and tingling in the lower legs recurs with a terrible vegance."

"Tell me about your alcohol ingestion", I said.  

He looked at me.  

"I'll be honest with you.  I had considerable alcohol consumption from about 1966 to 1975, then a period of no consumption lasting until about 1983.  Then I again had heavy consumption lasting until about 1995, then again a period of no consumption for 4 years.Then I began to drink heavily again, and haven't had a drink since Feb of 2004.  I attend AA meetings now."  

"Any respiratory problems?" I asked.

"I've got some nasal drainage and cough in the fall, but that's a minor issue" he said.

"How about your diet and your intestinal function?" I asked.

"Well, I am bothered by alot of intestinal bloating and gas" he admitted.  "I've also found that some foods aggravate my pain--yogurt, peanut butter, nuts, citrus all intensive the symptoms in my feet and legs so I avoid them. "

I looked at the personal questionnaire he had typed out before the visit.  He had a litany of problems in addition to his presenting one:  glaucoma, rosacea, gout, sleep apnea, venous stasis dermatitis, tinnitus, hypertension, and a prior history of nasal polyposis.  

When I examined him, he needed a cane for walking, and although his Romberg was intact, he had a very unsteady heel-to-toe walk, for which he needed assistance.  He had decreased knee reflexes bilaterally, but at the time of exam, sensory exam was intact to light touch on both legs.  Pedal edema was noted bilaterally.  Mild pharyngeal posterior nasal drainage was seen.  

                                  Tests:

IgG RAST:

Egg--Class II

Dairy--Class II

Wheat--Class I

Corn, peanut, soy, yeast, gluten--Negative

Celiac Antibodys:

Gliadin IgA    9.45 (nl <5)

Gliadin IgG   6.98  (nl <7)

Tissue Transglutaminase IgA    2.31 (nl <20)

Challenge Tests:

milk:  increased pain, tingling in feet, swelling sensation in feet, imbalance & unsteady; flu-like sensation throughout body; increased pain in forehead & cheeks; increased impairment on heel-to-toe walking (on exam)

corn:  increased impairment on heel-to-toe walking (on exam), slight numbness in feet

gluten: incresed impairment on heel-to-toe walking (on exam), weakness on walking

yeast:  heavy sensation in legs "felt like wooden blocks"., slightly unsteady heel-to-toe walk

Candida:  pain increasing from feet up to legs, heavy sensation in legs, 

IDT Tests:

Antigen                          Immediate rxn               Delayed rxn

dust                                  8mm dil 2                         +

alternaria                           9 mm dil 1                        ++

Cladosporium                    9 mm dil 1                        ++

Candida                            8 mm dil 2                        +++

Histamine control              10 mm dil 2

Pollens (tree/grass/weed)    6 mm dil 2    

Assessment:

1.  Neuropathic pain, multifactorial, related to former alcohol abuse,--variant nature of pain related to celiac disease, food sensitivities, and Candida related illness.

2.  Abnormal celiac antibodies, with evidence of gluten sensitivity clinically on challenge

3.  Abnormal IgG antibodies to dairy & egg, with evidence of dairy sensitivity clinically on challenge

4.  Abnormally strong ID delayed reaction to Candida, with evidence of Candida and food yeast sensitivity on challenge

5.  Impaired gut integrity, with increased intestinal permeability likely, as a result of chronic alcohol use, and celiac disease, and enhanced carriage of Candida in gut secondary to chronic antibiotic use for rosacea

6.  Chronic Tinnitus probably aggravated by allergy

7.  Mild mold sensitivity causing seasonal fall congestion.

8.  Sleep apnea

9.  Hypertension

10. Rosacea

11. Glaucoma

12. Chronic tinnitus

13. Venous stasis dermatitis

14. Penicillin allergy

15. s/p nasal polyposis

16. gout

Discussion

Here is my "discussion" that I shared with my patient in writing: 

"I mentioned to Mr. X that I felt it would be possible that low grade food sensitivities have been worsened following a probable increase in intestinal permeability that could have occured as a result of chronic alcohol ingestion historically.  His use of antibiotics chronically since 1999 for Rosacea could have caused Candida overgrowth and further impairment in intestinal integrity and heightened intestinal permeability or "leaky gut". The combination of alcohol ingestion and increasing Candida growth could have, in summary, caused a leaky gut with more food reactions developing.  Clinically, he is already aware that certain foods bother him and seem to increase neuropathic pain.  This would include yogurt, raspberries, peanut butter, nuts, and citrus.  The fact that he has a very atypical neuropathic pain problem, with no concurrent muscle wasting, and the fact that his symptoms include intestinal issues, and areas of involvement outside of his lower legs per se would suggest that food sensitivities and yeast issues are aggravating his condition..."  

1.  SLIT for offending foods

2.  Rotary-diversified elimination diet, both gluten and dairy free, and also eliminating eggs, yeast, citrus, corn, tomatos, nuts.  

3.  Nystatin antifungal medication, probiotics

4.  Continuation of medications, except for doxycycline

5.  Continuation of vitamin supplements already on

Treatment course:

When I saw the patient back in the clinic, he was no longer using a cane.  His heel-to-toe walk was unimpaired, and could be done without assistance.  He handed me a written summary of his progress: 

"My strength and stamina have increased dramatically since going on the diet 3 months ago... I have rapidly lost 40 pounds to date, and have eliminated the taking of protonix and gabapentin.  I have reduced the steroid infusions to once every three weeks.  Neuropathic pain still remains if I don't take Lycra, but greatly reduced.  It appears that an element of neuropathy is reversing as I seem to have more control over the awareness of the need for urination and defecation and sexual responsiveness is improved.  

As Grossman points out in his article, , 

"This literature has become quite controversial, with disputes over the definition of coeliac disease and gluten sensitivity, whether neurological complications are caused by coeliac disease or are epiphenomena, and whether the proposed complications respond to a gluten-free diet."

Later, Dude

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