Eosinophilia-myalgia syndrome

We describe the cases of three women with pulmonary involvement in the eosinophilia-myalgia syndrome. The illness was characterized by elevated peripheral blood eosinophil counts, myalgias, fatigue, and dyspnea. Two of three patients had bilateral infiltrates on chest roentgenograms. All three had markedly decreased carbon monoxide diffusing capacities and pulmonary hypertension. High-dose prednisone therapy provided only partial resolution of the pulmonary symptoms. Open lung biopsy specimens showed chronic interstitial and perivascular infiltrates in two of the patients and moderate fibrointimal hyperplasia of pulmonary vasculature in the third. High-dose prednisone therapy prior to the biopsies may have modified the original histologic features.

[Sa.O.sub.2] = hemoglobin oxygen saturation; PND = paroxysmal nocturnal dyspnea Dco = diffusing capacity of carbon monoxide; TLC = total lung capacity; RAP = righ atrial pressure; RVP = right bentricular pressure; PAP = pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; PA = pulmonary artery; CT = computed temography Pulmonary Involvement in the Eosinophilia-Myalgia Syndrome

In late 1989, an epidemic of myalgia and eosinophilia called the eosinophilia-myalgia syndrome was first described in New Mexico. [1] L-tryptophan consumption has been linked with the syndrome. [2] Clinical manifestations have included myalgias, fatigue, muscle weakness, arthralgias, extremity edema, dyspnea, cough, nonspecific skin rash, oral ulcers, vaginal ulcers, scleroderma-like changes, and ascending polyneuropathy. [1-10] Although pulmonary involvement has been noted, to our knowledge, only two reports exist in the literature. [5, 6] We describe the cases of three patients with pulmonary involvement in the eosinophilia-myalgia syndrome.

CASE REPORTS

Significant clinical features of the three patients are summarized in Table 1.

CASE 1

A previously healthy 17-year-old woman patient presented with a one-week history of myalgias, dyspnea, hives, and fluid retention. The dyspnea occurred at rest and with exertion without associated fevers, cough, wheezing, paroxysmal nocturnal dyspnea (PND), or orthopnea. Results of physical examination were unremarkable. Initial laboratory studies were significant for a WBC of 12,500/cu mm with 43 percetn eosinophils.

Progressive dyspnea, increased weakness, and fatigue over the next week prompted further pulmonary evaluation. Findings from the examination were unchanged. The WBC was 22,400 with 49 percent eosinophils. Chest roentgenogram (CXR) showed diffuse bilateral reticulonodular infiltrates. The ECG was normal. Exercise oximetry showed a resting [SaO.sub.2] of 95 percent desaturating to 73 percent with brisk walking. Pulmonary function tests (PFTs) showed an [FEV.sub.1] of 2.31 L (81 percent predicted), FVC of 2.63 L (84 percent predicted), [FEV.sub.1]/FVC of 87 percent, and a Dco of 8.5 ml.min.mm Hg (43 percent predicted). Chest computed tomogrpahy (CT) was normal and echocardiogram revealed only minimal pericardial fluid.

It was learned that for four months the patient had been taking 1 g of L-tryptophan per day for premenstrual syndrome. The L-tryptophan therapy was stopped and prednisone therapy, 40 mg/day, was started. Within a week, her dyspnea was improved and the prednisone dose was tapered over four weeks. The Dco was minimally improved to 13.9, but soom after discontinuing the prednisone therapy, her dyspnea became debilitating again and the Dco was 10.7. The CXR was now normal, but the ECG showed more rightward axis (104 vs 95). Pulmonary hypertension was suspected and confirmed by cardiac catheterization with a mean pulmonary aertery (PA) pressure of 42 mm Hg. There was no left-to-right shunt. Ventilation/perfusion scan was normal.

Prednisone therapy of 40 mg/day was restarted. After one month of treatment, the dyspnea and fatigue persisted. An open lung biopsy was performed.

CASE 2

A 45-year-old woman in previously good health presented with a two-week history of myalgias, fatigue, and progressive dyspnea on exertion. There were no fevers, cough, PND, or orthopnea. The patient had been taking 1.5 to 2.0 g of L-tryptophan foe eight months and had a 10 pack-year smoking history.

Results of physical examination were remarkable for a lower extremity maculopapular rash and a loud P2 on chest examination. The WBC was 5,200/cu mm with 50 percent eosinophils. The CXR was normal, and the ECG showed right axis deviation with a right ventricular strain pattern. Room air arterial blood gas showed a pH of 7.45, [Pco.sub.2] of 27, and [Po.sub.2] of 84. Exercise oximetry was without desaturation. The PFTs revelaed [FEV.sub.1] of 2.30 L (93 percent predicted), FVC of 2.80 L (94 percent predicted), [FEV.sub.1]/FVC of 82 percent, and Dco of 8.7 ml/min/mm Hg (46 percent predicted). Echocardiogram showed a dilated right ventricle, paradoxic septal motion, small pericardial effusion, and estimated high mean pulmonary artery pressure of 37.5 mm Hg. Ventilation/perfusion scan was normal.

The L-tryptophan therapy was stopped and high-dose prednisone (40 to 60 mg/day) was given for two weeks without improvement of her dyspnea. Repeated PFTs were significant for a Dco of 8.1 ml/ min/mm Hg (43 percent predicted). Cardiac catheterization showed severe pulmonary hypertension with a mean pulmonary artery pressure of 56 mm Hg. There was no left-to-right shunt.

Several months of high-dose prednisone therapy (60 mg/day) ensued. The dyspnea and fatigue progressively worsened and signs of cor pulmonale developed. An open lung biopsy was performed.

CASE 3

A 47-year-old woman with a long history of fibromyalgia presented with a three-week history of myalgias, arthralgias, and dyspnea on exertion. There were no associated fevers, cough, PND, or orthopnea. Along with long-term amitriptyline use for the fibromyalgia, she had been taking 2 g of L-tryptophan per day for four months as treatment for insomnia.

Results of examination were normal except for slightly decreased breath sounds and dullness to percussion at the left lung base. The WBC was 13,600/cu mm with 35 percent eosinophils. The CXR revealed bilateral basilar infiltrates and a small left pleural effusion.

The L-tryptophan therapy was discontinued and the patient was started on a regimen of prednisone, 60 mg/day, with rapid clearing of the CXR and musculoskeletal symptoms. The dyspnea persisted and on attempted tapering of the prednisone dosage, the myalgias and arhtralgias returned.

Room air arterial blood gas showed a pH of 7.45, [PCO.sub.2] of 28, and [PO.sub.2] of 85. Exercise oximetry revealed an [SaO.sub.2.] drop from 91 percent to 78 percent with a brisk three-minute walk. The ECG was normal. The PFTs showed an [FEV.sub.1] of 3.07 L (115 percent predicted), FVC of 3.56 L (110 percent predicted), [FEV.sub.1]/FVC of 86 percent, and a Dco of 10.3 ml/min/mm Hg (37 percent predicted). Ventilation/perfusion scan was normal. Cardiac catheterization confirmed mild pulmonary hypertension with a mean pulmonary artery pressure of 23 mm Hg.

The dyspnea persisted with the high-dose steroids. An open lung biopsy was performed.

DISCUSSION

L-tryptophan has been available as an over-the-counter preparation for the treatment of insomnia, depression, tinnitus, and most recently, premenstrual syndrome. Prior to October 1989, myalgia nad eosinophilia were not associated with its ingestion.

The eosinophilia-myalgia syndrome usually occurs as a progressive subacute illness with variable resolution. As of April 1990, more than 1,400 cases of the syndrome had been reported to the Center for Disease Control. Pulmonary complaints were present in approximately 60 percent of the cases.

We describe three cases of the eosinophilia-myalgia syndrome with pulmonary involvement. There are clinical similarities with the Spanish toxic oul syndrome of 1981. [11] The common pulmonary symptom in our patients was dyspnea. The CXR abnormalities were seen in two of three patients and consisted of diffuse bilateral reticulonodular infiltrates in one and bibasilar infiltrates with a left pleural effusion in the other. Common to all three were markedly decreased carbon monoxide diffusing capacities and pulmonary hypertension (Tables 1 through 3).

All patients were treated with steroids and while receiving steroids, they underwent open lung biopsies because of continued symptoms. In patients 1 and 3, biopsy specimens showed nonspecific chronic interstitial and perivascular infiltrates (Table 4). The biopsy specimen from patient 2 showed fibrointimal hyperplasi of the pulmonary vasculature (Table 4).

In the May 1990 issue of Chest, Tazelar et al [6] reported five cases of pulmonary disease in the eosinophia-myalgia syndrome. Clinical findings similar to ours were described, including dyspnea, CXR abnormalities, decreased Dco, and pulmonary hypertension. Histologic findings between the two groups are also similar except for the lack of clear-cut vasculitis in our patients. The high-dose steroid therapy given to our patients prior to biopsy may have modified the histologic features. The patients of Tazelaar et al underwent biopsy before receiving steroids (personal communication).

Steroids provided fairly rapid resolution of pulmonary symptoms in the previously reported group (as early as three days). After eight months of therapy, our patients 1 and 2 have continued to have severe pulmonary hypertension. Patient 3 (who initially had mild pulmonary hypertension) is minimally improved.

The mechanism responsible for the pulmonary insult in the eosinophilia-myalgia syndrom is currently under investigation. Development of the syndrome itself may be related to a contaminant in the L-tryptophan preparations, a toxic byproduct of tryptophan metabolism, or host susceptibility factors. [8-11] An autoimmune mechanism has been postulated. [11] Lung involvement is variable and may be the result of one or a combination of the above inducing a pulmonary vasculitis. Further studies are needed to determine the pathogenesis of the pulmonary manifestations of the eosinophilia-myalgia syndrome as well as effective treatment modalities for the devastating pulmonary hypertension that sometimes occurs.

REFERENCES

[1] Eosinophilia-myalgia syndrome--New Mexico. MMWR 1989; 38:756-67

[2] Eosinophilia-myalgia syndrome and L-tryptophan-containing products--New Mexico, Minnesota, Oregon, and New York, 1989. MMWR 1989; 38:785-88

[3] Flannery MT, Wallach PM, Espinoza LR, Dohrenwend MP, Moscinski LC. A case of the eosinophilia-myalgia syndrome associated with the use of an L-tryptophan product. Ann Intern Med 1990; 112:300-01

[4] Vargo J, Peltonen J, Vitto J, Jimenez S. Deveopment of diffuse fascities with eosinophilia during L-tryptophan treatment: demonstration of elevated type I collagen gene expression in affected tissues. Ann Intern Med 1990; 112:344-51

[5] Travis WD, Kalafer ME, Robin HS, Luibel FJ. Hypersensitivity pneumonitis and pulmonary vasculities with eosinophilia in a patient taking an L-tryptophan preparation. Ann Intern Med 1990; 112:301-03

[6] Tazelar HD, Myers JL, Drage CW, King TE, Aguayo S, Colby TV. Pulmonary disease associated with L-tryptophan-induced eosinophilia myalgia syndrome. Chest 1990; 97:1032-36

[7] Clauw DJ, Nashel DJ, Umhau A, Katz P. Tryptophan-associated eosinophilic connective-disease: a new clinical entity? JAMA 1990; 263:1502-06

[8] Hertzman PA, Blevins WL, Mayer J, Greenfield B, Ting M, Gleich GJ. Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. N Engl J Med 1990; 322:869-73

[9] Silver RM, Heyes MP, Maize JC, Quearry B, Vionnet-Fuasset M, Sternberg EM. Scleroderma, fascitis, and eosinophilia associated with the ingestion of tryptophan. N Engl J Med 1990; 322:874-81

[10] Martin RW, Duff J, Engel AG, Lie JT, Bowles CA, Moyer TP, et al. The clinical spectrum of the eosinophilia-myalgia syndrome associated with L-tryptophan ingestion. Ann Intern Med 1990; 113:124-34

[11] Kilbourne EM, Rigau-Perez JG, Heath CW, Zack MM, Falk H, Martin-Marcos M, et al. Clinical epidemiology of toxic-oil syndrome: manifestations of a new illness. N Engl J Med 1983; 309:1408-14

(*) From Internal Medicine Spokane, Sacred Heart Medical Center and Spokane Pulmonary Clinic, Spokane.

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