Epidemiologic Notes and Reports Eosinophilia-Myalgia Syndrome and L-Tryptophan-Containing Products -- New Mexico, Minnesota, Oregon, and New York, 1989

As of November 21, 360 cases of eosinophilia-myalgia syndrome (EMS) had been reported by state health departments to CDC. Studies examining an association of L-tryptophan-containing products (LTCPs) with the EMS epidemic (1) have been completed in New Mexico, Minnesota, and Oregon. In addition, a fatal case in New York has been reported.

New Mexico. In a New Mexico case-control study, EMS cases (N=12) were all persons for whom an eosinophil count of greater than or equal to 2000 cells/mm3 was recorded from May 1 through November 11, 1989, in nine laboratories in Albuquerque, Santa Fe, and Los Alamos and for whom incapacitating myalgia was documented, either in the medical record or by interview with the patient. Potential cases were excluded if eosinophilia could have been caused by any of a predetermined list of approximately 20 infectious, neoplastic, allergic, or other chronic diseases. EMS cases were compared with controls (two per case) who had been matched with case-patients by age (plus or minus 5 years), sex, and neighborhood of residence. Comparisons were made for factors such as the use of different vitamins, other health foods or raw food products, medications, and different water sources. All case-patients and two (8%) controls used LTCPs (odds ratio (OR) not calculable) (X((2))=20; p=6.9 x 10-6). There were no statistically significant differences between cases and controls on 32 other potential risk factors studied.

Minnesota. In Minnesota, potential cases for an initial case-control study of risk factors for EMS were identified by rheumatologists (who were asked by the Minnesota Department of Health to report patients recently diagnosed with eosinophilia and either severe myalgia or muscle weakness) and by clinical pathologists and a pediatric neurologist (who were asked to identify patients with muscle biopsies showing eosinophilic perimyositis or perivasculitis). Criteria necessary for these patients to be considered as cases were eosinophil count of greater than 1000 cells/mm3, myalgia or muscle weakness of severity sufficient to affect normal daily activities, and a muscle biopsy (if done) showing perimyositis, perivasculitis, or unspecified fasciitis. As in the New Mexico study, potential cases were excluded if EMS could have been caused by any of a predetermined list of diseases known to be associated with eosinophilia. Investigators had no prior knowledge of patients' use of LTCPs. Twelve cases were identified and compared with controls (one per case) matched by age, sex, and telephone exchange. All case-patients and no controls used LTCPs (OR not calculable) (p=8 x 10-4) during the month before onset of illness for case-patients and during a similar time period for matched controls. Nine (75%) case-patients and four (33%) controls were taking some type of prescription medication (not statistically significant after adjustment for use of LTCPs). Illness was not associated with consumption of vitamins and health-food products, wild game, undercooked meat or fish products, or nonprescription medications.

A follow-up study compared 30 EMS cases fitting the CDC surveillance case definition of EMS (1) with 36 asymptomatic users of LTCPs who responded to a public request and contacted the Minnesota Department of Health. Twenty (67%) case-patients reported using brands of LTCPs from one particular tablet manufacturer, compared with eight (22%) asymptomatic users (OR=7.0; 95% confidence interval (CI)=1.5-24.6 (p less than 0.0002)). Asymptomatic LTCP users were similar to case-patients for age, sex, and geographic areas of residence; additional population-based studies of LTCP use continue in Minnesota.

Oregon. The Oregon Health Division studied 29 EMS patients who conformed with the CDC case definition. All had eosinophilia and myalgia; four also reported respiratory signs or symptoms. These patients, all users of LTCPs, were compared with users of LTCPs identified by a random telephone survey of Oregon residents (control group A; N=32) and asymptomatic LT users who contacted the Oregon Health Division (control group B; N=24). Fourteen (48%) case-patients were exposed to LTCPs from a single lot of 4500 bottles, compared with two (6%) persons in control group A and two (8%) persons in control group B (ORs=14.0 (95% CI=2.5-103.0) and 10.3 (95% CI=1.8-76.8), respectively) who were so exposed. This association remains statistically significant when controlled for age, sex, or average daily LTCP consumption.

New York. In New York, a 58-year-old woman with EMS died September 17, 1989. The patient, who had become ill in July 1989 with myalgia, fatigue, and marked progressive weakness, had been taking 5-6 g of LT daily. She had leukocytosis (19,800 cells/mm3) with 18% eosinophils. Electron myelographic and nerve conduction studies were most consistent with axonal neuropathy. Studies considered to be within normal limits included: cerebrospinal fluid glucose, protein, and cell counts and celiac and renal arteriograms. Serologic tests for a variety of autoimmune diseases were negative. The patient developed an ascending polyneuropathy with near-total quadriplegia and a bifacial hemiparesis. She failed to improve on corticosteroid and cyclophosphamide treatment and died following cardiorespiratory arrest. Reported by: M Eidson, DVM, R Voorhees, MD, M Tanuz, CM Sewell, DrPH, State Epidemiologist, New Mexico Health and Environment Dept. SL Glickstein, MD, WE Muth, MD, Park Nicollet Medical Center, Minneapolis; MT Osterholm, PhD, State Epidemiologist, Minnesota Dept of Health. DW Fleming, MD, LR Foster, MD, State Epidemiologist, Oregon Health Div, Oregon Dept of Human Resources. A Finn, Jr, MD, Univ Medical Center, Stonybrook; J Melius, MD, DL Morse, MD, State Epidemiologist, New York State Dept of Health. Div of Field Svcs, Epidemiology Program Office; Health Studies Br and Surveillance and Programs Br, Div of Environmental Hazards and Health Effects, Center for Environmental Health and Injury Control, CDC.

Editorial Note

Editorial Note: The case-control studies in New Mexico and Minnesota establish a statistically significant association between use of LTCPs and development of EMS. The strength of this association, the temporal relationship, the absence of apparent selection or data-ascertainment biases, and the failure of different potential confounders to account for this association support the potential causal relationship. In addition, of the 85 case-patients who initially called CDC before the full implementation of the state-based reporting system and for whom information on LTCP use was available, only one (1%) did not use LTCPs. However, the biologic mechanism for the development of EMS among LTCP users is unclear.

The report of an EMS-associated death in New York emphasizes the potential severity of this condition, and confirmatory data are being sought on other possible EMS-associated deaths. In the fatal case, the severe Guillain-Barre syndrome-like ascending polyneuropathy resembles clinical manifestations in patients with the intermediate and chronic phases of toxic-oil syndrome (TOS), a disease similar to EMS that was epidemic in Spain in 1981 (2-5). Frank vasculitis has been reported in some EMS cases. Physicians caring for patients with EMS should be alert to the possibility that such patients may develop clinical manifestations similar to those of chronic TOS, including peripheral neuropathy (mononeuritis multiplex), thromboembolic phenomena, sclerodermiform skin changes, joint contractures, and pulmonary hypertension (2-5). Case reports received at CDC suggest that, as with TOS, the clinical manifestations of EMS may not regress immediately on removal of LTCPs.

The findings of the lot and brand-name studies in Minnesota and Oregon, suggest multiple interpretations: some LTCPs could contain a contaminant that is causally associated with EMS; or host factors mediating the response to LT may be unique to patients who use a particular brand or set of brands associated with illness. Studies under way include identifying possible chemical or microbial contaminants in LTCPs, tracing the sources of individual brands and lots, identifying host factors related to clinical manifestations, and determining factors associated with use and purchase of LTCPs.

On November 17, the Food and Drug Administration (FDA) announced its intention to seek a nationwide recall of all LTCPs in which LT is the sole or major component; this reinforced a November 11 alert to the public to refrain from using LTCPs. FDA is attempting to trace suspect lots of LTCPs and is evaluating production procedures at the companies in Japan where LT is produced for eventual sale and consumption in the United States.

CDC's initial surveillance case definition for EMS required specific serologic testing or muscle biopsy to rule out trichinosis (1). It now appears the clinical presentation of some EMS patients may be sufficiently distinct from that of trichinosis patients that such specific laboratory tests are not warranted. Accordingly, the CDC surveillance definition of EMS no longer requires specific laboratory testing for trichinella. CDC now recommends defining EMS as an illness characterized by 1) eosinophil count of greater than or equal to 1000 cells per mm3, 2) generalized myalgia (at some point during the course of illness) of severity sufficient to affect a patient's ability to pursue his or her usual daily activities, and 3) absence of any infection or neoplasm that could account for 1 or 2 above. This change has been communicated to state health departments.

Epidemiologic investigations and research studies of EMS should be directed toward further defining a causal association between LTCPs and EMS and identifying specific etiologic factors and possible cofactors that may modify risk. Additional questions relate to the existence of a possible dose-response effect, the latent period between exposure and disease, establishment of the beginning of the epidemic, determination of the full spectrum of clinical manifestations, elucidation of pathogenetic mechanisms, and determination of prognosis and the response to specific therapies.

References

1. CDC. Eosinophilia-myalgia syndrome--New Mexico. MMWR 1989;38:765-7.

2. Grandjean P, Tarkowski S, eds. Toxic oil syndrome: mass food poisoning in Spain--report of a WHO meeting, Madrid 21-25 March 1983. Copenhagen: World Health Organization Regional Office for Europe, 1984.

3. Toxic Epidemic Syndrome Study Group. Toxic epidemic syndrome, Spain, 1981. Lancet 1982;2:697-702.

4. Kilbourne EM, Rigau-Perez JG, Heath CW JR, et al. Clinical epidemiology of toxic-oil syndrome: manifestations of a new illness. N Engl J Med 1983;309:1408-14.

5. Martinez Tello FJ, Navas Palacios JJ, Ricoy JR, et al. Pathology of a new toxic syndrome caused by ingestion of adulterated oil in Spain. Virchows Arch (A) 1982;397:261-85. *Includes persons reporting they currently had a cataract, had had surgery for a cataract, or had had a lens implant for a cataract. **Includes persons who reported they had ever had coronary heart disease, angina pectoris, myocardial infarction, or any other "heart attack."

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