The December 2019 NEMSN newsletter, commemorating the 30th anniversary of the EMS epidemic, contains the most up to date information on EMS as of the date of publishing. Three articles from this newsletter are also found below. The first two articles are by Stephen Naylor Ph.D.: "Thirty Years of Understanding Eosinophilia-Myalgia Syndrome: Does it Still Exist and Persist?" and "What is in a Name? L-Tryptophan, 5-Hydroxytryptophan and Melatonin Explained". After that is an article by Gerald J. Gleich M.D.: "New Understanding of Eosinophils".
Following this are articles on EMS written by NEMSN Medical Advisory Panel members in 2009, marking the 20th anniversary of the EMS epidemic.
Thirty Years of Understanding Eosinophilia-Myalgia Syndrome: Does it Still Exist and Persist?
by Stephen Naylor Ph.D.
A fateful series of events unfurled thirty years ago. The subsequent outcome dramatically affected all of your lives. During October of 1989, three different women in the state of New Mexico manifested unique symptoms characterized by myalgia (pain), elevated white blood cell (eosinophils) levels and assorted other symptoms. One of those individuals was Ms. Bonnie Bishop, a current member of NEMSN. Dr. Edward Belongia (a member of the NEMSN Medical Advisory Board) recounts her story in his detailed book chapter entitled “Toxic Tryptophan? Investigating the Eosinophilia-Myalgia Syndrome in Minnesota” (1). I appreciate that all of you have your own individual experiences and stories to tell about that period. But at the time the situation was fraught with lack of any understanding, fear, anxiety and uncertainty. Another member of the NEMSN Medical Advisory Board, Dr. Gerald “Jerry” Gleich was also a central figure in helping to unravel the complex, unfolding events. He was a renowned expert in eosinophil biology and related disease states, and helped treat identified patients such as Bonnie Bishop with prednisone. Ultimately, as you all know, it was determined that contaminated L-Tryptophan, manufactured by the Japanese company was the cause of this condition and Eosinophilia-Myalgia Syndrome (EMS) was alas “born”.
2. CAUSE OF EMS
A number of epidemiological studies have demonstrated a clear correlation between consumption of Showa Denko L-Tryptophan and onset of EMS. In addition it is noteworthy that the epidemic was essentially curtailed when the FDA removed the L-Tryptophan from the retail market. Analyses of the Showa Denko L-Tryptophan by high performance liquid chromatography (HPLC) and HPLC coupled on-line with mass spectrometry (LC-MS) revealed, at the time over sixty contaminants. I should note that in recent studies done with my colleagues Dr. Klaus Klarskov (University of Sherbrook) and Dr. Gerald Gleich (University of Utah) we have found over six hundred contaminants present in the same Showa Denko L-Tryptophan! Careful and exhaustive epidemiological studies as well as sample lot analyses of contaminated L-Tryptophan revealed that “six” individual contaminants” were identified as being case-associated with the onset of EMS. In other words, these “six” contaminants had some significant probability of being responsible for the onset of EMS. These case-associated contaminants were labeled as Peaks UV-5, E, 200, C, FF and AAA, as determined by their unique analytical properties. Dr. Gleich and I, along with others have now identified all the case associated contaminants of Showa Denko L-Tryptophan. We recently determined the structure of the last case-associated contaminant Peak AAA with our colleague Dr. Klarskov. This contaminant turned out to be two closely related compounds re-labeled as AAA-1 and AAA-2, taking the total number of case-associated contaminants up to seven (2).
The determination of EMS causal onset has focused primarily on the structure determination and biology of the actual case-associated contaminants of Showa Denko L-Tryptophan. However there have been alternate suggestions as to the cause of EMS. Quinolinic acid (QA) is a metabolic product of L-Tryptophan. This compound has been shown to be a potent neurotoxin and implicated in a number of psychiatric disorders. In 2006 an Australian research scientist performed an unusual experiment. He injected himself with QA in order to show that it was a causative agent in eosinophilia. Whilst the experiments were unique the theory has found little credence as a cause of EMS. Another drumbeat suggesting that high doses of uncontaminated L-Tryptophan alone were solely responsible for the onset of the EMS epidemic has been proposed. Smith and Garrett suggested that the “reliance on a finite impurity from one manufacturer is both unnecessary and insufficient to explain the etiology of EMS” (3). They artfully suggested that excessive histamine activity induced blood eosinophilia and myalgia. However, it is difficult to reconcile their findings with the original epidemiological work carried out by Belongia and others. Indeed, numerous clinical studies utilizing mega-doses (up to 18 grams per day!) of L-Tryptophan have never resulted in any manifestation of EMS-like symptoms in those closely supervised trials.
One additional factor to consider for EMS patients is their genetic profile. In previous studies it has been shown that approximately 2-5% of all people taking Showa Denko L-Tryptophan ultimately manifested EMS symptoms. This suggested a genetic predisposition due to the presence/absence of one or more deleterious or protective genes. This has been further explored by other researchers, who have reported a number of genes present in EMS patients that likely led to a predisposition of disease onset (4,5). This field of enquiry is still nascent, but it is generally agreed that your genetics play a critical role in whether you may suffer EMS onset. However, in the case of the original outbreak, this was clearly brought about by the consumption of contaminated Showa Denko L-Tryptophan. Numerous studies demonstrated that the severity of EMS onset was also related to the amount of L-Tryptophan you consumed on a daily basis. Varga and colleagues have argued that “The pathogenesis of EMS is thought to involve exposure to certain preparations of L-Tryptophan in a genetically-susceptible host that trigger acute inflammation and eosinophil activation and degranulation with resulting chronic tissue fibrosis. However, because EMS has been reported in individuals who have never consumed L-Tryptophan, it is likely that xenobiotics other than L-Tryptophan preparations can also trigger a similar immune response” (5). I tend to agree with much of what Varga and his colleagues wrote back in 2011, but I would put it somewhat differently. The specific cause(s) of EMS is still uncertain. However I would suggest that it may be a combination of the following; i) genetic predisposition, ii) repeated consumption of L-Tryptophan (or structurally related compounds such as Melatonin or 5-Hydroxytryptophan (5-HTP)), iii) presence and amount of one (or more) contaminant(s) reported to be present in Showa Denko L-Tryptophan.
3. PERSISTENCE OF EMS
Few clinicians are aware of the existence of EMS and how to diagnose and treat the disease. In part this is because EMS is a relatively rare disease that occurs sporadically, and our understanding of causation and onset is still very limited. Nevertheless, based on information from NEMSN, as well as on occasional reports in the medical literature, EMS-like symptoms continue to be reported by patients worldwide
3.1 Continued Occurrence of EMS: The efforts of NEMSN in publicizing EMS as well as providing a website that provides a focused contact source has continued to facilitate individual reports from patients exhibiting EMS-like symptoms. These reports typically involve the use of L-Tryptophan (now available again in the USA), 5-HTP and Melatonin. Since 2011, when a systematic reporting protocol was adopted, approximately ninety new individuals have self-reported EMS-like symptoms to NEMSN. Nancy Grant and Lois Vierk have discussed this issue in their article entitled “Contacts from Epidemic Patients and Possible New EMS Cases” published in this same newsletter. Patients indicated in the completed questionnaires that consumption of L-Tryptophan (~30%), 5-HTP (~35%), Melatonin (~1%), some combination of L-Tryptophan/5-HTP/Melatonin (~8%) or Other/Unknown (~22%) had occurred prior to onset of symptoms. However, I should make clear that the vast majority of these individuals have not officially been diagnosed with EMS. Indeed in at least two cases, individuals were more likely to be suffering from Post-Finasteride Syndrome (PFS) since they had been taking Finasteride (Propecia) for years to treat hair-loss (6). A number of PFS symptoms are similar to those encountered by EMS patients, although there are notable symptomological differences. These examples highlight the difficulties of diagnosing EMS. In order to provide more inclusive and accurate diagnostic criteria, Hertzman and colleagues redefined EMS diagnostic criteria such that elevated eosinophils did not have to necessarily present to be diagnosed with this syndrome (7).
The NEMSN website (www.nemsn.org : see Updates and New Cases page) also contains details of more recent literature reported occurrences of EMS. Briefly they include: 1) The journal Arthritis & Rheumatism published an article by Varga and colleagues in 2011 that detailed a “new” diagnosed case of EMS from a Chicago woman who took Uber Rest L-Tryptophan (5). The article is entitled "Post-epidemic eosinophilia-myalgia syndrome associated with L-tryptophan". 2) The medical journal Case Reports in Rheumatology published an article in 2012 entitled "Severe Eosinophilic Syndrome Associated with the Use of Probiotic Supplements: A New Entity?" The abstract of the article details two current cases of an EMS-like illness from taking probiotic supplements. 3) The medical journal Reactions Weekly published an article in 2013, describing new EMS cases in France from 2001-2012, attributed to taking 5-HTP supplements.
In addition there have been several other reports and developments that include the following cases. There was a recent report in 2015 of a case involving a 59-year old female who started a special weight-reducing diet regimen that included excessive cashew nut ingestion. She presented several months after consumption of the cashew nuts with peripheral blood eosinophilia and constitutional symptoms. She was diagnosed with EMS due to extreme L-Tryptophan intake, a compound found in the cashew nut oil. She responded well to cashew nut withdrawal and steroid therapy. In the follow-up period she remained stable with a normal eosinophil count and there was no need for any specific therapy (8).
In a 2015 follow up investigation of Melatonin, eight L-Tryptophan related contaminants were detected and their structures determined. This was actually due to the PRESENCE of L-Tryptophan in the Melatonin. Most of the commercially bought samples (eleven out of seventeen) incorrectly listed the amount of Melatonin by 1.0–15% less than declared on the label. In addition the majority of Melatonin tablets tested actually contained L-Tryptophan. The researchers had been interested in evaluating the purity of the Melatonin supplements, yet they made the surprising discovery that L-Tryptophan, along with L-Tryptophan contaminants, were actually found in the Melatonin supplements. One Melatonin supplement tested listed L-Tryptophan on the label as an ingredient, but the rest of the samples tested did not (9). However, it should be noted that Melatonin itself contains contaminants that are very similar to those case-associated contaminants found in Showa Denko L-Tryptophan (10). This is discussed in a separate article entitled “What is in a Name? L-Tryptophan, 5-Hydroxytryptophan and Melatonin Explained”, published in this same anniversary newsletter.
Finally, it is noteworthy that two of the “new” patients that contacted NEMSN have continued to discuss their cases with the Medical Advisory Board. In addition both patients have kindly provided samples of the supplement they consumed prior to onset of their EMS symptoms. This is the first time since the epidemic that samples consumed by the patient can now be directly analyzed for the structure determination and amounts of contaminants present. In one case the patient is from Europe and was taking L-Tryptophan prior to manifestation of elevated eosinophils and myalgia. In the other case the patient is from the USA and was taking 5-HTP prior to onset of EMS -like symptoms. These samples were recently analyzed and both the L-Tryptophan and 5-HTP tablets/capsules contained numerous contaminants. Currently we are working through the data to determine the structures of all these contaminants to see whether there are case-associated compounds present in both samples. These current scenarios serve to remind us of two things: i) EMS continues to persist in the general population associated with individuals taking the supplements L-Tryptophan and 5-HTP (and possibly Melatonin); ii) exemplifies the value of NEMSN as an organization. This patient support and advocacy group continues to serve as a focal point for information, contacts and facilitates important interactions in furthering our understanding of EMS.
4. EMS - CURRENT UNDERSTANDING
Our understanding of the causal onset and progression of EMS is still poorly understood. In part this is due to the relatively small number of patients, and the very limited scientific and clinical literature on the subject. I have suggested above (Section 2) that onset of EMS is caused by consumption of contaminated L-Tryptophan (or other related compounds such as 5-HTP or Melatonin) that triggers an acute inflammatory response in genetically susceptible patients. This is indicative of an auto-immune response, and most clinicians with EMS expertise agree that EMS is an example of such a disease type. There are other examples where consumption of either food or therapeutic drugs have caused EMS-like symptoms. They include Toxic Oil Syndrome (TOS), drug reaction with eosinophilia and systemic symptoms (DRESS) and drug- induced lupus erythematosus (DILE). Whilst these conditions are not identical to EMS they all are auto-immune disorders, and patients have eosinophilia and associated pain symptoms. The evaluation of these closely associated disease states allow the expansion of the patient, scientific and clinical literature base in order to more fully understand what is occurring in EMS. For example if you do a scientific and clinical literature search on Google Scholar for EMS (in the title) since its occurrence in 1989 there have been 329 published papers, and since 2010, only 10 manuscripts on the subject have been published. This is in stark comparison to DRESS, where since 1989 there have been 11,100 papers published and an impressive 5,150 manuscripts since 2010 alone!
4.1 Persistence of EMS: The insights provided by consideration of the TOS, DRESS and DILE literature in conjunction with our limited EMS understanding prompted further questions. It is useful to consider all these disease states as part of a related spectrum, such that they have common symptoms and possible etiologies, but also have some distinct differences at a clinical level. A comparison with Type I, Type II and gestational diabetes is useful to consider as a model to understand the relationships of EMS, TOS, DILE and DRESS. For a variety of reasons these new analyses prompted me to revisit the concept of flare-ups. I had originally been of the opinion in the 1995-2010 period that the initial EMS event in individual patients did systemic damage due to the presence of excessive eosinophil cells releasing their toxic molecular cargo, but there was no reoccurrence. But on reconsideration, I began thinking about a “Destructive Cycle” possibly occurring in each EMS patient. Oxidative stress (molecular imbalance in your body) is something we all experience. This is different from the common everyday stress we are all familiar with in our daily lives. In the case of oxidative stress in EMS patients, this can lead to systemic inflammation, and as a result a chronic immune response. For EMS patients, whose immune system is already compromised, the aforementioned “Destructive Cycle” of oxidative stress coupled with systemic inflammation and systemic immune response leads to flare-ups. I must caution all of you that at the moment this is still an unproven theory. However in the past three years with help from Lois Vierk and the NEMSN Board I have spoken with a number of you about your continued health experiences post the epidemic. Many of you experience flare-ups on an episodic basis. But, not all of you report being subjected to flare-ups. This can be explained by the working hypothesis of the “Destructive Cycle”.
4.2 EMS and Flare-Ups - Treatments: In the case of flare-ups it is possible that careful attention to diet as well as therapeutic agents to alleviate inflammation and systemic auto-immune responses may be useful for treatment. Unfortunately, this is still a working hypothesis, and we still need to understand more fully about flare-ups in terms of occurrence, and factors that cause them. Therefore if you have the time and inclination please contact me to take the simple questionnaire developed for EMS patients concerning flare-ups. In addition any actions you take to alleviate flare-ups should be done in conjunction with your primary physician.
Patients that are experiencing EMS-like symptoms for the first time are typically administered corticosteroids such as prednisone. Whilst such treatments are effective in reducing eosinophil levels back to normal range, as well as reducing inflammation, the significant side effects are not conducive to long-term use. In this current newsletter Dr. Gleich in his article entitled “New Understanding of Eosinophils” describes a promising new drug Fasenra (benralizumab) for EMS treatment. In addition Rhonda Farro in her article entitled “Thirty Years Living with EMS” describes a combination therapy that has helped her personally to overcome the issue of elevated eosinophils as well as flare-up occurrences, namely gabapentin plus amitriptyline.
5. CONCLUSIONS - THE FUTURE
In the past three years Dr. Gleich, Dr. Klarskov, and I have devoted considerable time and effort to the structure determination of “Peak AAA”. We are currently in the process of evaluating if the AAA-1/AAA-2 case-associated contaminants cause eosinophils to migrate towards these compounds when present in the body. This process of a compound causing a cell, such as the eosinophil, to move towards it is known as chemotaxis. These findings may provide considerable insight into a possible mechanism of how contaminants in Showa Denko L-Tryptophan caused EMS onset in patients. In addition we have been analyzing current commercially available L-Tryptophan and 5-HTP that has been taken by patients who subsequently manifested EMS-like symptoms. This latter effort has been undertaken with considerable help from NEMSN board members who have identified individual patients who were then kind enough to provide original tablet/capsule samples. These new efforts have proved fruitful information and offer some ways forward in terms of our understanding of EMS auto-immune causation. If all these studies prove successful, then the goal is to submit an NIH grant application for additional funds to more fully evaluate AAA-1 and AAA-2 in appropriate animal models and better understand the cause of EMS.
Our understanding of flare-ups in epidemic patients is still in its infancy, but through conversations with NEMSN members we at least now recognize the existence of this phenomenon. In addition our working hypothesis suggests that flare-ups may be much more controllable and therefore less debilitating in the future. Finally, new therapeutic drugs are becoming available for treatment of EMS onset, and this includes Fasenra (benralizumab). Whilst there has been very slow progress in the past thirty years, a possible light on the horizon of our understanding of this disease as well as more effective and safe treatments is emerging. This provides us all with a sense of hope for the future in conquering this complex and debilitating syndrome!
(Please note the opinions expressed in this article are solely those of the author and do not necessarily reflect the viewpoint of NEMSN.)
I would like to thank all the people of NEMSN who have been so kind to me with their time, thoughts and ideas. My many questions about all the problems that you encounter in your daily lives have always been described with detail, dignity and humor. I would also like to thank Lois Vierk and the Board Members of NEMSN for the many hours of perseverance and willingness to share their thoughts and ideas, as well as facilitate all my NEMSN contacts over the past several years. Finally I would like to acknowledge my colleagues Dr. Jerry Gleich and Dr. Klaus Klarskov for their continued willingness to work on our unpaid research efforts into understanding causation and long-term effects of EMS on past, present and future patients.
1. Belongia, E. (2004). Toxic Tryptophan? Investigating the Eosinophilia-Myalgia Syndrome in Minnesota. In Cases in Field Epidemiology: A Global Perspective. (Dworkin, M.S., Ed.) Chapter 26, 313-337. Jones & Barlett Learning, Sudbury, MA, USA.
2. Klarskov, K., Gagnon, H., Boudreault, P-L., Normandin, C., Plancq, B., Marsault, E.,Gleich, G. and Naylor, S. (2018). Structure Determination of Disease Associated Peak AAA from L-Tryptophan Implicated in the Eosinophilia-Myalgia Syndrome. Tox. Lett. 282, 71-80.
3. Smith, M.J. and Garrett, R.H. (2005). A Heretofore-Undisclosed Crux of Eosinophilia-Myalgia Syndrome: Compromised Histamine Degradation. Inflamm. Res. 54, 435–450.
4. Okada, S., Kamb, M.L., Pandey, J.P., Philen, R.M., Love, L.A., and Miller, F.W. (2009). Immunogenetic Risk and Protective Factors for the Development of L-Tryptophan Associated Eosinophilia-Myalgia Syndrome and Associated Symptoms. Arthritis Rheum. 61,1305–1311.
5. Allen, J.A., Peterson, A., Sufi’s, R., Hinchcliff, M.E., Mahoney, J.M., Wood, T.A., Miller, F.W., Whitfield, M.L. And Varga, J. (2011). Post-Epidemic Eosinophilia-Myalgia Syndrome Associated with L-Tryptophan. Arthritis Rheum. 63, 3633-3639.
6. Post-Finasteride Syndrome Foundation. https://www.pfsfoundation.org/about-pfs-post-finasteride-syndrome/ . Visited October 29th, 2019.
7. Hertzman, P.A., Clauw, D.J.,, Duffy, J., Medsger, T.A. Jr, Feinstein, A.R. (2001). Rigorous New Approach to Constructing a Gold Standard for Validating New Diagnostic Criteria, as Exemplified by the Eosinophilia-Myalgia Syndrome. Arch Intern Med. 161, 2301–2306.
8. Baresic, M., Bosnic, D., Bakula, M. and Zarkovic, K. (2015). Eosinophilia-Myalgia Syndrome Induced by Excessive L-Tryptophan Intake from Cashew Nuts. Open Med. 10, 82-87.
9. Cerezo, A.B., Leal, A., Alvarez-Ferna, M.A., Hornedo-Ortega, R., Troncoso, A.M. and Garcia-Parrilla, M.C. (2016). Quality Control and Determination of Melatonin in Food Supplements. J. Food Comp. Anal. 45, 80–86.
10. Williamson, B.L., Tomlinson, A.J., Mishra, P.K, Gleich, G.J., and Naylor, S. (1998). Structural Characterization of Contaminants Found in Commercial Preparations of Melatonin: Similarities to Case-Related Compounds from L-Tryptophan Associated with Eosinophilia-Myalgia Syndrome. Chem. Res. Toxicol. 11, 234-240.
What is in a Name? L-Tryptophan, 5-Hydroxytryptophan and Melatonin Explained
by Stephen Naylor Ph.D.
The EMS epidemic of 1998-90 was caused by the consumption of contaminated Showa Denko L-Tryptophan. However, over the past twenty-five years there have been a number of sporadic reports of EMS-like symptoms from individuals taking either 5-Hydroxytryptophan (5-HTP) or Melatonin supplements. These include a number of patients who have self-reported through NEMSN, and this is detailed more in the article by Nancy Grant and Lois Vierk entitled “Contacts from Epidemic Patients and Possible New EMS Cases” published in the current NEMSN newsletter.
5-HTP & Melatonin: After the temporary withdrawal of L-Tryptophan due to the EMS epidemic, 5-HTP was marketed and promoted as a safer, superior replacement. The increased usage of 5-HTP and vigilance over the possible role of contaminants in EMS onset prompted a report in 1994 that three members of a Canadian family using 5-HTP manifested EMS-like symptoms. Analysis of the case-implicated product in 1994 revealed the presence of a unique contaminant, designated as Peak X. Dr. Gleich and I ultimately identified case-associated Peak X as 4,5-tryptophan-dione (4,5-TD) and detected its presence in a number of commercially available 5-HTP supplement brands. Our findings were subsequently confirmed by independent analyses carried out by the USA Food and Drug Administration.
There have been numerous reports from a variety of sources, including NEMSN, that taking Melatonin can also cause EMS-like symptoms. In a clinical study in 1993 where Melatonin was being evaluated as an anti-cancer agent, several patients developed eosinophilia. Based on these reports Dr. Gleich and I analyzed three commercially available Melatonin supplements bought from a local pharmacy in Rochester, Minnesota. Analysis of these Melatonin tablets enabled us to determine the chemical structures of seven contaminants. The structural similarity to the case-associated contaminates found in Showa Denko L-Tryptophan was striking. Two of these contaminants were identified as Peak C (L-Tryptophan case-associated contaminant) analogs. The other Melatonin contaminants were identified as Peak E (L-Tryptophan case-associated contaminant) analogs.
Chemical Structure of Contaminants: The contaminants found in L-Tryptophan, 5-HTP and Melatonin all have complex names and chemical structures. The determination of these structures is both expensive and complicated. These efforts require access to analytical instrumentation that can cost millions of dollars and requires many years of specialized training. So why go to such efforts to determine the structures of these contaminants? The structure of a molecule, particularly a contaminant, can provide valuable insight into how disease symptoms such as those in EMS occur. In other instances the structure and shape of a molecule determines how it interacts with the body. For example, everybody is familiar with the analgesic Aspirin, as well as the cholesterol reducing drug Statin. These widely used drugs have very different chemical structures and thus react with different parts of your body in order to bring about the effects we are all familiar with after taking them. The same principle applies to contaminants; by determining their structures it may be possible to unravel the mechanism by which they harm your body. Once we have such an understanding then it is both possible to prevent further damage as well as possibly treat the effects of the contaminant(s).
L-Tryptophan, 5-HTP and Melatonin Same or Different?: All three supplements have been used to facilitate sleep, control weight gain, aid in the relief of depression and other assorted maladies. Many people who take L-Tryptophan, 5-HTP and/or Melatonin believe that they are unrelated, and very different supplements. So why has each one of these supplements been associated with EMS-like symptoms after consumption by individuals? Organic Chemists and Toxicologists would inform you that all three supplements are closely related based on their chemical structures. As an example think about three different houses you are evaluating to purchase for you and your family. All three houses have an identical foundation and structural framework. However, they differ in color and type of siding, window frames and door entranceways. Casual observation suggests three distinct houses, but to the building constructor they are essentially the same type of house with cosmetic changes. Those minor changes can elicit very different responses form potential buyers.
In the case of L-Tryptophan, 5-HTP and Melatonin the structural framework is identical, and consists of what organic chemists call an indole ring system. However, just like the house analogy, some of the appendages (called functional groups) are different. These minor structural changes determines that each of these compounds can react differently in the human body. But L-Tryptophan, 5-HTP and Melatonin also react with other molecules in such a way that produces structurally similar contaminants that may induce identical symptoms of a disease like EMS. All individuals should remember that L-Tryptophan, 5-HTP and Melatonin are very similar from a chemical structure perspective and this must be considered the next time you think about purchasing a supplement for personal consumption.
(Please note the opinions expressed in this article are solely those of the author and do not necessarily reflect the views of NEMSN.)
New Understanding of Eosinophils
by Gerald J. Gleich M.D.
NEMSN offers this introduction, as approved by Dr. Gleich:
This article written by Gerald J. Gleich M.D. describes the new drug Benralizumab (known as Fasenra), manufactured by AstraZeneca and approved for the treatment of eosinophilic asthma. The drug works by removing eosinophils from the patient's circulation. For new patients who may have EMS it is worthwhile to discuss this new drug with your physician as a possible therapeutic intervention agent. In the case of NEMSN epidemic patients, if you are experiencing a flare-up, you should consult with your primary physician and have your blood eosinophil levels checked. If the levels are elevated then it may be worthwhile to also discuss with your physician about Fasenra and whether it may be of some value in treating your flare-up.
In the past, the eosinophil was thought to repair tissue damage after allergic events, such as anaphylaxis, and after attacks of asthma. However, observations on patients with asthma showed that eosinophils track with disease severity (the sicker the patient with asthma, the more eosinophils are present). This observation suggested that eosinophils mighty be mediating tissue damage during disease.
Analyses of eosinophil granules showed the presence of a protein, called the major basic protein (MBP). MBP is a potent toxin for mammalian cells, it kills bacteria and, perhaps most importantly, it kills helminths (worms). MBP is extensively deposited on damaged tissues, such as the airway of patients dying of asthma. Thus, a protein toxin, MBP, was present is disease in association with damage. This observations suggested that the eosinophil plays an inimical role in human disease by damaging tissues.
This view of what eosinophils do has now been essentially proven by the use of a new medication, termed benralizumab. Benralizumab binds to the eosinophil and causes its destruction. Patients receiving this drug are essentially eosinophil deficient with an absence of blood and tissue eosinophils. Benralizumab depletes the eosinophil in patients with asthma and benefits them by reducing asthma exacerbations. Because the only effect of benralizumab is eradication of eosinophils from the blood and tissues, the beneficial effect in asthma indicates that the eosinophil is a key cell causing asthma worsening (and likely worsening in numerous other diseases).
However, a startling new observation has emerged from the utilization of benralizumab for the treatment of asthma. Presently, approximately 40,000 patients are receiving this drug, and, remarkably, the absence of the eosinophil does not seem to be associated with any abnormality. Whereas some studies suggested that the eosinophil has a variety of functions, including bone marrow maturation, breast development and even a role in reproduction, the findings in patients receiving benralizumab argue that we do not need eosinophils for our normal health in 2019.
Therefore, one wonders why we have eosinophils. Observations dating back over 100 years have shown that eosinophilia is strikingly present in helminth (worm) associated diseases, and paleontologists (scientists concerned with studies of the past) have evidence that humans have been afflicted with helminthic diseases essentially since our presence on the planet. Whereas now helminth infections are uncommon (in modern societies with proper hygiene), in the past, these diseases may have been a significant threat to overall health.
Knowledge that benralizumab eradicates eosinophils and benefits eosinophil-related diseases without significant adverse effects should be encouraging to sufferers of the eosinophil myalgia syndrome (EMS). Any recurrence of EMS would be treated with this drug (and others, such as mepolizumab and reslizumab which also reduce eosinophils) and the eosinophils would be markedly reduced in blood and tissues. An advantage of these new treatments is that they are very well tolerated; in contrast, prednisone that was our main treatment in the past has many adverse side effects.
In 2009, the 20th anniversary of the EMS epidemic, NEMSN Medical Advisory Panel members wrote the three articles found below, “Could EMS have been Prevented? Will Future Outbreaks be Prevented?” by Edward Belongia M.D., “Eosinophilia Myalgia Syndrome Revisited -- 1989-2009” by by Luis R. Espinoza M.D. and “EMS Disappointments” by Gerald J. Gleich M.D.
Could EMS have been Prevented? Will Future Outbreaks be Prevented?
Edward Belongia M.D.
EMS took everyone by surprise in 1989. Now that 20 years have passed, it is useful to revisit the question as to whether the EMS epidemic could have been prevented, and what has been done since then to protect consumers from unsafe dietary supplements? In the 1980s there was no regulatory oversight of companies that manufactured amino acids and other food supplements, yet these products were widely sold and consumed for their pharmacologic effects. L-tryptophan in particular was widely promoted and used because multiple studies had shown that it was beneficial for insomnia, premenstrual syndrome, and other problems. It was the pre-internet era, but books, magazines and news articles amplified these findings and promoted them to the general public. The product labels made no therapeutic claims--they didn’t need to because all the advertising was done through the media and word of mouth.
In 1989 the FDA issued a recall of L-tryptophan when the link to EMS was first demonstrated by studies in Minnesota and New Mexico. It remained off the market for several years, but the situation changed in 1994 when Congress passed the Dietary Supplement Health and Education Act (DSHEA). Under this law, manufacturers of dietary supplements are responsible for determining that their products are safe before they are marketed, but there are no standards or requirements. Premarketing approval by FDA is not required. In 2001 the FDA issued a position paper that specifically stated that L-tryptophan could be marketed, and the manufacturers are responsible for ensuring that the products are safe. But how can that be done? The specific contaminant that triggered EMS has never been proven, and we know it was present in extremely low concentrations. I don’t think a manufacturer can determine that L-tryptophan is safe when there is no way to test for the causative agent. We have some good candidates, but it’s hard to prove that any of them caused EMS because the syndrome cannot be reproduced in animals. Although it was Showa Denko L-tryptophan that caused the 1989 epidemic, we have no way of knowing whether the same contaminant might occur in the manufacturing process at another company. People who take L-tryptophan now are choosing to participate in a natural experiment on the safety of manufactured L-tryptophan. No company or government agency can verify the safety of these products.
DSHEA defined ‘dietary supplements’ so broadly that it included amino acids, extracts, herbs, and other biologically active products (think melatonin and DHEA) that are used almost exclusively for therapeutic effect. Yet they are not regulated as drugs even though they are clearly marketed and purchased for their pharmacologic effects. In addition, virtually nothing is known about the interactions of these substances when people consume many different types of supplements. Drug-drug interactions are carefully evaluated in the world of pharmaceuticals, but interactions among different dietary supplements are largely unpredictable.
More than a decade after DSHEA, the FDA finally implemented standards for good manufacturing practices of dietary supplements. Since 2008, dietary supplement manufacturers and distributors have been required to monitor and document the production process for quality assurance, and perform laboratory analysis of raw materials and finished products to document product purity and the absence of contaminants. This is a meaningful step forward, but it does not guarantee another EMS-like epidemic will not occur. The number and variety of dietary supplements or ‘nutraceuticals’ is enormous, and the burden of evaluating safety and efficacy still falls on the consumer.
At least one private laboratory, ConsumerLab (www.consumerlab.com), now offers independent test reports for dietary supplements from different manufacturers. Their tests can determine if the product label accurately reflects the actual amount of active ingredient in the product, and they evaluate product purity and the presence of trace contaminants. The downside is that they charge a subscription fee to view their reports and test results, but I think it is a worthwhile service since the FDA is not doing this testing. Unfortunately, this still does not guarantee the safety of any particular product, since we have learned from EMS that a dietary supplement can be over 98% pure and still contain deadly contaminants. In addition, a product may be pure and still cause unanticipated health effects due to lack of safety testing.
The bottom line is that we have made some progress but we still have a long way to go. Hopefully the current FDA leadership recognizes this and will make greater efforts to protect consumers from unregulated products that are widely purchased and used for therapeutic purposes.
Edward Belongia M.D. is Senior Epidemiologist/Director of the Epidemiology Research Center, Marshfield Clinic Research Foundation in Marshfield, Wisconsin. As the center's website (www.marshfieldclinic.org) states, Epidemiology research focuses on population health issues. The Marshfield Epidemiology Research Center emphasizes consequential epidemiology - applied research that has a positive effect on public health and disease prevention." Dr. Belongia has published extensively on antibiotic resistance, vaccine-preventable diseases and tick borne diseases as well as on other topics, including EMS.
Eosinophilia Myalgia Syndrome Revisited -- 1989-2009
by Luis R. Espinoza, M.D.
Twenty years have elapsed since a newly recognized systemic inflammatory disorder of epidemic proportions, eosinophilia myalgia syndrome (EMS), began to unravel in the United States of America and several other countries worldwide. The CDC defined EMS on the basis of three laboratory and clinical criteria: a) presence of peripheral blood eosinophilia greater than 1000 cells/ul; b) incapacitating myalgias (muscle pain); and c) absence of infection or malignancy that could account for the previous findings. By July 1991, 1543 cases had been reported by the US Centers for Disease Control and Prevention (CDC) in Atlanta. Epidemiological and clinical observation made by several astute clinicians, however, rapidly led to the conclusion that EMS was secondary to the intake of L-tryptophan containing trace amounts of several contaminants and, more specifically, with particular lots of tryptophan that contained the trace contaminant 1,1'-ethylidenebis (tryptophan) (EBT) and another trace contaminant ("peak UV-5") 3-(phenylamino) alanine (PAA). Patients with EMS ingested significantly higher amounts of both EBT and PAA than did control tryptophan users. Of great interest and importance is the fact that PAA is chemically similar to 3-phenylamino-1,2-propanediol, an aniline derivative isolated from samples of oil that were consumed by persons from Spain in whom the toxic oil syndrome developed. [Editor's note: Toxic oil syndrome broke out abruptly in Spain in 1981. The disease has symptoms similar to EMS and was found to be caused by contaminated cooking oil.]
From its initial description in 1989 to subsequent follow-up it became clearly established that EMS was associated with a relatively high morbidity and mortality. The overwhelming majority of patients (>97%) were white, most (>80%) were female, and age of occurrence was between 35 and 60 years. Early stages of the disease (lasting 3 to 6 months) were characterized by the presence of severe generalized myalgias, fatigue, weakness, edema, and skin rash. During the acute illness, over 30% of patients required hospitalization for incapacitating myalgias, muscle cramps, or pulmonary involvement. Late clinical stages were characterized by the presence of a multitude of ill-defined complaints including paresthesias [skin sensations such as tingling, numbness, burning, etc.], muscle cramps, and alopecia [hair loss]. Long-term follow-up exceeding a year demonstrated that most EMS patients continued to be symptomatic with fatigue, cognitive dysfunction, arthralgias [joint pain], myalgias, alopecia, and skin rash as main clinical manifestations. Follow-up over 5 years has shown that a significant proportion of EMS patients have exhibited significant improvement of their major complaints, although a large proportion remains symptomatic but with a tendency for a gradual and slow recovery. A significant high mortality was seen during the early stages in some epidemiological studies, and by July 1991, 31 deaths had been reported. Most deaths were secondary to severe neurologic and cardiovascular involvement, and also to superimposed infection.
Epidemiological studies have conclusively demonstrated that the most important and reproducible risk factor for EMS was the dose of contaminated L-tryptophan consumed. In addition, the severity of symptoms experienced by individual patients and degree of disability were directly related to the daily dose of L-tryptophan ingested (individuals taking doses higher than 4000 mg/day were more predisposed to develop definite EMS).
What have we learned from this epidemic?
The similarity of EMS and other contaminated foodstuff products-related disorders such as the toxic oil syndrome (TOS) highlights the potential for environmental agents to induce autoimmune disorders, particularly systemic sclerosis and related disorders.
Secondly, the precise identification of the causative agent is difficult to be determined despite intense investigation.
Thirdly, the development of EMS and TOS reminds us that even developed countries are not exempt from being affected by large epidemics of environmental origin.
Lastly, although disease activity in a large proportion of affected individuals continues to lessen, the ultimate consequences of their disease are not well-defined and need further study.
Luis R. Espinoza M.D, is Chief, Section of Rheumatology, Department of Medicine, at Louisiana State University in New Orleans. Over the years Dr. Espinoza has treated many EMS patients. He has authored research articles on EMS and on many other topics in rheumatology. His articles have been published in numerous medical journals. Dr. Espinoza has recently been elected president of the Pan-American League of Associations for Rheumatology.
Besides the above article that Dr. Espinoza just wrote for us, NEMSN also recommends his excellent article from 1999 which appears on our website: "Eosinophilia-Myalgia Syndrome--Long Term Complications" (www.nemsn.org/Articles/Espinoza2.htm).
by Gerald J. Gleich, M.D.
It was late in October 1989. Three women in New Mexico had become ill with a devastating illness that was associated with marked increases in blood eosinophils. All of them had ingested a popular health food, L-tryptophan. Shortly thereafter, other cases came to light prompting the Centers for Disease Control to track down the cause of epidemic. By early November the Minnesota Department of Health had linked the illness and the eosinophilia to L-tryptophan ingestion. By mid-November the Food and Drug Administration banned the sale of L-tryptophan, and existing supplies were removed from the shelves of drug stores across the land country.
In our laboratory at the Mayo Clinic in Rochester Minnesota, the activity level was high. The disease, now termed the eosinophilia myalgia syndrome (EMS), was a serious systemic illness with marked increases in eosinophils in the blood and with striking fibrosis in affected individuals. Because the link to L-tryptophan was so strong, it seemed that investigation of this link would be important in understanding how EMS occurs. However, L-tryptophan itself was an unlikely cause of the disease because L-tryptophan is part of our diet and a normal body constituent. Therefore, it seemed that an L-tryptophan contaminant must be responsible for the disease. If so, then the bottles of L-tryptophan being removed from the shelves of drug stores should be useful as a tool for EMS investigation.
I contacted the local drug stores and soon had cartons of L-tryptophan bottles littering my office. However, later information would show that the contaminants most strongly implicated in the causation of EMS were in relatively low concentrations in those particular bottles. Furthermore, as information from the CDC and the various state health departments accumulated, it seemed likely that EMS had peaked in October and was decreasing by mid-November. By early 1990, after studies by state departments of health, especially in Minnesota, New York and Oregon, L-tryptophan produced by Showa Denko and not by any of the other Japanese companies was clearly the culprit. The way seemed clear to utilize the Showa Denko L-tryptophan to identify the critical contaminants and to determine their role in EMS.
Arthur Mayeno, a skilled analytical chemist working in our laboratory, set about testing L-tryptophan from the various companies and from various lots produced by Showa Denko. Our laboratory had forged a strong link to the Minnesota Department of Health, and Arthur was in daily contact with Michael Osterholm, Craig Hedberg and Ed Belongia, epidemiologists investigating EMS. With their help, Arthur had the critical samples needed to find the contaminant, and he employed high performance liquid chromatography to dissect the L-tryptophan and to determine which of the many contaminants marked EMS. One day, Arthur called a meeting in our laboratory conference room and showed the data. One constituent, which we called peak E, was particularly prominent in Showa Denko L-tryptophan consumed by EMS patients. Ed Belongia then summarized the epidemiological data from the Minnesota Department of Health’s efforts, and his paper in the New England Journal of Medicine showed the link to Showa Denko and the existence of Peak E. But what was peak E? Arthur Mayeno focused his chemical skills and soon had a tentative structure. Although his solution was challenged, Arthur proved that the structure he had identified was the correct one. Peak E consisted of two tryptophan molecules linked together. So the stage appeared to be set for a series of critical experiments linking peak E to EMS.
Our optimism was limitless at this point. Because EMS resembled other diseases associated with fibrosis, particularly scleroderma, it seemed that we had a wonderful opportunity to not only understand the mechanism of EMS but also to begin to understand why scleroderma occurs. We applied for a grant from the National Institutes of Health, and the grant was awarded. Hirohito Kita was a visiting scientist from Japan and a skilled bench scientist. Hirohito began experiments testing whether blood from normal individuals and individuals with EMS could be stimulated by the various L-tryptophan and Peak E preparations we had accumulated.
At first our results indicated that certain batches of L-tryptophan were particularly active, and we thought we had a bioassay to detect the contaminants. However, as we proceeded, it became clear that the reactive factor in L-tryptophan was a well known contaminant, endotoxin, that is the bane of research scientists utilizing biological systems. [Editor's note: Endotoxin is known as a dead end to research experiments since it falsifies results.] By this time, implicated L-tryptophan from Showa Denko had been injected into animal species from rats to mice to guinea pigs and to monkeys, and, although the animals may have become fat, they did not become ill. Moreover, although we persisted in our studies on the blood from patients with EMS, the results were unproductive; none of the methods we employed to stimulate blood was fruitful.
Arthur Mayeno continued his chemical analyses and was able to link the contaminants in L-tryptophan to contaminants in the toxic oil responsible for a massive epidemic in Spain in 1981, referred to as the Spanish toxic oil syndrome (TOS). Remarkably, investigations of TOS had failed to generate an animal model or a bioassay, even though many animal species were exposed to contaminated oil. Thus, the same frustrations experienced by the TOS investigators were shared by our group (and many others) probing EMS. Both TOS and EMS scientists failed to identify any useful tools (such as a bioassay or an animal model) to determine which contaminants in the L-tryptophan and the toxic oil were the critical ones.
In retrospect, the epidemiologists obtained the most significant information about EMS. They showed the critical relationship to L-tryptophan ingestion and the link to L-tryptophan produced by Showa Denko. We were able to identify a series of contaminants in Showa Denko L-tryptophan, but without a bioassay or animal model we were not able to understand how the contaminants caused the disease or which contaminant(s) were the critical ones.
Sometime in the future, another epidemic related to TOS and EMS will likely occur. Hopefully, the experiences from these epidemics will allow future investigators to start where we ended. However, the failure to provoke either the Spanish toxic oil syndrome or EMS in experimental animals or stimulate reactions in patients' cells in test tubes may indicate that these diseases are uniquely human and related to a peculiar human biochemical or immunological characteristic.
Gerald J. Gleich M.D. is recognized as one of the world's foremost experts on the eosinophil and on eosinophilia of all sorts. From 1965 to 2001 he was a researcher at the Mayo Clinic, Rochester, Minnesota. At present he is Research Professor of Dermatology and Medicine at the University of Utah, Salt Lake City. He lists his medical interests on the University of Utah website (http://uuhsc.utah.edu/derm/bios/facultybios/ggleich.htm) as including "diseases associated with eosinophilia, such as the hypereosinophilic syndrome, Churg-Strauss syndrome, the eosinophilia myalgia syndrome, the Spanish toxic oil syndrome, and the syndrome of episodic angioedema and eosinophilia . . . " Dr. Gleich's research papers and articles have been published in many medical journals.