After my not-so-pleasant encounter with the attending allergist at E’s soy challenge I changed my approach. I realized that I was actually more angry with myself than with the doctor. I was approaching FPIES all wrong and wasn’t being true to myself. Maybe that is why it all seemed so difficult.
So I started over. I did what I always do when I have a problem. I hit the books. Well, more specifically, I hit the online databases. It occurred to me that I really didn’t know all that much about FPIES. When E was first diagnosed with his IgE milk allergy I bought a book and read and researched as much as I could in the small amounts of free time and on the small amounts of sleep I had. I was able to wrap my head around IgE allergies and felt pretty confident moving forward. After it started to become clear that we were actually dealing with FPIES I never went back and researched FPIES. I’m not sure why, maybe I was just too exhausted, or in denial, who knows the reason, but I didn’t do the research.
Now we had all kinds of practical questions and some information from an allergist (who wasn’t E’s primary allergist) and nothing concrete to go on. I considered making an appointment with E’s allergist but felt like it was most important to me that I arm myself with data first. I actually started with lists of articles that the International Association for Food Protein Enterocolitis (IAFFPE) and the FPIES Foundation provided on their websites. I also used related article searches on PubMed. I spent about a week reading everything that I could.
Let’s stop there for a minute. A week. I could read everything that has been published about FPIES in one week. I’m not talking about a week of 24/7 reading, either. I’m talking nap times and after E’s bedtime but before mine (which is a pretty small window). A week is an incredibly short amount of time to read all of the scientific literature on a topic. For example, I have been reading about psychological factors and diabetes for about nine years and could never hope to read it all. All this is to say that there isn’t much out there about FPIES.
And that is pretty much what I ended up learning: no one really has the FPIES answers.
Sadly, most of the FPIES literature is still at the point of describing the symptoms of chronic and acute FPIES. There aren’t really any guidelines for living with and treating the syndrome, though the IAFFPE is working really hard to change that. There were a couple of papers that describe one doctor’s or clinic’s experience with FPIES and that is the best that we have to go on. At this point I was most interested in when to challenge a food that is thought to be an allergen. Specifically, I wanted to know if I should go ahead with E’s rice challenge that was scheduled for February, about 11 months after his last exposure and end of chronic FPIES symptoms. I also wanted more information about food trials – how to know a food is safe. Specifically, how many days before we are in the clear. We were still basically doing 4 day trials, 7 for riskier foods, but the attending at E’s soy challenge declared that 12 days of a food was necessary.
Here’s what I learned from the scientific literature (by the way, a few more articles have come out since I did my research blitz in December, so I updated what I found and have included everything I could find as of June 2014):
Waiting for the IV Team at E’s Soy Challenge
Best Timing for an Oral Food Challenge
Food challenges suck. It sucks that the only way to tell if your child is allergic to a food is to feed him that food and then wait and see if he reacts. But it’s all we’ve got and when they are passed it makes it all worth it, so I guess they are a necessity. I obviously want to time food challenges so that they have the highest probability of being passed, so I was looking for recommendations about when to challenge and/or time to resolution of FPIES allergies. I was most focused on rice FPIES at the time, but also kept notes on E’s other allergens so that I could make informed decisions about when to challenge all of them.
Solid Food FPIES (Rice and Oat)
There are only few articles available about solid food FPIES, as it is a relatively newly recognized syndrome (historically it was believed that you could only have FPIES to milk or soy). What I did find was not reassuring. In one sample only 40% of the participants tolerated rice at 3 years (17). The same study reported that 66% resolved FPIES to oat and 67% to vegetables by 3 years (17). Thankfully, another study reported 80% of rice FPIES resolved by age 3 (111). And a study that only contained two patients with solid food FPIES (one to rice, beef, and egg, and the other to shellfish and fish) reported that both children outgrew their sensitivities by age 2 (108), better, but we are basically talking about a case study here. Unfortunately, the most recent research suggests that the median age of resolution is much later – 4.7 years for rice and 4 years for oat (106). The authors of this study used a statistical tool called survival curves to determine the probability of outgrowing FPIES at different ages. At age 2 the probability of outgrowing rice FPIES is about 13%, and oat was not quite 20% (106). So, by the numbers, it doesn’t really seem worth testing rice until at least age 2, and age 3 would be even safer. There is also some data that suggests that reactions to rice are the most severe FPIES reactions and require IV fluids most frequently (111). The closest thing I found to recommendations for when to try rice was to wait 12-18 months after the last reaction (5, 106). These data did not really make me want to rush my 17 month old into a rice challenge only 11 months after his last reaction. I decided that not enough was gained by passing rice and the chance of a fail was too high and risky at this point so I decided to postpone the rice challenge for a while.
Cow’s Milk FPIES
There’s more data available regarding resolution of milk and soy FPIES. Again, this question was usually addressed in terms of age of the patient. The study that examined the youngest participants reported that 27% of 6 month-olds tolerated cow’s milk, 42% of 8-month-olds, and 64% of 10 month-olds. These authors reported that all participants were able to tolerate cow’s milk by 20 months (108). But perhaps the most cited study on the topic reported that only 50% of children recover from cow’s milk FPIES by one year, 75% by 18 months, 89% by 2 years, and 94% by 30 months. In this study, the average child outgrew cow’s milk FPIES by 12 months (109). In a study that measured how long it took for the allergy to resolve (presumably after their last positive challenge), milk FPIES was outgrown in 60% of (10) patients over a median time of 24 months (ranging between 6 and 30 months (112).
Unfortunately a brand new paper that is currently in press has some pretty bleak findings regarding resolution of cow’s milk FPIES (106). They report that the median age of resolution is 61 months (106)! The survival curves suggest that at age 2 the probability of outgrowing milk FPIES is only 10% (106). Based on these findings and a review of the literature, the authors of this recent study suggest challenging cow’s milk between 18 and 24 months after the last reaction (5, 106).
There’s also some interesting data about positive IgE tests in children with FPIES. Remember, E’s initial skin prick test (a test for IgE allergies) was positive to milk, so this is relevant to us. It seems that patients who had a positive IgE test to milk at any point in their history have a more persistent FPIES course (106, 112). In that study, none of the children who had a positive IgE test resolved their milk FPIES during the study period of over 13 years (106)! Several authors recommended that a skin prick test should be conducted prior to a challenge and an IgE challenge protocol followed if there is any positive reaction to the IgE test (5, 106).
I don’t really know what to make of E’s positive initial skin test. All others have been negative and the result was small for the first one (but so was he – he was only 4 months old!). The majority of the data suggest that we should wait to try milk until at least 2 years. The most recent article is pretty depressing but it’s also a bit of an outlier so it’s hard to put too much weight on it. Besides, those authors are still the ones that recommend the 18-24 month waiting period. By age 2, E will have been dairy-free for 19 months, so I think waiting until then is a good plan for us.
The numbers for soy are a little more confusing because they are so divergent. One study reported that only 25% of their sample outgrew soy FPIES after 24-36 months (112). However, others have found that the average patient outgrew soy FPIES by 8 months (108). Some authors have reported that all of their patients were tolerant by 14 months (8) and others have said that 83% outgrow it by age 3 (111). The most recent (and dismal) data suggest that the median age of soy FPIES resolution is 6.7 years and the probability of outgrowing soy FPIES by age 2 is less than 10% (106). Again, the recommendation is to challenge soy at least 12-18 months after the last soy reaction (5, 106). Given the divergent data and that we have heard the 18 month rule of thumb before (13), we’ll plan to wait until at least May 2015 to try soy again. At that point E will have been soy- (and hopefully reaction-) free for 18 months and will be almost 3 years old.
Like I said there wasn’t much to go on, but there was enough to draw some conclusions and make some decisions. So I moved on to my next question – what are the guidelines for an at-home food trial? Were our 4 day trials enough? Should we be doing 7 days? Are 12 day food trials really necessary? And how much should he be eating during these trials?
E digging in to a plate of salmon during our at-home trial.
I have to say that the lack of information about food trials is one of the most disappointing thing about FPIES. I really wish someone had told me sooner about the importance of introducing foods in a controlled way and the high likelihood that E would react to more than just milk. But after my review of literature I realize that no one told me this because no one has studied it. The data here were practically nonexistent.
Length of Trial
The question of whether or not you have to be exposed to an allergen to be “sensitized” to it is a hard one to answer (16), let alone how many times you might have to be exposed or how sensitized you have to be to react. While it is generally believed that the initial reaction usually occurs on the first or second exposure (6), I only found one article that presented data to address the question. In that study, it was observed that approximately 64% of infants reacted to cow’s milk within one day of regular exposure, 16% tolerated it for more than 4 days before a reaction and 11% tolerated it for 14-30 days before they reacted (109). One other paper (6) indicated that the food needs to be removed from the diet for 2-3 days to see an acute reaction (specifically after chronic FPIES). In general, when looking for a good food trial protocol we are told that “Data are limited and […] it is not possible to suggest a specific course of action applicable to all situations” (13). So it seems that a reaction will likely occur on the first day but could occur after up to 30 exposures. Weighing the pros and cons of a longer vs shorter trial period is tough. Thirty is a big time commitment, especially if only four days are necessary. But no one wants to be surprised by a reaction to a food they thought was safe… There may also be some merit to building a waiting period into a food trial to be sure that there won’t be a reaction when it is next introduced, which of course makes the trail even longer and there is no indication at which point to institute the waiting period.
Dose of Food in a Trial
The best information available regarding the amount of food to give during a trial is presented in terms of oral food challenge protocol for FPIES. The guidelines proposed by Dr. Sicherer (112) are the most widely accepted and used. He recommends administering 0.6g of protein per kg of body weight (or 0.15-0.30g/kg when there was a history of a severe reaction) in increasing doses over 45-60 minutes as part of the oral food challenge for diagnosis (112). This calculation takes into account the fact that different foods contain more or less of the protein, so it is a very scientific way to determine dose. However, it obviously requires research to determine how much of the protein is in the food and then calculations of the appropriate dose based on body weight. You must also remember that these guidelines were designed based on the assumption that there are trained medical personnel available during the challenge. It may be prudent, therefore, to administer smaller doses when conducting an at-home trial. I couldn’t find any recommendations in the scientific literature about how much of a protein to administer during an at-home food trial.
All of this research left me feeling frustrated by the lack of good data and recommendations. However, surprisingly, I also felt better. I finally had a decent understanding of what FPIES is and at least I knew as much as the doctors and researchers knew about when and how to try to challenge foods. I didn’t have all the answers but I had more than I did the week before. I was able to make some decisions to move forward but I also knew what I didn’t know. There was still going to be a lot of trail and error in my future but I felt a little more prepared to approach it an educated and scientific way, which alleviates just a little bit of stress from the process.