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Lisa Klimas

I'm a 35 year old microbiologist and molecular biologist with systemic mastocytosis, Ehlers Danlos Syndrome, Postural Orthostatic Tachycardia Syndrome, Adrenal Insufficiency, and an assortment of other chronic health issues. My life is pretty much a blast.

Food allergy series: Eosinophilic colitis

Eosinophilic colitis is a controversial diagnosis. It can occur secondary to a number of conditions, including worm infestation and medical reactions, but cases without a primary cause have been reported less than 100 times in literature.

Eosinophilic colitis patients often have generic lower GI symptoms, including abdominal pain, constipation, diarrhea, and rectal bleeding. More severe cases can cause malabsorption, protein losing enteropathy, colonic wall thickening, obstructive features, eosinophilic ascites and weight loss. Unusually, these symptoms have a relapsing-remitting course, with sudden, inexplicable remission from symptoms. Eosinophilic colitis affecting infants has been segregated into its own diagnoses, which are allergic proctocolitis and FPIES. These are both due to allergic reactions from food proteins.

Eosinophilic colitis most often affects otherwise healthy infants or young adults, in whom it is more often chronic. The only defined feature is a dense eosinophilic infiltration in the colon. Infiltration can be contiguous or diffuse. Endoscopy reveals edema and patchy granularity. Crypt abscesses and lymphonodular hyperplasia may be present.

One study on typical eosinophil values in patients without history of GI issues found that there was a mean eosinophil count of 17/hpf. However, the range of cell count was wide, from 1-52. 28% of biopsies averaged more than 20 eosinophils/hpf. A mean of 35/hpf was found in the cecum, with a mean of 10/hpf in the rectum. Another study found 5-35 eosinophils/hpf in the colon, with count decreasing closer to the rectum. A diagnostic marker of greater than 60 eosinophils/ 10 hpf has been suggested for eosinophilic colitis. Others have used greater than 30/hpf.

Eosinophilic colitis patients sometimes have peripheral eosinophilia and are more likely to have an elevated total serum IgE level. Some patients with eosinophilic colitis have self reported other types of EGID, but there is not yet a biopsy proven link. Interestingly, eosinophilic colitis is not related to a history of atopy. It has been linked to scleroderma and liver transplantation in children. Two cases of eosinophilic colitis have occurred in children with autism. Eosinophilic colitis is thought to occur via a CD4+ Th2 lymphocyte mediated mechanism rather than an IgE mediated mechanism.

Due to its rarity, eosinophilic colitis has not been well researched and is not well understood. In particular, the relapsing-remitting course is baffling. It is worthwhile to note that eosinophils are seen readily using the standard H&E stain employed as a first measure in hospital labs, so they are unlikely to go unseen like mast cells. Some doctors believe it presents as a part of a larger syndrome that is sometimes missed when evaluating patients.

Treatment is much the same as other eosinophilic GI diseases. Elimination dieting is strongly recommended. Corticosteroids, such as budesonide, are often employed. Azathioprine is sometimes used. Ketotifen may be used in place of steroids.

 

References:

Alfadda, Abdulrahman A., et al. Eosinophilic colitis: epidemiology, clinical features, and current management. Ther Adv Gastroenterol (2010) 4(5): 301-309.

Gonsalves, N. Food allergies and eosinophilic gastrointestinal illness. Gastroenterol Clin North Am 36: 75-91, vi.

Food allergy series: Eosinophilic esophagitis (Part 3)

A first step in addressing EoE should be to eliminate primary GERD or PPI responsive esophageal eosinophilia. This is done by using proton pump inhibitors (PPI’s) at doses of 20-40 mg, 1-2/daily for 8-12 weeks in adults and 1 mg/kg per dose, twice daily for 8-12 weeks in children. This treatment is effective when esophageal eosinophilia is due to GERD.

There is a subset of patients with primary EoE and secondary GERD. These patients may or may not meet conventional pH criteria for diagnosing reflux. In these patients, PPI’s alone are not sufficient to treat EoE.

Dietary management is a mainstay of EoE treatment. It is extremely effective in children, with near-complete resolution of symptoms and histological abnormalities. Strict use of amino acid based formula, dietary restriction based on extensive allergy testing, and elimination of most likely allergens have all been used. Elemental therapy is the most effective. Food tolerance is unlikely to be achieved, even after long term elimination. Methods at achieving food tolerance in EoE patients have not been well studied.

Corticosteroids are effective in adults and children, but disease almost always recurs even stopped. Systemic steroids should be used in emergencies only due to the host of long term problems associated with chronic use. Topical steroids are usually effective, but steroid resistance has been reported and local fungal infections can occur. Fluticasone and oral viscous budesonide have been effective in studies. Budesonide can potentially reverse esophageal fibrosis.

Some medications used to manage mast cells, which are often elevated in EoE patients, have been trialed for EoE. Cromolyn sodium has not apparent therapeutic effect for EoE patients. Leukotriene receptor antagonists might be effective at high dosages, but this is unclear. One study on TNF-a blocker did not show benefit. Disappointingly, clinical response to anti IL-5 was variable. Anti-IL-5, anti-IL-13 and anti-eotaxin are possible future therapies.

Food impaction, in which food is retained in the esophagus, requires emergency intervention. This has been found to occur in 11-55% of EoE adults across multiple studies.

Esophageal rings are commonly found in EoE patients and inherently imply stricturing. Strictures larger than 1 cm are found in 11-31% of adults with EoE. 10% of adults have narrow caliber esophagus.

19 patients with EoE have reported perforations that were spontaneous or not due to dilation. Of 14 of these, two suffered full perforations, in which esophageal or gastric contents were found in the chest cavity. Surgical intervention was required. The remaining 12 patients had partial perforations, in which limited air or contrast media moved into the mediastinum from the esophagus. Five patients had partial perforations following endoscopy without dilation. Of the 19 total, 7 needed surgery. None were fatal.

Three instances of circumferential intramural dissection have been noted, and many cases of intramural tearing, either spontaneous or subsequent to endoscopy. Intramural tears are deep lacerations reaching the esophageal submucosa. Circumferential intramural dissection occurs where the esophageal lumen comes away from the esophageal wall in a way that affects a contiguous ring.

There is no evidence that esophageal cancer or generalized EGID results as a complication or progression of EoE. Six patients have reported concurrent Barrett esophagus. However, merely having EoE is not predictive for Barrett esophagus.

Dilation is still considered controversial in the management of EoE with high grade stricturing. This is in part because of a study done before 2008 that found that in a group of 84 adults, 5% suffered perforation and 7% hospitalized for chest pains following the procedure. These rates are much higher than in patient groups who underwent dilation for non-EoE reasons. However, three more recent retrospective studies reported lower rates of complications. Of 404 patients who underwent 839 dilations, only 3% of procedures resulted in perforations – a rate of 0.8%. Perforations were partial and did not require surgery. Chest pain occurred in 5%. One patient had major bleeding that required intervention. Dilation can induce long lasting relief from dysphagia when high grade stricturing is present. Many patients have reported a preference for periodic stricturing rather than daily medication or food elimination.

 

References:

Liacouras, Chris A., et al. Eosinophilic esophagitis : Updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011, pp. 3-20.

Furata, Glenn T., et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 2007; 133:1342-1363.

Immunity, vaccination and disease transmission

Okay, everyone. Cold and flu season is upon us, so it’s time to talk to you about immunity and disease transmission.

Herd immunity occurs when a large portion of the population is immune or less susceptible to a disease. It is mostly mediated by humoral immunity, when B cells have made antibodies and memory cells in response to an earlier infection.  Infectious diseases are transmitted from person to person, but when herd immunity is achieved, the chains of transmission are broken. This means that susceptible persons are much less likely to interact with infectious persons, thus reducing the risk of infection by those susceptible.

Practically speaking, herd immunity is achieved mostly by vaccination. The number I see most often to achieve herd immunity is 95%, meaning 95% of the population needs to be vaccinated in order to prevent widespread transmission of the disease. In reality, the requisite percentage is very specific to the disease and its natural history. For most diseases for which we vaccinate, 80-95% vaccination rate is needed to achieve herd immunity.

I’m going to tell you guys a secret now. A few months ago, someone was rolling out some unsubstantiated facts and figures on vaccination in my facebook group. I asked them to cite their source. Their response was to mock me and insist that it wasn’t worth it since I would never read them anyway. Being as I have feelings and go out of my way to be accepting even to lines of thought I do not personally endorse, I got pretty fucking mad. I don’t know what other people do when they get mad, but when I get mad, I learn everything I can about the subject in question. In this case, that included reading a vast amount of garbage and dangerous misinformation. I am talking 1-2 hours a day of reading articles and watching videos on completely inaccurate myths about vaccination.

So let me be really clear here: I read lots of posts and memes and even “scientific articles from medical doctors” supporting the anti-vaccination movement and I fervently, wholeheartedly, and without reservation of any kind, reject its merit. This information does not convey an accurate understanding of epidemiology, immunology or microbiology of infectious disease. I agree that, rarely, vaccine injury can occur. My niece had an ADEM reaction at the age of four which may or may not have been due to a vaccine (but probably not, because correlation does not equal causation.) I also agree that the risk of death or serious injury from illnesses for which we vaccinate is greater than the risk from vaccination.  I do not agree that any scientific link exists between vaccination and autism.

There is a very small portion of the population who have truly valid reasons for not vaccinating, and an even smaller portion who have truly valid reasons for completely not vaccinating. These include people with primary immunodeficiencies (for whom vaccination cannot be effective), those too young to be vaccinated, transplant recipients, and those with severe secondary immunodeficiencies (such as from medications.) Universally, these are also the people at highest risk from infection. These people cannot be vaccinated and are more likely to be killed by communicable diseases.

Mast cell patients are recommended to receive all vaccines per CDC (or relevant governmental body) guidelines. Premedicating with antihistamines is practiced by many mast cell patients prior to receiving vaccines. (Please note that steroids can interfere with vaccine action, and as such should be avoided if possible.) Simply having mast cell disease is not a contraindication to vaccination.

 

One of the best descriptions of how herd immunity works goes like this:

There is a population of 1,000,002 people. 1,000,000 are vaccinated for disease X and 2 are not.

An outbreak of disease X causes infections in 101 people. 100 are vaccinated and 1 is not vaccinated.

This means the rate of infection among the vaccinated population is 0.01% and the rate among the unvaccinated is 50%, 5000x higher.

A vaccinated person can still become infected, it is just less likely. They often experience less severe disease, but not always. It is also important to get boosters at appropriate intervals to maintain strong immunity.

 

Let’s address some specific cases.

Seasonal flu viruses are spread by droplets dispersed by coughing, sneezing or talking. Most often, the flu is spread when these droplets contact with the mouth or nose of another person. Less often, an uninfected person may become infected by touching a surface upon which droplets still rest and then touching their mouth, nose or eyes.

If you are infected, you can start infecting others more than a full day before you have any symptoms and for up to a week after. Young children and those with weakened immune systems can be contagious for even weeks longer.

For some, the flu is just a painful and unpleasant inconvenience, with no permanent damage to their health. However, for others, it can be disabling or fatal. In the 2012-2013 flu season, 171 children died from the flu. 50% of the children had no previous risk factors for complications. 90% of the children who died were not vaccinated.

In the 2010-2012 seasons, the risk of PICU admission for flu related illness was reduced by 74% through vaccination. The CDC estimates that 7.2 million flu related illnesses will be prevented by vaccination in the 2014-2015 flu season.

 

Measles is seeing a resurgence in the US, largely due to increased rates of vaccine refusal. Measles is still very common in other parts of the world. Prior to vaccination in the US, measles caused about 450 deaths a year. From 2000-2013, there were 37-220 cases annually in the US, with most being contracted by unvaccinated individuals outside of the country. This year, we have had a record 610 cases in 24 states, most as a result of 20 individual outbreaks.

Measles is unbelievably contagious. It has an R0 (pronounced “R naught”) of 12-18, which means that 12-18 other people can be infected by one person. 90% of the people close to a measles patient will contract it. An 83-94% vaccination rate is required for herd immunity against measles. It is transmitted by droplets as described above and can live on a surface for up to two hours. An infected person can infect others up to four days before they have a rash and up to four days after.

Measles is a very serious disease. It can cause a wide array of complications, including death. It can cause severe ear infections resulting in permanent deafness. Approximately 5% of children with measles get pneumonia, the most common complication resulting in death. It can also cause a fatal condition affecting the central nervous system 7-10 years after infection.

 

Pertussis, also known as whooping cough, has an R0 of 12-17. Almost everyone in the same house will be infected if not vaccinated. It is also spread by droplets and 92-94% herd immunity is required to be effective. A person can be contagious for up to three weeks before they have symptoms. Once the cough appears, they are most contagious, for up to 2-3 weeks after. After five days on antibiotics, a person is usually no longer contagious. A really important thing about pertussis is that the laboratory test used to detect it is not great. A negative test does NOT mean you don’t have pertussis, especially if you have been exposed.

Pertussis is especially dangerous for infants and young children, and can transmitted by holding infants too young to be vaccinated. 23% of infants under 1 year who get pertussis will develop pneumonia. 1.6% will die. People of any age can develop complications, including permanent loss of bladder control, rib fractures from severe coughing, and encephalopathy. Uncomplicated pertussis can cause severe coughing for up to 10 weeks.

In 2012, 48,277 cases of pertussis were reported in the US, but it has historically been underreported. 20 people died. This was the most cases in a year in the US since 1955.

I am going to California this February and I am literally terrified that I am going to get pertussis while I’m there and end up in the hospital. How unfortunate and unnecessary.

So how do you prevent getting sick and spreading illnesses?

  • Wash your hands often. Soap and water is best.
  • Regularly disinfect surfaces that might be contaminated.
  • Avoid close contact with sick people.
  • If you get sick, the CDC advises staying home for at least 24 hours after the fever is gone.
  • Cover your nose and mouth when you cough or sneeze.  Coughing or sneezing into your elbow is better than into your hand.
  • If you are sick, or have been exposed to someone who is, especially stay away from people at increased risk of danger from infection. This includes people with chronic diseases like mast cell disease. Infections are activating to mast cells. Furthermore, many of us have other health conditions and/or take medications that suppress our immune system. Patients with primary or secondary immunodeficiencies are at greatest risk. For these people, infection with even mundane diseases can be fatal.

All information on this topic is available at the CDC or WHO websites, with citations for corroborating peer reviewed literature on the applicable pages.

Winter, the dark.

I am not a summer girl. I never have been. Years before the heat made me sick, I would look forward to fall and the smell of fallen leaves and the way they crunched underfoot.

Summer was never for me. It was just too bright.

September and October are my favorite time of the year. I am a Boston girl and I love everything about New England autumn. I love the way the light looks icier, bluer coming through the trees. I love the feel of chilly air on my cheeks as I walk through the city. I love opening the window at night and falling asleep to the scent of frost. I love Halloween. I love watching scary movies every night while I write in my journal. I love the way bare tree branches silhouette against the swollen harvest moon.

I love all these things; but I still feel the coming dark.

I get very introspective in the fall. For the rest of the year, I look forward, move forward, but in the fall, it seems I can only think back. Festive October gives way to cold November nights, to bleak Decembers, where the horizon swallows the sun before 4:30 and everything tastes like regret. I write a lot about life, about my past. I wonder about the moments that my life hinged upon, about who I would be if I had turned differently.

I like my life. It’s just that the darkness makes the past seem so large. It unlocks in me this door to melancholy and it unfurls around me, splendid and devastating.

Depression is an organic process of mast cell disease. It is part of the disease, not a side effect of living with a chronic illness. I know that these racing thoughts and weariness with the world are from masto. I know that I’m not really hopeless on the bad days, but it doesn’t matter. By the time December is half over, I don’t even think I can tell the difference.

Tomorrow is the shortest day of the year. Then the light will return.

There is beauty in the darkness. It’s just so cold here.

Food allergy series: Mast cell food reactions and the low histamine diet

When I started my posts on food allergies, I listed out the causes of food hypersensitivity. Notably absent from this list was mast cell disease. Even among detailed publications on mast cell disease, food reactions are often unmentioned (though potentially subsequent anaphylaxis is usually included.) Unfortunately, food reactions in mast cell disease are still not well understood. Even among experts, the nature and importance of food reactions in overall disease is the subject of much disagreement. Some contend that food reactions are a manifestation of general mast cell reactivity, while some think the foods specifically are sources of reactions. Following this logic, some experts believe in the validity of observing a low histamine diet while others do not.

So please keep in mind that the science behind the low histamine diet is not well accepted or even well defined. I’m going to give you my general comments on the low histamine diet, how I eat and how it has worked for me. It is my personal opinion.

A low histamine diet is one which eliminates or minimizes histamine in the food consumed. I have talked at great length about histamine so I’m not going to reiterate that here. What I will say is that exogenous histamine has been shown to induce mast cell degranulation, which means that histamine from an outside source can cause degranulation. It makes sense to me as a scientist that eating histamine rich foods will cause mast cell degranulation. It especially makes sense because the most commonly problematic food substances for mast cell patients, like alcohol, vinegar and aged cheeses, are major degranulators. I have never been able to tolerate alcohol, so it made sense to me that it was because of degranulation. Again, I prefer to lean on good studies, but in the absence of that, I will accept my own experience living in this body.

Last winter, I was in a lot of pain and generally having a sucky time of life. One of the changes I discussed with my doctors was the low histamine diet. It was in the “this can’t hurt” category. I had put off elimination dieting for a long time due to time and financial constraints, but it seemed like the appropriate time to do it had arrived.

One of the first things that became aware to me was that there is no universally agreed upon low histamine diet. There are lots of websites that discuss it and lay out diet guidelines and none of them are in complete agreement. So I just picked the one that seemed the most reasonable to me and went from there. As a mast cell patient, any diet you pick will require customization.

The diet I picked was the Histamine and Tyramine Restricted Diet by Janice Joneja. It can be found on the Mastocytosis Society Canada page.   I like this diet a lot. I do not know Dr. Joneja personally, but when I read diet/nutrition articles by her, I find them to be based in science. They meet my common sense rule. I’m going to summarize the general guidelines of the diet below along with my comments.

Key guidelines for a low histamine diet:

  • Anything fermented should be avoided. Fermentation produces histamine as a side product. Some are only sensitive to yeast fermented products while some find that fermentation from any organism is triggering.
  • No preservatives and no dyes.
  • No leftovers and nothing overly ripe. This is one of the harder parts of this diet, but I find it very important. Fresh or frozen products seem okay. I have mixed success with thawing frozen meat, but lots of people do it successfully. The key is to not cook something, put it in the fridge and eat it three days later.
  • No canned products.
  • No pickled products.

Milk and milk products: Avoid fermented products, like cheeses of all kinds, kefir, yogurt, sour cream, cottage cheese and cream cheese. A fair amount of milk products are allowed. Milk (cow, goat, coconut) is allowed, as are cheese type products that are made without fermentation (mascarpone, ricotta, panir.) Some versions of this diet allow mozzarella cheese and I find that it is safe for me. Ice cream is allowed if it doesn’t contain other disallowed ingredients. Cream products are okay, too.

Grains, breads: Yeast is the component most likely to be triggering in these products. Many people choose to restrict gluten due to their individual biologic reactions to it. Gluten is not specifically restricted on this diet, but I can tell you that it basically ends up being excluded anyway because gluten containing products usually also contain yeast. Pure, unbleached flour or grain of any kind is allowed. Products that use baking powder for leavening are allowed, like biscuits, soda bread, scones and muffins. Crackers without yeast are allowed, as are cereals if they don’t contain excluded ingredients, including artificial dyes or preservatives. I have a very difficult time finding low histamine baked products that are premade, so I generally make my own. It is surprisingly easy to make good tasting baked products with safe ingredients at home.

Vegetables: The list of vegetables that aren’t allowed feels really disjointed and counterintuitive. There is not much to do beyond committing it to memory. Not allowed: potato, avocado, green beans, eggplant, pumpkin, sauerkraut, spinach, sweet potato, tomato, any overly ripe vegetable. I personally can eat potato and sweet potato without any problem and do pretty much every day. Removing tomato was a revelation for me. It’s hard to live around because we use it for so much, but I really feel so much better. I will sometimes have a little for immediately get a stuffy nose and headache. All other vegetables are allowed. Any green that is NOT spinach is allowed. I eat a huge amount of squash, which is a really versatile ingredient. I get lots of different types from supermarkets or farmers’ markets and I make soups, purees, baked squash, squash lasagna, squash steaks, and a million other things. I can always tolerate it. This diet has also pushed me to get familiar with less common ingredients, like taro root, breadfruit and lotus root.

Fruits: Again, the list of fruits that aren’t allowed doesn’t provide any obvious unifying factor to quickly identify something as safe or not. Not allowed: citrus fruits, including lemon and lime; berries, including cranberries, blueberries, blackberries, gooseberries, loganberries, raspberries, strawberries; stone fruits, including apricots, cherries, nectarines, peaches, plums, prunes; bananas, grapes, currants, dates, papayas, pineapples, raisins. Allowed fruits: melons (keep in mind that some people may have an oral allergy syndrome reaction to melons), apple, pear, fig, kiwi, mango, passion fruit, rhubarb, starfruit (not safe for those with impaired kidney function), longans, lychees. I eat a lot of fruit, especially apples and mangoes.

Meat, fish and eggs: All shellfish are prohibited. They naturally have a huge amount of histamine. No processed meats (cold cuts.) Eggs are allowed if they are allowed. Raw egg white is a HUGE histamine liberator. Fish is allowed ONLY IF IT IS FRESHLY CAUGHT, GUTTED AND COOKED. There are differing opinions on what this means but several sources estimate it must be cooked in less than 30 minutes from catching. So unless you are or are married to a fisherman/woman, I think this is unlikely to happen. Any meat should be fresh or thawed from frozen. Leftover meat should not be consumed.

Legumes: Soy is the big culprit here because it’s in everything and is not allowed. Also not allowed: green peas, sugar or sweet peas, red beans and tofu. Everything else is allowed, including lima beans, chickpeas (I eat a ton of chickpeas), pinto beans, white beans, navy beans, black eyed peas, black beans, lentils (I also eat a ton of lentils), split peas, peanuts, and real peanut butter.

Nuts and seeds: All okay except for walnuts and pecans.

Oils: All okay except for oils that contain preservatives like BHA or BHT.

Spices: No anise, cinnamon, clove, curry, cayenne, nutmeg. Everything else is okay.

Sweeteners: No unpasteurized honey, chocolate, cocoa beans, cocoa. Most others are fine, including pasteurized honey, sugar (of really any kind), maple syrup, pure jams and jellies. This diet says plain, artificial sweeteners are okay. They are definitely not for me. One of the very first things I was told by mast cell specialist was not to use artificial sweeteners. So you can judge for yourself.

Drinks: A lot of drinks are restricted, including all teas. Most fruit juices and drinks have some type of unapproved ingredient. Milk, pure juices, water, mineral water and coffee are the allowed drinks. I also sometimes make “muddled” drinks where I crush some safe fruit with a mortar and pestle, make a simple syrup, and then put the muddled fruit in some soda water with some simple syrup.

Miscellaneous: Not allowed: Yeasts, yeast extract, all vinegars, flavored gelatin. Allowed: plain gelatin, cream of tartar, baking soda and baking powder.

The diet recommends a strict four week adherence to determine if it works. I think this is pretty accurate. I did it with no cheating for five weeks. It helped a lot. I slept better, I wasn’t swollen all the time and I was less nauseous. But there were some downsides. The first is that it is a royal pain in the ass if you work because you really have to cook every day. The restrictions on meat meant that I had meat about once every 2-3 weeks. Not everything freezes well so making a lot ahead of time isn’t always a good idea.

Finding recipes can be hard because the fact that they are labelled low histamine does not mean that they ARE low histamine. Please be very careful with that. I also find that some sources for low histamine recipes seem to assume a high level of economic freedom in food purchasing, as well as access to expensive and difficult to find ingredients. I can shop at Whole Foods, which has a knowledgeable staff and a good stock of ingredients for diets like these. There were several components I still cannot find. I also spent literally $1000 at Whole Foods for the five weeks when I initially did this diet.

One unexpected result of this diet was that it resensitized me to foods that I had become desensitized to. So foods that used to bother me a little now cause a severe reaction (sometimes anaphylactic, requiring epinephrine.) I understand that the reason for this is because these foods always caused reactions but I was effectively “used” to them so I didn’t notice. Regardless of the reason, my life is a lot more difficult foodwise than it used to be. I can “cheat” with some foods with medications but the reactions are still bad. I don’t always know how I feel about my choice to do the low histamine diet in my particular situation, but the fact is that since I did, I now am forced to observe a version of it, probably for life.

So that’s my run down on the low histamine diet.

 

 

Food allergy series: Eosinophilic esophagitis (Part 2)

Diagnosis of EoE can be difficult. Endoscopy with biopsy is the only reliable method currently available. Often in these patients, the esophagus may look unremarkable, so biopsies are recommended regardless of gross appearance. 2-4 biopsies from the proximal and distal esophagus should be collected. Biopsies of the gastric antrum and duodenum may also be taken to rule out other conditions.

Fibrosis of the lamina propria is present in most biopsies of both child and adult patients. Though less prevalent, this finding is still found sometimes in GERD cases. Basal zone hyperplasia, elongation of rete pegs and dilated intercellular spaces are EoE associated findings. Additionally, mast cells are increased in biopsies from EoE patients more so than GERD patients. IgE bearing cells are found more often in EoE than GERD.

There is some dispute over whether the peak value (the cell count in the single high powered field with the most eosinophils) is more representative than the average value (the average of cell counts in several high powered fields.) Some studies have found a correlation between eosinophil count and symptom presentation, while others have not. There are also some patients with active eosinophilic inflammation in the esophagus with few symptoms.

Other diagnostic methods should be included to rule out other conditions.   Esophageal manometry and pH testing in EoE children demonstrated that dysfunctional peristalsis correlated with difficulty swallowing. Esophageal manometry with pressure topography can reveal abnormal pressurization patterns in EoE that are not found in GERD. Endoscopic ultrasound has shown thickening of both the muscles and the mucosa in EoE. Impedance planimetry, a method that measures both pressure and volume changes, has recorded significant changes in compliance and distensibility of the esophageal wall in EoE patients. Barium contrast swallow testing was normal in 12/17 children with EoE, including four who had required endoscopy for food impaction. X-ray can detect stricturing of the proximal cervical esophagus. Some studies have linked motility issues to EoE, while others have found the opposite.

pH testing is usually undertaken to exclude GERD. In multiple studies, transnasal and wireless capsule pH measuring systems have shown variability in acid pH. When coupled with impedance testing, pH testing seems to correlate better with symptoms, but this has not been fully investigated yet. In children, both acid and non-acid reflux is comparable to controls.

40-50% of EoE patients have an increase in circulating eosinophils. When EoE is effectively treated with topical corticosteroids, peripheral eosinophilia has been shown to decrease. One study noted that in EoE patients, esophageal eosinophils display HLA DR, which means that they act as antigen presenting cells. Antigen presenting cells recruit other cells in the immune system and generate a strong inflammatory response.

Periostin, an extracellular matrix protein, is increased in the esophagus of EoE patients. Importantly, it correlates with eosinophil levels in EoE patients. Expression of eotaxin 1 and 3 is also increased in EoE. Fibroblast growth factor 9, IL-13, IL-15 and TGFB-1 can be elevated in both EoE and GERD.

A crucial finding in EoE research was the characterization of a signature transcriptome, which measures which genes the cells are using and which proteins they are making. This transcriptome is distinct from nonspecific chronic esophagitis, which has a peak eosinophil count or 6 or fewer eosinophils/hpf. Studies have demonstrated that the transcriptome can distinguish from GERD. Eotaxin 3 is hugely overexpressed in EoE patients. IL-13 is also overexpressed, with data to indicate that it may be the key regulator in EoE disease processes. In patients who have successfully achieved symptom remission, abnormal gene expression has returned to normal. However, some genes in epithelial cells continue to be expressed abnormally, which may factor into relapse.

Genetic studies have revealed that the first genome wide susceptibility locus for EoE is at 5q22. The study that found this common variable included 550,000 common genetic variants collected from various institutions. In this susceptibility locus lie genes associated with thymic stromal lymphopoietin (TSLP), a cytokine that influences behavior of Th2 cells. In a second study that looked at 53 potential genes that affected allergic or epithelial responses, or both, the TSLP gene was also identified as a susceptibility locus for EoE. This continued to be true when the data was controlled for atopic conditions. The TSLP receptor gene on the X chromosome has also been tied to EoE in male patients. These findings make a strong case for EoE as a Th2 mediated disease.

Another genetic factor found to be overrepresented in EoE patients was a common deletion variant in the filaggrin gene, 2282del4. This mutation has been associated strongly with atopic dermatitis. However, even in EoE patients who don’t have atopic dermatitis, this genetic variant is found more frequently than in the general population.

 

References:

Liacouras, Chris A., et al. Eosinophilic esophagitis : Updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011, pp. 3-20.

Furata, Glenn T., et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 2007; 133:1342-1363.

Food allergy series: Eosinophilic esophagitis (Part 1)

Eosinophilic esophagitis (EoE) is a well studied, well defined eosinophilic disease localized to the esophagus. With a few exceptions, it is usually diagnosed pathologically by a peak value of 15 eosinophils/hpf in esophagus biopsy samples. Currently, endoscopy with biopsy evaluation is the only diagnostic for EoE considered accurate, but patient symptoms must be considered to make a diagnosis.

EoE patients are mostly male, with three times more males than females affected. Most patients are atopic, with a history of other allergic conditions. EoE usually presents in childhood or in third or fourth decade of life, but can onset at any time.

Adult EoE patients present with more uniform symptoms. They have dysphagia (difficulty swallowing), food impaction and upper abdominal pain. About 15% of dysphagia cases are caused by EoE. Food impaction requiring endoscopic intervention occurs in 33-54% of EoE adults. Children with EoE have less specific symptoms and are more likely to have vomiting and generalized abdominal and chest pain.

As mentioned above, other atopic conditions are commonly found in EoE patients. 50-60% of EoE patients have had at least one atopic condition. 40-75% have allergic rhinitis, 14-70% have asthma and 4-60% have eczema.

15-43% of EoE patients have immediate IgE mediated food hypersensitivity reactions. Food induced anaphylaxis is more likely in EoE patients than in other populations. Furthermore, a history of IgE mediated food allergy is correlated with EoE in both adults and children.

Most EoE patients are sensitized to food allergens or aeroallergens as determined by skin prick testing or serum IgE values. Local IgE production and FceRI positive cells (cells that can be activated by IgE) are elevated in biopsies from EoE patients. Six separate articles have documented seasonality in symptom severity and presentation in EoE.

High amounts of eosinophils in the esophagus (esophageal eosinophilia) can be caused by a number of conditions in addition to EoE. This includes the broader classification of EGID, GERD, Celiac disease, Crohn’s disease, hypereosinophilic syndrome, achalasia, drug hypersensitivity, vasculitis, pemphigoid vegetans, connective tissue disease, graft versus host disease, and infection. It is necessary to effectively rule out these other conditions before diagnosing EoE, and this can be difficult. Particularly, it can hard to distinguish between EoE and GERD.

Some studies have reported that significant eosinophil driven inflammation occurs in the proximal esophagus of adults with EoE but not with GERD. Surface layering of eosinophils is more typical of EoE than GERD. Some reports indicate that extracellular eosinophilic granules, including eosinophil peroxidase, major basic protein and eosinophil derived neurotoxin, are more indicative of EoE than FERD.

The cut off of 15 eosinophils/hpf is also problematic for diagnosing EoE. Surface layering and microabscesses are only found when 15/hpf are present. Additionally, basal zone hyperplasia is 44% more likely with 15/hpf and over 100% more likely with 20/hpf. Some studies have found that a large proportion of adults meeting this threshold actually have GERD. Further confusing the issue, there is a growing subpopulation of GERD excluded patients diagnosed with EoE that demonstrate a response to PPIs. This situation is increasingly being referred to as PPI responsive esophageal eosinophilia rather than EoE.

 

References:

Liacouras, Chris A., et al. Eosinophilic esophagitis : Updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011, pp. 3-20.

Furata, Glenn T., et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 2007; 133:1342-1363.

Self evident

For hundreds of years, prominent practitioners of medicine believed that miasma was responsible for disease. This so called “bad air” was thought to arise from rotting flesh and to contaminate its surroundings. This idea was widely believed and identified convergently in various traditions, from the ayurvedics in India to the plague doctors in Europe. As epidemics decimated the population, artists drew black robed spectors with scaly feet and sickles – miasma, the very incarnation of Death.

In 1546, Girolamo Fracastoro described a theory in which epidemics are caused by seeds that transmit disease through either direct contact or indirectly. In the coming centuries, various scientists proved links between disease and organisms –Louis Pasteur, who connected puerperal fever and Vibrio; Ignaz Semmelweis, who realized that women died disproportionately in delivery when attended by physicians responding directly from autopsies; and Robert Koch, who at long last solidified germ theory as the basis for infectious disease. He proved that organisms cause disease. Like all good science in years down the road, this fact seems self evident.

In 1972, Stanley Prusiner met a patient with Creutzfeldt Jakob Disease (CJD.) A devastating neurologic disease, it literally causes the brain to develop large porosities and to look like a sponge on autopsy. CJD is just one of several known spongiform encephalopathies, which include Kuru, a disease transmitted by cannibalism in Papua New Guinea; scrapie, which affects sheep; and the most famous, Bovine Spongiform Encephalopathy, better known as Mad Cow Disease. These diseases are universally fatal. All of them were thought to be due to a “slow virus” that had never been isolated.

Ten years after his fateful encounter with a CJD patient, Prusiner published a paper in Science that identified the cause of these diseases: not an organism, not a bacterium or a virus, but a protein. His experiments described how this protein, found in abundance in the brain, when misshapen, could somehow induce the rest of their proteins to refold themselves the wrong way. His data described not an infection by a living thing, but a completely novel disease causing process. It involved no DNA or RNA, it involved no replication or gene expression. It just involved one molecule with the wrong shape causing everything around it to fall apart.

The ensuing fallout from Prusiner’s publication was nasty. Science, real science, is cutthroat. It is competition for funding. It is spreading rumors. It is discrediting. In 1986, an article in Discover accused Prusiner of seeking fame over science – the very worst slur in research. They said he didn’t care about the damage he was doing to the dogma of biology, that he didn’t even care whether or not he was right.

That’s the thing though – sometimes it doesn’t matter if you want to be right, if you are. In 1997, Stanley Prusiner was awarded the Nobel Prize for his identification of prions (infectious proteins) as the causative agents of these transmissible spongiform encephalopathies. And while prions still have detractors, for microbiologists of my generation, we find prion theory to be self evident.

A hard fact about mast cell disease is that the science behind it is being unspooled right now. That is the trouble with learning things in real time – the pull of history is still so strong for many doctors and scientists. They are loath to unlearn the things they know, to look at the data, to change their perspectives.

In the last few days, I have spoken with several people with masto kids who have either had their children removed from their care or who are at great risk of this occurring. And there is another family that I suspect is right now living this nightmare of losing their child because their rare disease is poorly understood and under recognized.

Medical professionals turning aside solid science in favor of accusations and ego is not just a failing in the system. It is life ruining, traumatizing, unthinkable. It is a tragedy.

I am not a religious person. But I kneel faithfully at the altar of science. When the monsters howl at the door, science protects us, comforts us, promises us that these horrors cannot go on without end. People say that there isn’t a time limit on important discoveries, but of course there is. If it doesn’t arrive in time to help, it is utterly devoid of meaning.

It is not enough that our bodies try to kill us, that the treatments cannot give us our lives back, that current diagnostic methods are inaccurate. We are told over and over again that we are not as sick as we say, or that we are not sick at all, or that parents project these diseases onto their children, that our suffering is the result of anxiety and overactive imaginations. They take our dignity, our livelihoods, our children.

Saying we are crazy, that we are liars and deceivers, does not make us not sick. It just makes us sick with little chance of effective treatment.

I don’t know how much longer we can live like this, how many more weeks like this I can stand. I don’t know how much longer I can wait for doctors to realize that mast cell activation disorders are real. I don’t know how much longer I can wait for them to agree that these diseases, that our suffering, is self evident.

 

Food allergy series: Eosinophilic gastrointestinal disease (part 3)

The exact incidence of primary EGID is not known, but it has become an increasingly common diagnosis in the last ten years. EGID has been associated with food allergy and atopic conditions. 70% of patients have a family history of allergies. 50% of the time, EGID is seen without accompanying blood eosinophilia. EGID, like many conditions, is thought to have both an environmental and a genetic component. 10% of patients with EGID have an immediate family member with an EGID. Both inhaled and ingested allergens can be provocative for EGID patients.

Patients suffer from a variety of symptoms, including abdominal pain, GI motility issues, vomiting, diarrhea, dysphagia, microcytic anemia, hypoproteinemia and failure to thrive. Visually, the GI tract can be normal, so multiple biopsies from each segment are crucial for diagnosis. Malabsorption and protein losing enteropathy are often coincident in EGID patients.

EGID patients are particularly sensitive to foods. Eggs, milk and fish are the most common problematic foods for EGID patients. Though food specific IgE is often found in EGID patients, food anaphylaxis is rare in this population. Due to the coexistence of EGID and food specific IgE, it is considered a mixed IgE- cell mediated allergic disorder.

Elimination diets and avoidance of aeroallergens are first line treatments for these conditions. Elemental diet improves symptoms and lowers number of eosinophils in EE patients. Significant histological improvement of esophageal inflammation is documented in more than 70% of patients studied. Complete resolution of eosinophilic gastroenteritis is usually seen when the patient transmissions to an elemental amino acid based diet. Unfortunately, reintroduction of foods typically causes immediate onset of symptoms, and thus tolerance is not usually obtainable.

Steroids are often used for EGID acute management. Topic al steroids are sometimes used long term management when diet restriction has not improved symptoms. When treated with oral steroids for four weeks, decrease in eosinophilic count was seen and 65% of patients had complete resolution of symptoms. However, symptoms returned in most patients when steroids were stopped.

Montelukast blocks the D4 receptor of cysteinyl leukotrienes in eosinophils. Leukotrienes are responsible for eosinophil attraction, constriction of smooth muscle, airway swelling, and mucus hypersecretion. However, when leukotriene levels were measured in biopsies from EGID patients, only eosinophilic gastroenteritis patients showed a statistically significant increase in leukotrienes. Still, patients report symptom improvement for the duration of treatment, with relapse when it is removed.

A pilot study treated four patients with eosinophilic gastroenteritis with one dose of anti-IL-5 antibody, mepolizumab. IL-5, eotaxin, is a molecule released by T cells and mast cells that is critical in eosinophil activation. After treatment, there was a mean decrease of 70% in peripheral eosinophilia and 50-70% decrease in tissue eosinophilia (3 out of 4 patients.) Symptoms improved minimally. One patient had a 43% increase in GI eosinophil count following treatment. Approximately two months after treatment, half of the subjects had a significant increase in peripheral eosinophil counts and worsening of symptoms.

One EE patient received three doses of mepolizumab at four week intervals. This induced a ten fold decrease in mean tissue eosinophils, reduced inflammation and stricture, resulted in cessation of vomiting, and allowed the patient to successfully introduce solids. This result in encouraging, but controlled trials need to be undertaken.

Mast cells are both increased and activated in esophageal biopsies from patients with EGIDs. An association between mast cell numbers and severity of esophageal epithelial hyperplasia and eosinophil count has been recorded. Omalizumab has been observed in some studies to lower eosinophil counts in blood and lungs of asthmatics. Foroughi and colleagues ran a 16 week open label study with omalizumab of nine patients with allergic eosinophilic gastroenteritis, with confusing results. A study using anti-TNF medications did not appear promising.

 

References:

Mueller, Susanna. Classification of eosinophilic gastrointestinal diseases. Best Practice & Research Clinical Gastroenterology 2008, 22 (3): 425-440.

Spergel, Jonathan, et al. Variation in prevalence, diagnostic criteria, and initial management options for eosinophilic gastrointestinal diseases in the United States. JPGN 2011, 52 (3): 300-306.

Jawairia, Mahreema, et al. Eosinophilic gastrointestinal diseases: review and update. ISRN Gastroenterology (2012).

Food allergy series: Eosinophilic gastrointestinal disease (Part 2)

The following are conditions that can cause a secondary increase in eosinophil count in the GI tract. These conditions should be ruled out before giving a diagnosis of EGID, which is inherently primary.

Allergy associated colitis affects adults, with females accounting for 2.5x more patients than males. The age of diagnosis ranges from 20s to 60s. It affects the colon and ileum, with rectum being unaffected. Eosinophils are found in the mucosal, muscular and submucosal layers. Studies have defined it as anywhere from 10-60 eosinophils/hpf, more than one eosinophil/hpf in the intraepithelial layer, or merely having clusters and evidence of degranulation. It is thought to be driven by an allergic response and has been found in association with NSAID allergy.

Hypereosinophilic syndrome (HES) can sometimes affect the colon. People with this condition produce too many circulating eosinophils, as evidenced by persistently high eosinophil count and affect to one or more of the heart, nervous system or bone marrow. Rarely, it can cause elevated eosinophils in the mucosal layer or deep bowel wall of the colon. The mechanism behind this is unclear, but thought to be due to IL-5 stimulating eosinophils inappropriately.

Crohn’s disease can affect the entirety of the GI tract and mostly presents initially in young adults. It can affect continuous or discontinuous portions of tissue. Ulceration, erosion, infiltrates of various inflammatory cells, including eosinophils, lymphoid nodules, granulomas, fibrosis, and vascular and neural lesions are often found on biopsy. It is thought to be due to cooperation of several factors.

Ulcerative colitis affects either diffuse or continuous areas of the left sided colon and rectum. Eosinophils are often found in the mucosa or superficial supermucosa. Edema, erosion, ulceration, granulocytes, and presence of plasma cells are common findings. The etiology is unclear.

Collagenous colitis is mostly found in middle aged and elderly patients, which are predominantly female. It can affect the colon and rectum and is usually discontinuous. Eosinophils are found in the mucosal layer, along with subepithelial collagen deposition, white cells in the intraepithelial layer,and various inflammatory infiltrates. It is thought to sometimes be associated with drug reactions.

Lymphocytic colitis can affect a person of any age. It affects diffuse portions of the colon and eosinophils are found in the mucosal layer. Intraepithelial lymphocytes are often found (surface epithelium >20 IELs per 100 epithelial cells). The etiology is unknown.

Autoimmune colitis occurs in conjunction with other autoimmune conditions. It can affect people of all ages, with activity in the small and large bowels. Eosinophils are found in the mucosal layer of affected tissue, with evidence of degranulation and crypt destruction. Mast cells are often found in the same tissue portions.

Graft versus host disease is a complication of bone marrow transplant and can affect anyone who has been a recipient of one. GvHD can affect the entirety of the body, and therefore can affect the whole length of the GI tract. Eosinophils are often identified in the mucosal layers, along with apoptotic crypt destruction, mixed inflammatory infiltrates and interepithelial lymphocytes.

Peripheral/intestinal T-cell lymphoma overwhelmingly affects adults over 50. It predominantly affects small bowel, but also the stomach and colon. Inflammatory infiltrates with many eosinophils and tumor cells are sometimes found. It is sometimes seen along with gluten-sensitive enteropathy.

 

References:

Mueller, Susanna. Classification of eosinophilic gastrointestinal diseases. Best Practice & Research Clinical Gastroenterology 2008, 22 (3): 425-440.

Spergel, Jonathan, et al. Variation in prevalence, diagnostic criteria, and initial management options for eosinophilic gastrointestinal diseases in the United States. JPGN 2011, 52 (3): 300-306.

Alfadda, Abdulrahman. Eosinophilic colitis: epidemiology, clinical features and current management. Ther Adv Gastroenterol 2010, 4(5) 301-309.