Tablets and capsules containing the essential amino acid L-tryptophan are currently being investigated as a cause of the newly recognized eosinophilia/myalgia syndrome. In the five histologically documented cases reported herein, L-tryptophan ingestion was associated with prominent pulmonary complications. All patients were women ranging from 34 to 65 years, and all presented with respiratory symptoms that began after one to nine months of L-tryptophan therapy. Peripheral eosinophilia was present in four patients as were bilateral interstitial infiltrates on chest roentgenograms. One patient had a normal chest roentgenogram. Lung biopsies were done in all patients and biopsy specimens showed a vasculitis and perivasculitis associated with a mild chronic interstitial pneumonitis and eosinophilia. Three patients had clinical and/or histologic evidence of pulmonary hypertension, and one had a follicular bronchiolitis. Four patients recovered promptly with steriod therapy and discontinuation of L-tryptophan therapy, and one patient has had minimal symptomatic improvement.
L-tryptophan ingestion has been implicated as a causal agent in the newly recognized eosinophilic myalgia syndrome. Most patients have presented with severe myalgias, fatigue, and muscle weakness, although some have had dermatologic manifestations, fever, and neurologic symptoms. Some patients have also had respiratory complaints and chest roentgenographic abnormalities. We report the clinical and histologic findings in five patients with suspected L-tryptophan-related pulmonary disease.
The clinical histories and lung biopsy specimens from five patients with L-tryptophan-associated eosinophilic myalgia syndrome were reviewed. Clinical information was obtained from medical records, pathology reports and referring physicians. Chest roentgenograms were available for review in three patients and descriptions were available in the other two. The lung biopsies included four open biopsies and one transbronchial biopsy.
The clinical findings are summarized in Table 1. All patients were female and ranged in age from 34 to 65 years. Four patients were cigarette smokers. All patients presented with rapidly progressive shortness of breath that was associated with nonproductive cough in three, subjective fevers in one, and symptoms of an upper respiratory tract infection in another. All had been taking L-tryptophan for one to nine months prior to the development of lung disease with doses ranging from 100 to 1,500 mg/day. One patient had discontinued taking the drug herself one month prior to seeking medical attention.
Peripheral eosinophilia were present in four patients. Results of pulmonary function tests were also abnormal in four patients, two having mild and two having moderate restriction. Chest reontgenograms showed diffuse bilateral interstitial opacities in four (Fig 1) which had a predominantly basilar distribution in one. A chest roentgenogram was reported as "normal" in patient 2. There was an associated pleural effusion in patient 1. [TABULAR DATA OMITTED]
All patients were treated with oral prednisone. Four had rapid (as early as three days) symptomatic improvement and roentgenographic clearing. One patient (case 2) is minimally improved after six weeks.
The pulmonary pathologic findings varied somewhat from case to case, although all five patients had an interstitial infiltrate and vascular changes (see Table 2). The most striking changes were in association with vessels (Fig 2). Small arteries and veins were surrounded by tight cuffs of lymphocytes admixed with small numbers of eosinophils. In two cases, the lymphocytes were mildly atypical and had enlarged nuclei with irregular contours and cospicuous nucleoli. The inflammatory infiltrate traversed the wall to involve the media and intima in some vessels but without necrosis. The arteriolar and venular intima had prominent endothelial cells and was thickened by subendothelial fibromyxiod proliferation and small numbers of inflammatory cells in three cases. Three cases showed medial hypertrophy consistent with mild pulmonary hypertension. Eccentric fibrointimal plaques suggesting prior healed thromboemboli were also present in one case (case 2), although medial hypertrophy was not noted. A granulomatous vasculitis was present in case 5, characterized by the presence of palisading histiocytes within the vessel wall associated with giant cells and a focus of necrosis. This was the only case where vessel wall necrosis was observed. Case 5 also had a chronic follicular bronchiolitis. In three cases (cases 1, 2, and 3) there was evidence of cigarette smoking manifested by a respiratory bronchiolitis. The pleura in case 1 showed a mild fibrinous pleuritis. Table 2--Pulmonary Abnormalities Associated with
(*1) See text.
The chronic pneumonia (Fig 3) consisted of mild interstitial accumulations of lymphocytes, occasional plasma cells, and a rare giant cell. Eosinophils were present in all cases but prominent in only two. There was also associated patchy alveolar septal thickening and focal hyperplasia of type II pneumocytes. The alveoli in all cases contained widely scattered clusters of macrophages and lymphocytes with occasional eosinophils which in one case suggested the diagnosis of chronic eosinophilic pneumonia.
The essential amino acid L-tryptophan is currently being prescribed for the treatment of insomnia, depression, obesity, hypertension, and aggression.[2-4] Tablets and capsules containing L-tryptophan are also sold in health food stores, and self-administration of L-tryptophan to help induce sleep has become relatively widespread. Various side effects have been reported, including nausea and diarrhea, exacerbations of asthma,[5,6] confusion, delirium, agitation, and myoclonus.[7,8] The latter occur particularly when L-tryptophan is combined with other drugs known to have an effect on neurotransmitter metabolism, eg, monoamine oxidase inhibitors and fluoxetine.
Recently, L-tryptophan has been etiologically linked to the development of a newly recognized illness referred to as the "eosinophilic myalgia syndrome." Available data on the eosinophilic myalgia syndrome indicate that major complaints usually include severe myalgia and muscle weakness. Dermatologic manifestations, fever, and neurologic involvement may also occur. Muscle biopsy specimens have shown an eosinophilic fasciitis, perimyositis with eosinophilic infiltrates, and/or a perivasculitis.
Pulmonary symptoms were the major presenting complaints in the patients with the eosinophilic/myalgia syndrome whose cases were reported herein. Four had peripheral eosinophilia and four had abnormal chest roentgenograms consistent with diffuse interstitial lung disease. Two patients had clinical evidence of pulmonary hypertension and a third had abnormal pulmonary vessels observed on high-resolution computed chest tomography. Given the diversity of findings, the clinical differential diagnosis was extensive in each of our patients, although the possibility of drug-induced disease was not considered until after lung biopsy. Despite the fact that these five patients were very ill, four of five patients had a prompt clinical and roentgenographic response to steroid treatment and discontinuation of L-tryptophan ingestion.
The most consistent histopathologic changes were a chronic interstitial pneumonia and the presence of distinctive tight cuffs of mixed inflammatory cells surrounding and involving the vasculature, occasionally associated with fibrointimal proliferation. Eosinophils were present within the interstitium and as part of the vascular inflammation, but they were not always prominent. With this constellation of histologic findings, the pathologic differential diagnosis of L-tryptophan-related lung disease is extensive and includes the pulmonary eosinophilic and vasculitic syndromes, interstitial lung diseases, and pulmonary hypertension.
None of these patients had asthma, making the diagnosis of Churg-Strauss syndrome unlikely. Although one patient had a granulomatous vasculitis, other histologic (and clinical) features diagnostic of Wegener's granulomatosis were absent, eg, large zones of necrosis, pulmonary hemorrhage, and the typical giant cells. Although the presence of atypical lymphocytes suggested the possibility of lymphoma in two patients, the actual number of lymphocytes was relatively small and the infiltrates lacked the lymphangitic distribution typical of pulmonary lymphoma.
Chronic eosinophilic pneumonia is also associated with an interstitial and air space infiltrate of mononuclear cells and eosinophils, but this diagnosis was only seriously considered in one patient. The possibility of extrinsic allergic alveolitis was considered in one of our patients due to the presence of interstitial infiltrates and granulomas, but again, the vascular changes mitigated against that diagnosis. However, extrinsic allergic alveolitis is not generally associated with vascular changes. The findings in case 5 also suggested the possibility of collagen vascular disease, especially since this patient had a history of an autoimmune process several years earlier. However, she had no other evidence of an active collagen vascular disease at the time of her presentation. Although two patients had mild pulmonary hypertension, they lacked the plexogenic lesions usually seen in plexogenic pulmonary arteriopathy, and it is not associated with an interstitial pneumonia. Pulmonary veno-occlusive disease may have associated interstitial inflammation; however, our patients lacked the occluded venules.
The mechanism of L-tryptophan toxicity as it is related to the eosinophilic myalgia syndrome and the lungs is currently under investigation. It is not known whether the source of the illness is related to a contaminant, a toxic byproduct, or host susceptibility factors. It is interesting to note that all of our patients were women and the majority were also smokers, but this association may be fortuitous.
In summary, we describe five patients in whom L-tryptophan ingestion was associated with pulmonary complications. Lung biopsy specimens showed distinctive vascular abnormalities and mild interstitial changes. We suggest that L-tryptophan toxicity be considered as a potential cause in all patients with pulmonary infiltrates and eosinophilia, particularly when lung biopsy specimens show evidence of vasculitis.
Since submission of this report, we have seen three additional cases of L-tryptophan-associated pulmonary disease which manifested primarily as pulmonary hypertension. Two cases resolved with steroid therapy and one patient currently has unremitting disease.
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