Case Report Acute Respiratory Failure Caused by Pulmonary Vasculitis after L-Tryptophan Ingestion1.2
ARTHUR S. BANNER and DENNIS BOROCHOVITZ
Introduction he pulmonary vasculitides are a heterogeneous group of disorders with variable clinical manifestations (1). Although the nosology of these disorders is complex, they clinically present as either well-definedpulmonary disorders, with characteristic radiographic and pathologic characteristics, or in a nonspecific fashion, accompanying a systemic vasculitis. The former entities consist of the angiocentric granulomatous disorders. In these conditions, the pulmonary manifestations are clearly attributable to the vasculitis. The latter comprise a variety of systemicvasculitides such as polyarteritis nodosa, hypersensitivity angiitis, mixed cryoglobulinemia, and collagen diseases. These disorders are diagnosed by clinical manifestations, serology, and biopsy of organs other than the lung. Lung findings are usually nonspecific. When lung disease is attributed to vasculitis, this is often done by inference rather than by direct histologic confirmation. The appropriate treatment of the pulmonary manifestations of these disorders is often unclear. In this report, wedescribe two patients who presented with an illness resembling the adult respiratory distress syndrome. Both underwent open lung biopsies, which revealed a unique form of nongranulomatous, smallvessel vasculitis as the most prominent morphologic finding. Both appeared to respond to large doses of intravenously administered corticosteroids. The clinical, radiographic, ' and histologic features of the illnessweresimilar in the two patients. A cause for the vasculitis could be not be found in either case. However, both patients had been treated with t-tryptophan,
T
Case Reports Patient 1 The patient was a 62-yr-old woman who had previously been in good health except for a history of anxiety. Seven months prior to admission she was started on t-tryptophan for insomnia. At that time she had also been taking temazepam, doxepin hydrochloride, and triazolam. She received t-tryptophan, 500mg daily for 6 wk, but then she stopped because of lack of efficacy. She did well until 3 months later when she began to note fatigue and malaise. She also noted numbness and pallor in the left hand. For I wk prior to admission she noted progressive shortness of breath and was admitted on October 6, 1989.She was found to be afebrile
SUMMARY This report describes two women who presented with severe respiratory failure and diffuse pulmonary infiltrates In the fall of 1989. Both required prolonged assisted ventilation because of severe shunt physiology. Open lung biopsies on admission revealed a small vessel vasculi· tis as the sole morphologic abnormality in both patients. Both responded to high dose corticosteroids. Neither patient exhibited evidence of systemic vasculitis, and neither had serologic evidence of an immune disorder. Common to both patients was Ingestion of l·tryptophan. One patient exhibited several features of the eosinophllla.myaigia syndrome. The other patient did not appear to have the syndrome, but the temporal relationship between the onset of symptoms and initiation of l·tryptophan treatment was striking. The presentation of these patients alters our notions concerning the spectrum of clinical manifestations caused by this agent, and the response to methylprednisolone supports Its efficacy In the treatment of this disorder. AM REV RESPIR DIS 1991; 143:661-664
and with normal vital signs. Physical examination revealed crackles at the lung bases and faint left radial and brachial pulses. The cardiac examination was normal, and there was no peripheral edema. Neurologic examination was normal, and there were no skin lesions. A chest radiograph revealed bilateral diffuse infiltrates (figure I). An arterial blood gas analysis, obtained while breathing room air, revealed a pH of 7.39, a Po, of 44 mm Hg, and a Pco, of 28 mm Hg. The whiteblood cellcount was 14.9thousand with 54% neutrophils, 3010 bands, 1O% eosinophils, 5% atypical lymphocytes, and 7% monocytes, and the hemoglobin was 15.3g/dl. The next day the white blood cellcount was 18thousand with 19% eosinophils. Urine analysis was normal except for a trace of protein. A ventilationperfusion scan was negative. Past health included treatment for a herniated lumbar disk 3 months prior to admission. On admission, medications included captopril for hypertension, alprazolam, c1onazepam, and synthroid. There was no history , of allergies. On the second hospital day, there was marked progression of pulmonary infiltrates and gas exchange abnormalities necessitating assisted ventilation. With 90% oxygen, and a positive endexpiratory pressure of 12.5 cm/H,O, the arterial Po, was 64 mm Hg. An echocardiogram revealed no valvular abnormalities and good left ventricular function. A Swan-Ganz catheter was inserted; cardiac index was 3.5 Lzrnin/m", pulmonary artery pressure was 39/19 mm Hg, and pulmonary capillary wedge pressure was 12 mm Hg. A Doppler study of the left upper extremity revealed obstruction of a proximal vessel to the arm. A CAT scan failed to reveal an aneurysm ofthe subclavian artery. An open lung biopsy was performed, which revealed a small-vessel vasculitis (see below). All previous medications other than the synthroid were stopped, and the patient was treated with methylprednisolone 1 g once a day for IOdays, at which time the steroid was slowly tapered over several weeks to a maintenance dose of prednisone 20 mg
each day. With institution of steroids there was gradual clearing of pulmonary infiltrates over a 2wk period at which time the patient was extubated. The patient was discharged on November 3, 1989and started on a regimen of daily prednisone and cyclophosphamide IOmg/kg intravenously every 3 wk. Over a period of 9 months the patient has done well and has not exhibited evidence of skin, renal, or joint involvement. There was transient but minimal elevations of liver enzymes. The Wintrobe erythrocyte sedimentation rate was never elevated and determinations for antinuclear antibodies, rheumatoid factor, and cryoglobulins were negative, and total complement levels were within normal levels. A pulmonary function test performed on November 16, 1989revealed normal lung function except for a hemoglobin-corrected diffusing capacity of 40% of predicted. Repeat studies 2 months later were identical.
Patient 2 The patient was a 48-yr-old woman who had been in good health except for chronic anxiety and depression. One month prior to admission, the patient was started on t-tryptophan 500mg three times daily, which she continued to take until admission. One week prior to admission she noted a nonproductive cough, weakness, and dyspnea on exer-
(Received in originaljorm March 30, 1990 and in revised jorm August 23, 1990) 1 From the Division of Pulmonary Medicine and the Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania. 'Correspondence and requests for reprints should be addressed to Arthur S. Banner, M.D., Pulmonary Unit, Montefiore Hospital, 3459 Fifth Avenue, Pittsburgh, PA 15213.
661
662
CASE REPORT
Fig. 1. Chest radiograph of Patient 1 showing diffuse lung infiltrates.
roentgenogram cleared gradually in about 12days, at which time she was successfully extubated. The steroids were tapered, and she was started on cyclophosphamide I mg/kg daily on November 12, 1989. At no time during her course did she exhibit renal or neurologic dysfunction or skin lesions. She did exhibit transient hepatic dysfunction, but hepatitis core antigen and antibody were negative. A pleural effusion was noted on the left side on the seventh day, which was shown to have the characteristics of a transudate. She was discharged on the twenty-fifth hospital day and has done well since. A pulmonary function test obtained on November 21, 1989revealed borderline restrictive disease with a hemoglobin-corrected diffusing capacity of 37010 of predicted. Repeat studies performed 7 months later revealed that diffusing capacity had improved to 74010 of predicted.
Histology
Fig. 2. Chest radiograph of Patient 2 showing diffuse lung infiltrates.
tion. Worsening of these symptoms led to her admission on October 31, 1989.At that time her vital signs were normal except for a temperature of 38° C. The chest was clear, and cardiac examination was normal. There wereno skin lesions. A chest radiograph revealed diffuse bilateral infiltrates (figure 2). An arterial blood gas analysis obtained while breathing room air revealed a pH of 7.51, a Po, of 37 mm Hg, and a Pco, of 28 mm Hg. The white blood cell count was 20.2 thousand with 91% neutrophils, 2% bands, 4010 lymphocytes, 2010 monocytes, and 1010 eosinophils. Urine analysis was normal except for a trace of protein. The Wintrobe sedimentation rate was 28 mrn/h; RA factor, ANA, and cryoglobulins were negative. Her past history was negative except for surgery for a herniated lumbar disk 6 months previously. She had smoked a pack of cigarettes a day for 20 yr. She denied aller-
gies. Medications included diclofenac, misoprostol, orphenadrine citrate, arnitryptiline hydrochloride, and L-tryptophan. A ventilation-perfusion scan was performed, which was normal. Her respiratory condition rapidly deteriorated, and she was promptly intubated and placed on mechanical ventilation with a positive end-expiratory pressure of 15 cm H,O and a fraction of inspired oxygen of 90010. The Po, on these settings was 97 mm Hg. A Swan-Ganz catheter was inserted; cardiac index was 3.411/min/m', pulmonary artery pressure was 40/23 mm Hg, and the pulmonary capillary wedge pressure was 15 mm Hg. An echocardiogram revealed good left ventricular function and no valvular disease. An open lung biopsy was performed that re~ vealed a small vesselvasculitis(seebelow). All previous medications were stopped, and she was started on methylprednisolone 100mg every 8 h. The chest
The lung biopsies from each patient were obtained from the right lung. The first was a portion oflung tissue measuring 4.0 x 2.0 x 0.5 ern, and on gross examination appeared congested. On cutting the specimen, edema fluid was observed on the surface of the cut edge of the lung tissue. The specimen from the second patient measured 4.0 x 1.5 x 1.0 ern, and, similarly, appeared congested. Cut section showed no significant abnormality. Histologic examination of both biopsies showed similar features (figure 3). The pleural surfaces were unremarkable. The general architecture of the lung tissue and arrangement of the bronchial triads were normal. The bronchial triads appeared prominent and showed under low power microscopy an increase in inflammatory cells. The pulmonary septa appeared edematous. The bronchioles were normal. The respiratory ducts, terminal respiratory pathways, alveolar sacs, and alveoli showed minor abnormalities with occasional, small focal areas of hemorrhage and, especially in the second case, focal desquamation of type 2 pneumocytes. The abnormalities in the vascular system were striking. The large arteries, a few of which were included in both biopsies, showed occasional organizing thrombi associated with focal areas of intimal thickening by infiltrates of cells including lymphocytes, polymorphonuclear leukocytes, and occasional eosinophils. A similar mixed inflammatory infiltrate involved the small arterioles and the periarteriolar connective tissue. Electromicroscopic examination of the second patient confirmed the presence of a mixed inflammatory infiltrate in the endothelium of the large arteries and in the entire wall of the arterioles. There were no extraneous electron-dense deposits. Cultures of both biopsies were negative for bacteria, fungi, mycobacteria, and viruses. Direct immunofluorescence for Legionella species was negative.
Discussion
The two patients described were seen within 1 month of one another and each suffered a nearly identical illness. Both developed rapidly progressive respiratory failure of unknown etiology, both required assisted ventilation, and both appeared to respond to corticosteroids. The past history was also similar' in the two patients. Both of them suffered from chronic anxiety and depression, had abused tranquilizers and antidepressants, and had been treated with t-tryptophan. Our patients presented with a clinical picture consistent with the adult respiratory dis-
CASE REPORT
663
Fig. 3. Photomicrographs of lung biopsies from Patient 1 (A) and Patient 2 (6) . Both biopsies revealed similar abnormalities. PUlmonary arteriolar walls are thickened by edema and a mixed inflammatory infiltrate including eosinophils (Giemsa stain, oil immers ion; x 160).
tress syndrome, i.e., diffuse pulmonary infiltrates, severe and progressive respiratory failure, and normal capillary wedge pressure (2). However, the histologic findings were distinct from those associated with this disorder. There was no evidence of alveolitis. The sole abnormality was a vasculitis involving the arterioles and small arteries. Vasculitis involving the lung has been classified in a useful fash ion by Saldana (3). He groups the lesions into three categories. One group consists of necrotizing, granulomatous lesions and includes Wegener's granuloma-
tosis, Churg-Strauss disease, and necrotizing sarcoid. The second group contains the angiocentric lymphoproliferative disorders, including benign lymphocytic angiitis, lymphomatoid granulomatosis, and angiocentric large cell lymphoma. Finally, in the third group of vasculitides, he includes polyarteritis nodosa, hypersensitivity vasculitis, and other miscellaneous causes of vasculitis. The two cases reported here represent an entity not readily recognized as falIing into any of these subclassifications. There was no evidence of necrosis, granuloma, or atypical lym-
phocytic exudate in either of the two patients. The large arteries did not show a panarteritis as is seen in classic pol yarteritis nod osa. The hallmark of hypersensitivity angiitis is skin involvement , which was not evident in our patients. A small-ve ssel vasculitis may also be a feature o f collagen vascular disease (4) but neither of our patients had clinical or serologic evidence of any of these disorders. One of our patients did exhibit evidence of a large vessel occlusion (Patient I), which is seen in Takayasu's arteritis. Howe ver, this disorder is confined mo stly to younger women and involves the larger vessels. When the lung is affected, the lesions tend to be confined to the large elastic arteries, and the histologic findings are characterized by mononuclear cell infiltrates, often with giant cells. Symptomatic pulmonary disease is rare and is due to pulmonary hypertension consequent to narrowing and occlusions of the large pulmonary arteries (l). The histologic results described in our patients most closely resemble those of hypersensitivity ang iitis. Nevertheless, there were certain distinct differences. The lesions in our patients were characterized by lymphocytic infiltration in addition to neutrophils and eosinophils; there was no necrosis, and the proximal larger arteries, which were affected by a similar inflammatory exudate, contained mural thrombi. There is, to our knowledge, no similar lesion of this type. We do not know the etiology of this disorder, but suspect it may have been con sequent to ingestion of t-tryptophan. In on e patient, there was a close temporal relationship between the onset of her illness and beginning t-tryptophan treatment. The other patient became iII 3 months after stopping the agent and developed her pulmonary disease 4 months later. There have been recent reports of t-tryptophan causing a systemic illness that can involve the lungs. The illness ha s been termed the eosinophilia-myalgia syndrome (5), and it is probably caused by a chemical contaminant of an L-tryptophan product produced by a single company (6). The full spectrum of this disease is unknown. It has been defined for epidemiologic purposes as a disorder having a subacute course, characterized by myalgias, fatigue, and eosinophilia after ingestion of't-tryptophan (7). The disease may occur concurrently with ingestion of t-tryptophan or it may have its onset weeks or months after discontinuation of the agent (7). A variety of organ systems may be involved, and respiratory complaints are common. Frank vasculitis has been noted, and there has been one report of a patient suffering hypersens itivity pneumonitis with vasculit is (8). Tazelaar and coworkers (9) reported a group of five patients who presented with pulmonary symptoms cau sed by pulmonary vasculitis and interstitial pneumonitis after ingesting L-tryptophan. As far as we know, there have been no reports of severe respiratory failure associated solely with pulmonary vasculitis caused by this agent. One of our patients had many of the manifestations of the
664
eosinophilia-myalgia syndrome. She experienced a subacute course with severe fatigue, marked peripheral eosinophilia, hepatic dysfunction, and symptoms and signs suggestive of systemic embolization. The other patient did not appear to have the eosinophiliamyalgia syndrome, but the temporal relationship between starting treatment with L-tryptop han and the occurrence of her respiratory disease was striking. Both of our patients had used a variety of medications, but none of them has been reported to cause pulmonary vasculitis. Of interest, the patients described by Tazelaar and coworkers (9) also failed to exhibit the typical eosinophilia-myalgia syndrome. Only one of the five experienced myalgias, and one did not have peripheral eosinophilia. It would thus seem likely that L-tryptophan toxicity may present with pulmonary disease unassociated with the other manifestations of the eosinophilia-myalgia syndrome. Thus, severe respiratory disease may occur concurrent with, or many months after,
CASE REPORT
L-tryptophan ingestion; furthermore, the respiratory disorder may occur without the other manifestations of the eosinophilia-myalgia syndrome. A history of t-tryptophan ingestion should be sought in those patients who present with severe respiratory failure of unknown etiology, and lung biopsy should be considered. Most importantly, the disease appears to respond to corticosteroids. The therapeutic role of cyclophosphamide is uncertain. The fact that diffusing capacity returned to a nearly normal value after 6 months of treatment in one patient suggests that the vascular disorder may be fully reversible.
References 1. Leavitt RY,Fauci AS. Pulmonary vasculitis. Am Rev Respir Dis 1986; 134:149-66. 2. Hansen-Flaschen 1, Fishman AP. Adult respiratory distress syndrome: clinical features and pathogenesis. In: Fishman AP, ed. Pulmonary diseases and disorders. Vol 3. New York: McGrawHill, 1988; 2201-13. 3. Saldana Ml. Vasculitides and angiocentric Iyrn-
phoproliferative processes. In: Dail DH, Hammer SP, eds. Pulmonary pathology. New York: SpringerVerlag, 1988; 447-60. 4. Hunninghake GW, Fauci AS. Pulmonary involvement in the collagen vascular diseases. Am Rev Respir Dis 1979; 119:471-503. 5. Eosinophilia-myalgia syndrome and L-tryptophan-containing products: New Mexico, Minnesota, Oregon, and New York, 1989.MMWR 1989; 38:785-8. 6. Belongia EA, Hedberg CW, Gleich Gl, et al. An investigation of the cause of the eosinophiliamyalgia syndrome associated with tryptophan use. N Engl 1 Med 1990; 323:357-65. 7. Kilbourne EM, Swygert LA, Philen RM, et al. Interim guidance on the eosinophilia-myalgia syndrome. Ann Intern Med 1990; 112:85-6. 8. Travis WD, Kalafer ME, Robin HS, Luibel Fl. Hypersensitivity pneumonitis and pulmonary vasculitis with eosinophilia in a patient taking an L-tryptophan preparation. Ann Intern Med 1990; 112:301-3. 9. Tazelaar HD, Myers Jl., Drage CW, et al. Pulmonary disease associated with L-tryptophaninduced eosinophilia myalgia syndrome. Clinical and pathologic features. Chest 1990; 97:1032-6.
ARTHUR S. BANNER and DENNIS BOROCHOVITZ
Introduction he pulmonary vasculitides are a heterogeneous group of disorders with variable clinical manifestations (1). Although the nosology of these disorders is complex, they clinically present as either well-definedpulmonary disorders, with characteristic radiographic and pathologic characteristics, or in a nonspecific fashion, accompanying a systemic vasculitis. The former entities consist of the angiocentric granulomatous disorders. In these conditions, the pulmonary manifestations are clearly attributable to the vasculitis. The latter comprise a variety of systemicvasculitides such as polyarteritis nodosa, hypersensitivity angiitis, mixed cryoglobulinemia, and collagen diseases. These disorders are diagnosed by clinical manifestations, serology, and biopsy of organs other than the lung. Lung findings are usually nonspecific. When lung disease is attributed to vasculitis, this is often done by inference rather than by direct histologic confirmation. The appropriate treatment of the pulmonary manifestations of these disorders is often unclear. In this report, wedescribe two patients who presented with an illness resembling the adult respiratory distress syndrome. Both underwent open lung biopsies, which revealed a unique form of nongranulomatous, smallvessel vasculitis as the most prominent morphologic finding. Both appeared to respond to large doses of intravenously administered corticosteroids. The clinical, radiographic, ' and histologic features of the illnessweresimilar in the two patients. A cause for the vasculitis could be not be found in either case. However, both patients had been treated with t-tryptophan,
T
Case Reports Patient 1 The patient was a 62-yr-old woman who had previously been in good health except for a history of anxiety. Seven months prior to admission she was started on t-tryptophan for insomnia. At that time she had also been taking temazepam, doxepin hydrochloride, and triazolam. She received t-tryptophan, 500mg daily for 6 wk, but then she stopped because of lack of efficacy. She did well until 3 months later when she began to note fatigue and malaise. She also noted numbness and pallor in the left hand. For I wk prior to admission she noted progressive shortness of breath and was admitted on October 6, 1989.She was found to be afebrile
SUMMARY This report describes two women who presented with severe respiratory failure and diffuse pulmonary infiltrates In the fall of 1989. Both required prolonged assisted ventilation because of severe shunt physiology. Open lung biopsies on admission revealed a small vessel vasculi· tis as the sole morphologic abnormality in both patients. Both responded to high dose corticosteroids. Neither patient exhibited evidence of systemic vasculitis, and neither had serologic evidence of an immune disorder. Common to both patients was Ingestion of l·tryptophan. One patient exhibited several features of the eosinophllla.myaigia syndrome. The other patient did not appear to have the syndrome, but the temporal relationship between the onset of symptoms and initiation of l·tryptophan treatment was striking. The presentation of these patients alters our notions concerning the spectrum of clinical manifestations caused by this agent, and the response to methylprednisolone supports Its efficacy In the treatment of this disorder. AM REV RESPIR DIS 1991; 143:661-664
and with normal vital signs. Physical examination revealed crackles at the lung bases and faint left radial and brachial pulses. The cardiac examination was normal, and there was no peripheral edema. Neurologic examination was normal, and there were no skin lesions. A chest radiograph revealed bilateral diffuse infiltrates (figure I). An arterial blood gas analysis, obtained while breathing room air, revealed a pH of 7.39, a Po, of 44 mm Hg, and a Pco, of 28 mm Hg. The whiteblood cellcount was 14.9thousand with 54% neutrophils, 3010 bands, 1O% eosinophils, 5% atypical lymphocytes, and 7% monocytes, and the hemoglobin was 15.3g/dl. The next day the white blood cellcount was 18thousand with 19% eosinophils. Urine analysis was normal except for a trace of protein. A ventilationperfusion scan was negative. Past health included treatment for a herniated lumbar disk 3 months prior to admission. On admission, medications included captopril for hypertension, alprazolam, c1onazepam, and synthroid. There was no history , of allergies. On the second hospital day, there was marked progression of pulmonary infiltrates and gas exchange abnormalities necessitating assisted ventilation. With 90% oxygen, and a positive endexpiratory pressure of 12.5 cm/H,O, the arterial Po, was 64 mm Hg. An echocardiogram revealed no valvular abnormalities and good left ventricular function. A Swan-Ganz catheter was inserted; cardiac index was 3.5 Lzrnin/m", pulmonary artery pressure was 39/19 mm Hg, and pulmonary capillary wedge pressure was 12 mm Hg. A Doppler study of the left upper extremity revealed obstruction of a proximal vessel to the arm. A CAT scan failed to reveal an aneurysm ofthe subclavian artery. An open lung biopsy was performed, which revealed a small-vessel vasculitis (see below). All previous medications other than the synthroid were stopped, and the patient was treated with methylprednisolone 1 g once a day for IOdays, at which time the steroid was slowly tapered over several weeks to a maintenance dose of prednisone 20 mg
each day. With institution of steroids there was gradual clearing of pulmonary infiltrates over a 2wk period at which time the patient was extubated. The patient was discharged on November 3, 1989and started on a regimen of daily prednisone and cyclophosphamide IOmg/kg intravenously every 3 wk. Over a period of 9 months the patient has done well and has not exhibited evidence of skin, renal, or joint involvement. There was transient but minimal elevations of liver enzymes. The Wintrobe erythrocyte sedimentation rate was never elevated and determinations for antinuclear antibodies, rheumatoid factor, and cryoglobulins were negative, and total complement levels were within normal levels. A pulmonary function test performed on November 16, 1989revealed normal lung function except for a hemoglobin-corrected diffusing capacity of 40% of predicted. Repeat studies 2 months later were identical.
Patient 2 The patient was a 48-yr-old woman who had been in good health except for chronic anxiety and depression. One month prior to admission, the patient was started on t-tryptophan 500mg three times daily, which she continued to take until admission. One week prior to admission she noted a nonproductive cough, weakness, and dyspnea on exer-
(Received in originaljorm March 30, 1990 and in revised jorm August 23, 1990) 1 From the Division of Pulmonary Medicine and the Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania. 'Correspondence and requests for reprints should be addressed to Arthur S. Banner, M.D., Pulmonary Unit, Montefiore Hospital, 3459 Fifth Avenue, Pittsburgh, PA 15213.
661
662
CASE REPORT
Fig. 1. Chest radiograph of Patient 1 showing diffuse lung infiltrates.
roentgenogram cleared gradually in about 12days, at which time she was successfully extubated. The steroids were tapered, and she was started on cyclophosphamide I mg/kg daily on November 12, 1989. At no time during her course did she exhibit renal or neurologic dysfunction or skin lesions. She did exhibit transient hepatic dysfunction, but hepatitis core antigen and antibody were negative. A pleural effusion was noted on the left side on the seventh day, which was shown to have the characteristics of a transudate. She was discharged on the twenty-fifth hospital day and has done well since. A pulmonary function test obtained on November 21, 1989revealed borderline restrictive disease with a hemoglobin-corrected diffusing capacity of 37010 of predicted. Repeat studies performed 7 months later revealed that diffusing capacity had improved to 74010 of predicted.
Histology
Fig. 2. Chest radiograph of Patient 2 showing diffuse lung infiltrates.
tion. Worsening of these symptoms led to her admission on October 31, 1989.At that time her vital signs were normal except for a temperature of 38° C. The chest was clear, and cardiac examination was normal. There wereno skin lesions. A chest radiograph revealed diffuse bilateral infiltrates (figure 2). An arterial blood gas analysis obtained while breathing room air revealed a pH of 7.51, a Po, of 37 mm Hg, and a Pco, of 28 mm Hg. The white blood cell count was 20.2 thousand with 91% neutrophils, 2% bands, 4010 lymphocytes, 2010 monocytes, and 1010 eosinophils. Urine analysis was normal except for a trace of protein. The Wintrobe sedimentation rate was 28 mrn/h; RA factor, ANA, and cryoglobulins were negative. Her past history was negative except for surgery for a herniated lumbar disk 6 months previously. She had smoked a pack of cigarettes a day for 20 yr. She denied aller-
gies. Medications included diclofenac, misoprostol, orphenadrine citrate, arnitryptiline hydrochloride, and L-tryptophan. A ventilation-perfusion scan was performed, which was normal. Her respiratory condition rapidly deteriorated, and she was promptly intubated and placed on mechanical ventilation with a positive end-expiratory pressure of 15 cm H,O and a fraction of inspired oxygen of 90010. The Po, on these settings was 97 mm Hg. A Swan-Ganz catheter was inserted; cardiac index was 3.411/min/m', pulmonary artery pressure was 40/23 mm Hg, and the pulmonary capillary wedge pressure was 15 mm Hg. An echocardiogram revealed good left ventricular function and no valvular disease. An open lung biopsy was performed that re~ vealed a small vesselvasculitis(seebelow). All previous medications were stopped, and she was started on methylprednisolone 100mg every 8 h. The chest
The lung biopsies from each patient were obtained from the right lung. The first was a portion oflung tissue measuring 4.0 x 2.0 x 0.5 ern, and on gross examination appeared congested. On cutting the specimen, edema fluid was observed on the surface of the cut edge of the lung tissue. The specimen from the second patient measured 4.0 x 1.5 x 1.0 ern, and, similarly, appeared congested. Cut section showed no significant abnormality. Histologic examination of both biopsies showed similar features (figure 3). The pleural surfaces were unremarkable. The general architecture of the lung tissue and arrangement of the bronchial triads were normal. The bronchial triads appeared prominent and showed under low power microscopy an increase in inflammatory cells. The pulmonary septa appeared edematous. The bronchioles were normal. The respiratory ducts, terminal respiratory pathways, alveolar sacs, and alveoli showed minor abnormalities with occasional, small focal areas of hemorrhage and, especially in the second case, focal desquamation of type 2 pneumocytes. The abnormalities in the vascular system were striking. The large arteries, a few of which were included in both biopsies, showed occasional organizing thrombi associated with focal areas of intimal thickening by infiltrates of cells including lymphocytes, polymorphonuclear leukocytes, and occasional eosinophils. A similar mixed inflammatory infiltrate involved the small arterioles and the periarteriolar connective tissue. Electromicroscopic examination of the second patient confirmed the presence of a mixed inflammatory infiltrate in the endothelium of the large arteries and in the entire wall of the arterioles. There were no extraneous electron-dense deposits. Cultures of both biopsies were negative for bacteria, fungi, mycobacteria, and viruses. Direct immunofluorescence for Legionella species was negative.
Discussion
The two patients described were seen within 1 month of one another and each suffered a nearly identical illness. Both developed rapidly progressive respiratory failure of unknown etiology, both required assisted ventilation, and both appeared to respond to corticosteroids. The past history was also similar' in the two patients. Both of them suffered from chronic anxiety and depression, had abused tranquilizers and antidepressants, and had been treated with t-tryptophan. Our patients presented with a clinical picture consistent with the adult respiratory dis-
CASE REPORT
663
Fig. 3. Photomicrographs of lung biopsies from Patient 1 (A) and Patient 2 (6) . Both biopsies revealed similar abnormalities. PUlmonary arteriolar walls are thickened by edema and a mixed inflammatory infiltrate including eosinophils (Giemsa stain, oil immers ion; x 160).
tress syndrome, i.e., diffuse pulmonary infiltrates, severe and progressive respiratory failure, and normal capillary wedge pressure (2). However, the histologic findings were distinct from those associated with this disorder. There was no evidence of alveolitis. The sole abnormality was a vasculitis involving the arterioles and small arteries. Vasculitis involving the lung has been classified in a useful fash ion by Saldana (3). He groups the lesions into three categories. One group consists of necrotizing, granulomatous lesions and includes Wegener's granuloma-
tosis, Churg-Strauss disease, and necrotizing sarcoid. The second group contains the angiocentric lymphoproliferative disorders, including benign lymphocytic angiitis, lymphomatoid granulomatosis, and angiocentric large cell lymphoma. Finally, in the third group of vasculitides, he includes polyarteritis nodosa, hypersensitivity vasculitis, and other miscellaneous causes of vasculitis. The two cases reported here represent an entity not readily recognized as falIing into any of these subclassifications. There was no evidence of necrosis, granuloma, or atypical lym-
phocytic exudate in either of the two patients. The large arteries did not show a panarteritis as is seen in classic pol yarteritis nod osa. The hallmark of hypersensitivity angiitis is skin involvement , which was not evident in our patients. A small-ve ssel vasculitis may also be a feature o f collagen vascular disease (4) but neither of our patients had clinical or serologic evidence of any of these disorders. One of our patients did exhibit evidence of a large vessel occlusion (Patient I), which is seen in Takayasu's arteritis. Howe ver, this disorder is confined mo stly to younger women and involves the larger vessels. When the lung is affected, the lesions tend to be confined to the large elastic arteries, and the histologic findings are characterized by mononuclear cell infiltrates, often with giant cells. Symptomatic pulmonary disease is rare and is due to pulmonary hypertension consequent to narrowing and occlusions of the large pulmonary arteries (l). The histologic results described in our patients most closely resemble those of hypersensitivity ang iitis. Nevertheless, there were certain distinct differences. The lesions in our patients were characterized by lymphocytic infiltration in addition to neutrophils and eosinophils; there was no necrosis, and the proximal larger arteries, which were affected by a similar inflammatory exudate, contained mural thrombi. There is, to our knowledge, no similar lesion of this type. We do not know the etiology of this disorder, but suspect it may have been con sequent to ingestion of t-tryptophan. In on e patient, there was a close temporal relationship between the onset of her illness and beginning t-tryptophan treatment. The other patient became iII 3 months after stopping the agent and developed her pulmonary disease 4 months later. There have been recent reports of t-tryptophan causing a systemic illness that can involve the lungs. The illness ha s been termed the eosinophilia-myalgia syndrome (5), and it is probably caused by a chemical contaminant of an L-tryptophan product produced by a single company (6). The full spectrum of this disease is unknown. It has been defined for epidemiologic purposes as a disorder having a subacute course, characterized by myalgias, fatigue, and eosinophilia after ingestion of't-tryptophan (7). The disease may occur concurrently with ingestion of t-tryptophan or it may have its onset weeks or months after discontinuation of the agent (7). A variety of organ systems may be involved, and respiratory complaints are common. Frank vasculitis has been noted, and there has been one report of a patient suffering hypersens itivity pneumonitis with vasculit is (8). Tazelaar and coworkers (9) reported a group of five patients who presented with pulmonary symptoms cau sed by pulmonary vasculitis and interstitial pneumonitis after ingesting L-tryptophan. As far as we know, there have been no reports of severe respiratory failure associated solely with pulmonary vasculitis caused by this agent. One of our patients had many of the manifestations of the
664
eosinophilia-myalgia syndrome. She experienced a subacute course with severe fatigue, marked peripheral eosinophilia, hepatic dysfunction, and symptoms and signs suggestive of systemic embolization. The other patient did not appear to have the eosinophiliamyalgia syndrome, but the temporal relationship between starting treatment with L-tryptop han and the occurrence of her respiratory disease was striking. Both of our patients had used a variety of medications, but none of them has been reported to cause pulmonary vasculitis. Of interest, the patients described by Tazelaar and coworkers (9) also failed to exhibit the typical eosinophilia-myalgia syndrome. Only one of the five experienced myalgias, and one did not have peripheral eosinophilia. It would thus seem likely that L-tryptophan toxicity may present with pulmonary disease unassociated with the other manifestations of the eosinophilia-myalgia syndrome. Thus, severe respiratory disease may occur concurrent with, or many months after,
CASE REPORT
L-tryptophan ingestion; furthermore, the respiratory disorder may occur without the other manifestations of the eosinophilia-myalgia syndrome. A history of t-tryptophan ingestion should be sought in those patients who present with severe respiratory failure of unknown etiology, and lung biopsy should be considered. Most importantly, the disease appears to respond to corticosteroids. The therapeutic role of cyclophosphamide is uncertain. The fact that diffusing capacity returned to a nearly normal value after 6 months of treatment in one patient suggests that the vascular disorder may be fully reversible.
References 1. Leavitt RY,Fauci AS. Pulmonary vasculitis. Am Rev Respir Dis 1986; 134:149-66. 2. Hansen-Flaschen 1, Fishman AP. Adult respiratory distress syndrome: clinical features and pathogenesis. In: Fishman AP, ed. Pulmonary diseases and disorders. Vol 3. New York: McGrawHill, 1988; 2201-13. 3. Saldana Ml. Vasculitides and angiocentric Iyrn-
phoproliferative processes. In: Dail DH, Hammer SP, eds. Pulmonary pathology. New York: SpringerVerlag, 1988; 447-60. 4. Hunninghake GW, Fauci AS. Pulmonary involvement in the collagen vascular diseases. Am Rev Respir Dis 1979; 119:471-503. 5. Eosinophilia-myalgia syndrome and L-tryptophan-containing products: New Mexico, Minnesota, Oregon, and New York, 1989.MMWR 1989; 38:785-8. 6. Belongia EA, Hedberg CW, Gleich Gl, et al. An investigation of the cause of the eosinophiliamyalgia syndrome associated with tryptophan use. N Engl 1 Med 1990; 323:357-65. 7. Kilbourne EM, Swygert LA, Philen RM, et al. Interim guidance on the eosinophilia-myalgia syndrome. Ann Intern Med 1990; 112:85-6. 8. Travis WD, Kalafer ME, Robin HS, Luibel Fl. Hypersensitivity pneumonitis and pulmonary vasculitis with eosinophilia in a patient taking an L-tryptophan preparation. Ann Intern Med 1990; 112:301-3. 9. Tazelaar HD, Myers Jl., Drage CW, et al. Pulmonary disease associated with L-tryptophaninduced eosinophilia myalgia syndrome. Clinical and pathologic features. Chest 1990; 97:1032-6.
