Eosinophilia-myalgia syndrome. Natural history in a population-based cohort.

BACKGROUND: To determine the natural history of eosinophilia-myalgia syndrome, we followed up all patients with eosinophilia-myalgia syndrome reported to the Oregon Health Division, Portland, during the recent epidemic caused by contaminated tryptophan. METHODS: Patients were interviewed by telephone from 1 to 5 months after illness onset and again at least 12 months after onset. Symptoms (type, onset, and duration), overall disability, treatment, and tryptophan lot and dose were assessed for each patient. RESULTS: Information was obtained for 55 (96%) of 57 case-patients: 53 patients completed interviews and two patients had died. For the 53 patients who were interviewed, symptoms with onset more commonly during the first 3 months of illness included severe myalgias, fatigue, generalized weakness, edema, and rash. Symptoms with later onset included paresthesias, muscle cramps, extremity weakness, and alopecia. At 12 months, 41 patients (77%) continued to report fatigue, 36 (68%) weakness, and 34 (64%) myalgias; 26 patients (49%) had difficulty climbing stairs, 23 (43%) had difficulty getting up from a chair, and 15 (28%) had difficulty holding a cup. Higher doses of tryptophan were correlated with more severe disability, both initially (rs = .33) and at follow-up (rs = .42). Although most patients reported improvement in symptoms at 12 months, only 14 (26%) patients reported that they were able to perform all normal daily activities. CONCLUSIONS: Most patients with eosinophilia-myalgia syndrome in this population-based cohort are still symptomatic 1 year after onset, primarily with the complaints reported early in the illness. The association between degree of disability and daily tryptophan dose suggests that ingestion of varying amounts of contaminant may be responsible, in part, for the severity of symptoms experienced by individual patients.

Eosinophilia in Rheumatologic/Vascular Disorders.

Peripheral and tissue eosinophilia can be a prominent feature of several unique rheumatologic and vascular diseases. These diseases span a wide range of clinical features, histologic findings, therapeutic approaches, and outcomes. Despite the rare nature of these entities--which makes large-scale studies challenging--knowledge has continued to grow regarding their epidemiology, pathophysiology, and management. This review compares and contrasts 5 rheumatologic and vascular conditions in which eosinophilia can be seen: eosinophilic granulomatosis with polyangiitis (Churg-Strauss), immunoglobulin G4-related disease, diffuse fasciitis with eosinophilia, eosinophilia-myalgia syndrome, and eosinophilic myositis.

Eosinophilia-myalgia syndrome and tryptophan production: a cautionary tale.

An epidemic of a new disease, termed eosinophilia-myalgia syndrome, occurred in the USA in 1989. This syndrome was linked to the consumption of L-tryptophan manufactured by a single company utilizing a fermentation process. All the findings indicate that the illness was probably triggered by an impurity formed when the manufacturing conditions were modified. This outbreak highlights the need for close monitoring of the chemical purity of biotechnology-derived products, and for rigorous testing of such products following any significant changes to the manufacturing process.

Eosinophilia-myalgia syndrome in Germany: an epidemiologic review.

OBJECTIVE: To review the epidemiologic features of eosinophilia-myalgia syndrome (EMS) in Germany. DESIGN: We determined the incidence of EMS in Germany through May 1992 and analyzed the dose of L-tryptophan used, the duration of intake, and the concurrent medications. MATERIAL AND METHODS: All patients receiving L-tryptophan preparations in Germany were already under medical supervision before the onset of the disease; thus, information on patient history and other potential risk factors was readily available. Because of the drug status of L-tryptophan preparations, brands could be accurately traced back to suppliers of raw materials. Statistical differences in age and gender of patients, dose of L-tryptophan, eosinophil count, and skin involvement were sought between patients with and those without concurrent medications. RESULTS: On the basis of guidelines established by the Centers for Disease Control and Prevention, 105 patients fulfilled the criteria for EMS. No apparent correlation was found between the incidence of EMS and the dose of L-tryptophan or the duration of intake before onset of EMS. Assessment of the study group showed that 45% were taking various other medications, whereas 55% were taking L-tryptophan only. Analysis by type of pharmaceutical agent showed no preponderance of a specific concurrent drug (in particular, psychotropic drugs). Thus, concurrently used medications did not seem to be an important variable. All cases of EMS were associated with L-tryptophan from formulators that had used raw materials from the previously implicated source. CONCLUSION: This study supports the pathophysiologic role of a contaminant in L-tryptophan in the occurrence of cases of EMS in Germany.

3-(Phenylamino)alanine, a novel aniline-derived amino acid associated with the eosinophilia-myalgia syndrome: a link to the toxic oil syndrome?

The eosinophilia-myalgia syndrome (EMS) is an inflammatory disease that occurred in epidemic proportions in the United States during 1989. Cases of EMS were also reported in Europe and elsewhere. Clinically, EMS resembles the Spanish toxic oil syndrome. EMS has been associated with ingestion of manufactured L-tryptophan and, more specifically, with lots of tryptophan that contained the trace contaminant 1,1'-ethylidenebis(tryptophan) (EBT). Another trace contaminant ("peak UV-5") has been reported, but the strength of its association with EMS has not been demonstrated. Herein we report independently that peak UV-5 is 3-(phenylamino)alanine (PAA). Patients with EMS ingested significantly greater amounts of both PAA and EBT than did control tryptophan users. PAA is chemically similar to 3-phenylamino-1,2-propanediol, an aniline derivative isolated from samples of oil that were consumed by persons in whom the toxic oil syndrome developed. The discovery of an aniline-derived contaminant in tryptophan raises the possibility that EMS and toxic oil syndrome may have a common etiologic trigger.

Toxic oil syndrome and eosinophilia-myalgia syndrome: May 8-10, 1991, World Health Organization meeting report.

In May 1991, researchers and clinicians from throughout the world met at a workshop sponsored by the Regional Office for Europe of the World Health Organization in collaboration with the Fondo de Investigación Sanitaria, Spain, and the U.S. Food and Drug Administration, National Institutes of Health, National Institutes of Mental Health, and Centers for Disease Control and Prevention to share information about two very similar diseases--toxic oil syndrome and eosinophilia-myalgia syndrome. In this paper the interpretation of conference proceedings is presented, current knowledge of the two disorders is summarized, and some possible areas for future research are mentioned. Toxic oil syndrome and eosinophilia-myalgia syndrome have many similarities. Both are related to consumer products that were presumed to be safe but have been found to have numerous trace contaminants, many of which remain to be identified, including the etiologic agents of both disorders. Both illnesses affect patients clinically by causing intense, incapacitating myalgias and a marked peripheral eosinophilia. Other rheumatologic manifestations are common in both, including arthralgias, sicca syndrome, scleroderma-like skin changes, carpal tunnel syndrome, and joint contractures. No clinical or laboratory feature has been found to be pathognomonic of either disease, and accurate diagnosis rests on the clinical judgment of the attending physician. Deaths have occurred in both diseases, and the cumulative mortality for each is approximately 2.5% for the first 2 years. Long-term complications include pulmonary hypertension, peripheral neuropathies, and joint contractures. Although treatment with corticosteroids has resulted in significant symptomatic relief in persons with either disorder, it does not alter the clinical course or long-term outcome. Research into the etiologic agents, preferred treatments, and ways to avoid similar problems in the future is needed.

Epidemiology of potential association between L-tryptophan ingestion and eosinophilia-myalgia syndrome.

This article examines the methodology of the epidemiological studies of the association between L-tryptophan and eosinophilia-myalgia syndrome (EMS) and evaluates the validity of the conclusions from these studies. In the initial case-control studies of L-tryptophantryptophan and EMS there were a variety of methodological problems, including different sources and different exclusion criteria for cases and controls, which could have resulted in selection bias, as well as problems with information bias and confounding. The studies of manufacturer and brand also had similar potential for bias. The L-tryptophan-EMS association is based on two small studies that had important methodological inadequacies. Subsequent studies of brand of L-tryptophan also contained errors in design, which may have produced biased results and call the conclusions into question. The cause of eosinophilia-myalgia syndrome remains unknown.

Eosinophilic rheumatic disorders.

Almost any rheumatic disorder can occasionally be characterized by the presence of eosinophilia, but there are only a few in which eosinophilia is a defining characteristic. These include eosinophilic fasciitis as well as toxin-induced disorders such as eosinophilia-myalgia syndrome and toxic oil syndrome. The epidemiology, clinical features, and pathogenesis of these conditions are reviewed in this article, and a rational approach to management of these entities is discussed.

The eosinophilia-myalgia syndrome: current concepts and future directions.

The eosinophilia-myalgia syndrome (EMS) is a recently described systemic disorder distinguished by the development of characteristic muscle spasm, myalgia, neuropathy, and scleroderma-like cutaneous induration. Life-threatening manifestations have included cardiopulmonary and acute ascending neuropathic syndromes. Current evidence indicates that this is a severe illness with the potential for long-term disability. Careful follow-up studies will help to better define new features of this disease, such as the recent awareness of severe neurocognitive abnormalities in some patients. The association of EMS with the ingestion of L-tryptophan may provide important clues toward the understanding of idiopathic fibrosing syndromes, as well as toxin-induced autoimmune phenomena. Rational therapy will be dependent upon a more complete understanding of the pathogenesis of this and related diseases.

Safety of 5-hydroxy-L-tryptophan.

5-Hydroxy-L-tryptophan (5-HTP) is the immediate precursor in the biosynthesis of 5-hydroxy-tryptamine (5-HT; serotonin) from the essential amino acid L-tryptophan (L-Trp). The use of L-Trp as a dietary supplement was discontinued in 1989 due to an outbreak of eosinophilia-myalgia syndrome (EMS) that was traced to a contaminated synthetic L-Trp from a single manufacturer. 5-HTP has since become a popular dietary supplement in lieu of the removal of L-Trp from the market. Because of its chemical and biochemical relationship to L-Trp, 5-HTP has been under vigilance by consumers, industry, academia and government for its safety. However, no definitive cases of toxicity have emerged despite the worldwide usage of 5-HTP for last 20 years, with the possible exception of one unresolved case of a Canadian woman. Extensive analyses of several sources of 5-HTP have shown no toxic contaminants similar to those associated with L-Trp, nor the presence of any other significant impurities. A minor chromatographic peak (peak X) reported in some 5-HTP samples lacks credibility due to chromatographic artifacts and infinitesimal concentrations, and has raised undue speculations concerning its chemistry and toxicity.

Synthesis and formation of an EMS correlated contaminant in biotechnologically manufactured L-tryptophan.

Contaminants in biotechnologically manufactured L-Tryptophan (Trp) are suspected to be responsible for the outbreak of an unknown autoimmune disease in 1989. The contaminants, found in Trp-lots of a Japanese manufacturer, are classified in EMS-correlated and non EMS-correlated substances. Up to now six EMS-correlated substances are known. One of these compounds is 2-(3'-indolylmethyl)-indole (IMT). IMT was detected as a major contaminant in two investigated EMS-associated trp-samples. In a seven step chemical synthesis IMT was obtained for use as a reference substance. A model system to investigate the formation of IMT was created using Trp and 3-indolylmethanol (IM). IMT formation was observed at acidic and alkaline pH-values and the optimal molar ratio of Trp to IM is 100:1. In addition an IMT formation was observed from indole, formaldehyde and Trp as well as from Trp and 3-indolylacetaldehyde.

Pathogenesis of L-tryptophan eosinophilia myalgia syndrome.

Taken together, these studies suggest that many different etiologic agents alone or together may initiate the common final pathways of tissue pathologic response resulting in the clinical syndrome of eosinophilia, myalgias and fasciitis. Tryptophan itself may contribute to some of the scarring features of the illness, while impure L-tryptophan, and one or more of the impurities cause the characteristic features of the illness. The altered tryptophan metabolism in EMS is secondary to inflammation.

Clinical features of eosinophilia myalgia syndrome and related disorders.

EMS, EF, and TOS are all relatively rare disorders. There are considerable data to suggest that most (if not all) of these cases may be due to toxin exposure, although the precise etiologic agent(s) has yet to be identified. It is likely that the pathogenic mechanisms responsible for disease are similar in these entities, and thus the distinctions between these illnesses may be largely semantic. Rational therapy includes the removal of an inciting agent if identified, and the application of symptom-based treatment based on the organ or tissue involved, and whether there is evidence of active inflammation is present.

Analysis of Centers for Disease Control and Prevention criteria for the eosinophilia-myalgia syndrome in a geographically defined population.

OBJECTIVE: To test whether individuals can be identified in a geographically defined population who would meet criteria for the eosinophilia-myalgia syndrome (EMS) established by the US Centers for Disease Control and Prevention (CDC), i.e, (1) eosinophil count > 1 x 10(9)/l, (2) myalgia severe enough to limit usual activities of daily living, and (3) no evidence of infection or neoplasm that could explain the first 2 findings. METHODS: To discover the number of individuals who would meet CDC criteria, the population was exhaustively searched using methods adapted from active pharmacoepidemiologic surveillance. Medical consultants and primary care practitioners were questioned as many as 5 times in a search for patients with severe myalgia. A predetermined protocol was used to screen those patients who appeared to meet CDC criteria for EMS using active surveillance methods. The study population was limited to Québec and Ontario (combined population 18,980,000) with special attention to the period July 1, 1992, to June 30, 1993. RESULTS: The prevalence of severe incapacitating myalgia was 43 per 100,000 persons, including 19 individuals with eosinophilia > 1 x 10(9)/l, who met CDC criteria for EMS. None of these individuals were reported to have taken L-tryptophan (LT). CONCLUSION: The CDC criteria for EMS are met by individuals in the general population who have never been exposed to LT.