American Journal of Therapeutics 23, e311–e314 (2016)
Phenytoin-Associated Granulomatous Pulmonary Vasculitis Fayez Kheir, MD,1* Philip Daroca, MD,2 and Joseph Lasky, MD, FCCP1
Phenytoin was introduced in 1938 for the control of seizure disorders and remains widely used today. Since that time, many cases of phenytoin-induced allergic reactions and clinical pulmonary disease have been reported. However, pulmonary vascular pathology from phenytoin use has been only very rarely described. We report a case of phenytoin-associated vasculitis in a 39-year-old African American man presenting with progressive dyspnea and abnormal chest imaging. The importance of reviewing the medication history along with familiarity with the array of drug-associated lung diseases is crucial to recognize and treat pneumotoxicity. Keywords: pulmonary vasculitis, drug-associated lung disease, phenytoin
INTRODUCTION Phenytoin is a widely used anticonvulsant. Many adverse reactions have been attributed to phenytoin since its introduction in 1938, with an incidence that ranges from 1:1000 to 1:10,000.1 Common side effects include fever, cutaneous reaction, gingival hyperplasia, lymphadenopathy, hepatitis, splenomegaly, and granulocytopenia. However, only occasional reports of vasculitis were reported. We present a case of pulmonary vasculitis associated with the use of phenytoin.
CASE REPORT A 39-year-old African American man was referred for evaluation of dyspnea. He had no medical complaints until 6 years earlier, when he was diagnosed with a seizure disorder and was placed on phenytoin (400 mg/d). He noted progressive shortness of breath for several
1
Department of Pulmonary Diseases, Critical Care, and Environmental Medicine, School of Medicine, Tulane University Health Sciences Center New Orleans, LA; and 2Department of Pathology, Tulane University Health Sciences Center, New Orleans, LA. The authors have no conflicts of interest to declare. *Address for correspondence: Department Pulmonary Diseases, Critical Care, and Environmental Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, SL-9, New Orleans, LA 70112. E-mail: [email protected]
months preceding our evaluation, but denied cough, fever, chills, hemoptysis, leg swelling, palpitations, syncope, and chest pain. He had never smoked. He denied taking any other medication, herbal remedies, or illicit drugs. His medical history, social history, and review of systems were not otherwise remarkable and more specifically did not reveal other known causes of pulmonary hypertension (PH). On examination, there was jugular vein distention, but no edema or skin lesions. Lungs demonstrated vesicular breath sounds without wheeze or crackles, and there was no dullness to percussion. Cardiac examination was remarkable for a loud pulmonary component of the second sound. The remainder of his physical examination was normal. The patient’s chest computed tomography (CT) images (axial view) revealed mosaic attenuation involving both lungs (Figure 1). There was no evidence of pulmonary embolism on the chest CT. Pulmonary function testing (PFT) showed moderate restriction, with TLC (total lung capacity) 5 3.78 L (67% predicted), FEV1 (forced expiratory volume in one second)/FVC (forced vital capacity) ratio 5 0.78, FVC 5 2.64 L (74% predicted), and a mildly reduced DLCO (diffusion capacity for carbon monoxide) (66% predicted). Echocardiography revealed moderate to severe PH with an estimated pulmonary artery systolic pressure of 65 mm Hg, moderately enlarged right ventricle with tricuspid annular plane systolic excursion estimated as 1.4 cm (normal .1.6 cm), and preserved left ventricular systolic function. His blood work revealed mildly
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Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e312
Kheir et al
FIGURE 1. CT scan of the chest (lung window) showing mosaic attenuation involving both lungs.
elevated brain natriuretic peptide, 230 pg/mL (normal, ,100 pg/mL) and a negative autoimmune profile, including antinuclear antibody, antineutrophilic cytoplasmic antibody, and rheumatoid factor. Other laboratory works including serum creatinine, complete blood count, and urine sediment were unremarkable. Video-assisted thoracoscopic lung biopsies were obtained from the right upper, middle, and lower lobes. These showed (Figure 2) granulomatous vasculitis of muscular pulmonary arteries with focal obliteration of the lumen and focal lymphohistiocytic vasculitis. Muscular pulmonary arteries also showed concentric and eccentric myointimal hyperplasia, attenuated media, and obliteration of lumen with recanalization (Figure 3). No changes were seen in the pulmonary arterioles, capillaries, veins, or lymphatics. Additionally, patchy nonspecific interstitial chronic inflammation, focal subpleural interstitial fibrosis, and 2 small interstitial microgranulomas were seen. GMS and acid fast stains for microorganisms were negative.
The diagnosis is consistent with changes reported in phenytoin-associated vasculitis. His 6-minute walk test (6MWT) showed a desaturation to 88% while walking 1000 ft. Phenytoin was switched to zonisamide, and he was started on prednisone 40 mg orally daily, which was reduced to 20 mg daily after 4 weeks. After 2 months of phenytoin avoidance and steroid treatment, he reported less shortness of breath on exertion, and his lowest oxygen saturation on the 6MWT was 95%, while the distance walked improved to 1100 ft.
DISCUSSION An article published shortly after the introduction of phenytoin suggested that chest radiographic abnormalities occur in 87% of patients receiving phenytoin for at least 2 years.2 Moreover, abnormal PFT was found in 45% of patients receiving the drug for 2 or more years and
FIGURE 2. Video-assisted thoracic surgery (VATS) biopsy of lung showing (left, hematoxylin and eosin, 203) granulomatous vasculitis of muscular pulmonary artery with focal obliteration of the lumen. Slightly higher magnification (middle, hematoxylin and eosin, 1003) shows arteritis with mononuclear infiltrate and focal fibrinoid change. Higher magnification of another vessel (right, hematoxylin and eosin, 2003) showing smooth muscle arterial wall with adjacent infiltrate composed of lymphocytes and collections epithelioid histiocytes. American Journal of Therapeutics (2016) 23(1)
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Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Phenytoin-Associated Vasculitis
e313
FIGURE 3. Video-assisted thoracic surgery (VATS) biopsy of lung (left, hematoxylin and eosin, 403) muscular pulmonary artery with cellular myointimal hyperplasia and (right, hematoxylin and eosin, 1003) pulmonary artery with attenuated media obliteration with recanalization.
frequently in the absence of any symptoms or chest roentgenographic abnormalities.3 In contrast, another study of patients receiving phenytoin for at least 2 years found no abnormality in pulmonary functions among 43 patients and minimal radiological changes in two patients.4 Acute pulmonary disease caused by phenytoin has also been described,5 the patients presenting with fever, cough, dyspnea, hypoxemia, and bilateral radiographic infiltrates. Disease was reversible with cessation of the drug and treatment with corticosteroids. Phenytoin-induced lymphocytic interstitial pneumonitis, antineutrophilic cytoplasmic antibody-associated vasculitis, eosinophilic pneumonia, organizing pneumonia, and cavitary lung nodules have all been described in the literature.6–10 The mechanism of drug injury may involve drug-specific T cells,11 anticytochrome P450 antibodies,12 an inherited epoxide hydrolase deficiency,13 or polyclonal antibodies to phenytoin.14 Mosaic perfusion pattern may be seen when regions of higher attenuation are seen adjacent to regions of lower or normal attenuation of the lung. Such a pattern can be seen in parenchymal lung disease, airway abnormalities, and pulmonary vascular disease. In this case, the CT scan revealed mosaic perfusion pattern consistent with vascular abnormality. The lymphocyte transformation test (LTT) measures the proliferation of T cells to a drug in vitro and may be used to confirm a previous in vivo reaction because of sensitization. Phenytoin drug hypersensitivity can induce a positive LTT with a sensitivity of 60%–70% and specificity of 85%. However, vasculitis, caused by any drug exposure or toxicity, has only rarely (,10%) been found to be positive using the LTT.15 Although phenytoin might lead to a positive LTT with acceptable sensitivity www.americantherapeutics.com
and specificity, the test was not ordered for our patient since the yield is very low in the presence of vasculitis. Phenytoin-associated vasculitis is very rare and was reviewed in 2 case series published over 20 years ago. Gaffey et al16 reviewed 11 cases, of which 3 had disease limited only to the skin that was treated successfully with steroids. These 3 patients presented with a rash and systemic symptoms and skin biopsy showed vasculitis. All remaining 8 patients died, with postmortem studies showing severe diffuse granulomatous vasculitis in most organs. In addition, Yermakov et al17 reported 2 fatal cases of phenytoinassociated vasculitis with histology revealing necrotizing vasculitis in most organs. Our patient had evidence of granulomatous vasculitis that obliterated arterial lumina. Other muscular pulmonary arteries showed lymphohistiocytic vasculitis and focal fibrinoid change and myointimal hyperplasia. Some muscular pulmonary arteries showed recanalized lumens consistent with thromboembolic changes. In addition, our case differs from those reported in the literature where patients usually present with blood and tissue eosinophilia. Drugs associated with the development of small-vessel lung vasculitis and PH are shown in Table 1. Drugs that may cause pulmonary vasculitis. Antibacterials (sulfonamides, penicillin) Anticonvulsant (phenytoin) Cardiovascular agents (quinidine, hydralazine) Chemotherapeutic agents (all-trans-retinoic acid, busulfan, mitomycin) Thyroid blockers (thiouracil, propylthiouracil) Tranquilizers (phenothiazines) American Journal of Therapeutics (2016) 23(1)
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e314 Table 2. Drugs that may cause PH. Appetite suppressants (fenfluramine, dexfenfluramine) Illicit drugs (cocaine, heroin) Opiates (methadone) Interferon alpha Chemotherapeutic agents (busulfan, dasatinib, nitrosoureas) Psychostimulants (amphetamine, methylphenidate) Oral contraceptives
Tables 1 and 2, respectively.18,19 Diagnosis of drugassociated pulmonary vasculitis usually requires evidence of vasculitis on lung biopsy and a history of appropriate drug exposure. In our case, the pathology demonstrated granulomatous vasculitis with regional fibrinoid change without tissue eosinophilia, most probably related to drug ingestion. Ideally, follow-up echocardiography would be needed to confirm the improvement or nondeterioration of PH because of uncertain outcome even after withdrawal from phenytoin. Although the patient reported symptomatic improvement, he was unfortunately not able to afford any further testing including an echocardiography, PFT, or further imaging because of financial costs. Our patient reported an improvement of about 100 ft or 30.5 m. Mathai et al20 reported that the improvement in 6MWT of approximately 33 m is associated with improvement in quality-of-life measures and is a clinically meaningful measurement. The study subjects were retrospectively analyzed from the 16-week trial of PH response to Tadalafil trial. Although our patient had less than minimal important difference, he had a 6MWT at 2-month follow-up only. Unfortunately, we were unable to provide him any further testing because of his financial constraints. This case illustrates that drug reactions can mimic other pulmonary syndromes or diseases. Careful review of the patient’s medication history and up-todate knowledge about medication side effects were important in narrowing the differential diagnosis, planning subsequent investigations, establishing the diagnosis, and making important changes in the patient’s medication regimen. Treatment of druginduced pulmonary toxicity will require withdrawal of the offending agent and appropriate therapy.
REFERENCES 1. Vittorio CC, Muglia JJ. Anticonvulsant hypersensitivity syndrome. Arch Intern Med. 1995;155:2285–2290.
American Journal of Therapeutics (2016) 23(1)
Kheir et al 2. Moore MT. Pulmonary changes in hydantoin therapy. J Am Med Assoc. 1959;171:1328–1333. 3. Hazlett DR, Ward GW, Madison DS. Pulmonary function loss in diphenylhydantoin therapy. Chest. 1974;66: 660–664. 4. Livingston S, Whitehouse D, Pauli L. Study of the effects of diphenyl-hydantoin sodium on the lungs. N Engl J Med. 1961;264:648–651. 5. Michael JR, Rudin ML. Acute pulmonary disease caused by phenytoin. Ann Intern Med. 1981;95:452–454. 6. Chamberlain DW, Hyland RH, Ross DJ. Diphenylhydantoin induced lymphocytic interstitial pneumonia. Chest. 1986;90:458–460. 7. Mahatma M, Haponik EF, Nelson S, et al. Phenytoininduced acute respiratory failure with pulmonary eosinophilia. Am J Med. 1989;87:93–94. 8. Angle P, Thomas P, Chiu B, et al. Bronchiolitis obliterans with organizing pneumonia and cold agglutinin disease associated with phenytoin hypersensitivity syndrome. Chest. 1997;112:1697–1699. 9. Muren C, Strandberg O. Cavitary pulmonary nodules in atypical collagen disease and lupoid drug reaction. Report of two cases. Acta Radiol. 1989;30:281–284. 10. Merkel PA. Drug-induced vasculitis. Rheum Dis Clin North Am. 2001;27:849–862. 11. Mauri-Hellweg D, Bettens F, Mauri D, et al. Activation of drug-specific CD4+ and CD8+ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine. J Immunol. 1995;155:462–472. 12. Leeder JS, Riley RJ, Cook VA, et al. Human anti-cytochrome P450 antibodies in aromatic anticonvulsant-induced hypersensitivity reactions. J Pharmacol Exp Ther. 1992; 263:360–367. 13. Gennis MA, Vemuri R, Burns EA, et al. Familial occurrence of hypersensitivity to phenytoin. Am J Med. 1991; 91:631–634. 14. Kleckner HB, Yakulis V, Heller P. Severe hypersensitivity to diphenylhydantoin with circulating antibodies to the drug. Ann Intern Med. 1975;83:522–523. 15. Pichler WJ, Tilch J. The lymphocyte transformation test in the diagnosis of drug hypersensitivity. Allergy. 2004; 59:809–820. 16. Gaffey CM, Chun B, Harvey JC, Manz HJ. Phenytoin induced systemic granulomatous vasculitis. Arch Pathol Lab Med. 1986;110:131–135. 17. Yermakov VM, Hitti IF, Sutton AL. Necrotising vasculitis associated with diphenylhydantoin: two fatal cases. Hum Pathol. 1983;14:182–184. 18. Ozkan M, Dweik RA, Ahmad M. Drug-induced lung disease. Cleve Clin J Med. 2001;68:782–785, 789-95. 19. Schwarz MI, Fontenot AP. Drug-induced diffuse alveolar hemorrhage syndromes and vasculitis. Clin Chest Med. 2004;25:133–140. 20. Mathai SC, Puhan MA, Lam D, et al. The minimal important difference in the 6-minute walk test for patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:428–433.
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Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Phenytoin-Associated Granulomatous Pulmonary Vasculitis Fayez Kheir, MD,1* Philip Daroca, MD,2 and Joseph Lasky, MD, FCCP1
Phenytoin was introduced in 1938 for the control of seizure disorders and remains widely used today. Since that time, many cases of phenytoin-induced allergic reactions and clinical pulmonary disease have been reported. However, pulmonary vascular pathology from phenytoin use has been only very rarely described. We report a case of phenytoin-associated vasculitis in a 39-year-old African American man presenting with progressive dyspnea and abnormal chest imaging. The importance of reviewing the medication history along with familiarity with the array of drug-associated lung diseases is crucial to recognize and treat pneumotoxicity. Keywords: pulmonary vasculitis, drug-associated lung disease, phenytoin
INTRODUCTION Phenytoin is a widely used anticonvulsant. Many adverse reactions have been attributed to phenytoin since its introduction in 1938, with an incidence that ranges from 1:1000 to 1:10,000.1 Common side effects include fever, cutaneous reaction, gingival hyperplasia, lymphadenopathy, hepatitis, splenomegaly, and granulocytopenia. However, only occasional reports of vasculitis were reported. We present a case of pulmonary vasculitis associated with the use of phenytoin.
CASE REPORT A 39-year-old African American man was referred for evaluation of dyspnea. He had no medical complaints until 6 years earlier, when he was diagnosed with a seizure disorder and was placed on phenytoin (400 mg/d). He noted progressive shortness of breath for several
1
Department of Pulmonary Diseases, Critical Care, and Environmental Medicine, School of Medicine, Tulane University Health Sciences Center New Orleans, LA; and 2Department of Pathology, Tulane University Health Sciences Center, New Orleans, LA. The authors have no conflicts of interest to declare. *Address for correspondence: Department Pulmonary Diseases, Critical Care, and Environmental Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, SL-9, New Orleans, LA 70112. E-mail: [email protected]
months preceding our evaluation, but denied cough, fever, chills, hemoptysis, leg swelling, palpitations, syncope, and chest pain. He had never smoked. He denied taking any other medication, herbal remedies, or illicit drugs. His medical history, social history, and review of systems were not otherwise remarkable and more specifically did not reveal other known causes of pulmonary hypertension (PH). On examination, there was jugular vein distention, but no edema or skin lesions. Lungs demonstrated vesicular breath sounds without wheeze or crackles, and there was no dullness to percussion. Cardiac examination was remarkable for a loud pulmonary component of the second sound. The remainder of his physical examination was normal. The patient’s chest computed tomography (CT) images (axial view) revealed mosaic attenuation involving both lungs (Figure 1). There was no evidence of pulmonary embolism on the chest CT. Pulmonary function testing (PFT) showed moderate restriction, with TLC (total lung capacity) 5 3.78 L (67% predicted), FEV1 (forced expiratory volume in one second)/FVC (forced vital capacity) ratio 5 0.78, FVC 5 2.64 L (74% predicted), and a mildly reduced DLCO (diffusion capacity for carbon monoxide) (66% predicted). Echocardiography revealed moderate to severe PH with an estimated pulmonary artery systolic pressure of 65 mm Hg, moderately enlarged right ventricle with tricuspid annular plane systolic excursion estimated as 1.4 cm (normal .1.6 cm), and preserved left ventricular systolic function. His blood work revealed mildly
1075–2765 Copyright © 2013 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e312
Kheir et al
FIGURE 1. CT scan of the chest (lung window) showing mosaic attenuation involving both lungs.
elevated brain natriuretic peptide, 230 pg/mL (normal, ,100 pg/mL) and a negative autoimmune profile, including antinuclear antibody, antineutrophilic cytoplasmic antibody, and rheumatoid factor. Other laboratory works including serum creatinine, complete blood count, and urine sediment were unremarkable. Video-assisted thoracoscopic lung biopsies were obtained from the right upper, middle, and lower lobes. These showed (Figure 2) granulomatous vasculitis of muscular pulmonary arteries with focal obliteration of the lumen and focal lymphohistiocytic vasculitis. Muscular pulmonary arteries also showed concentric and eccentric myointimal hyperplasia, attenuated media, and obliteration of lumen with recanalization (Figure 3). No changes were seen in the pulmonary arterioles, capillaries, veins, or lymphatics. Additionally, patchy nonspecific interstitial chronic inflammation, focal subpleural interstitial fibrosis, and 2 small interstitial microgranulomas were seen. GMS and acid fast stains for microorganisms were negative.
The diagnosis is consistent with changes reported in phenytoin-associated vasculitis. His 6-minute walk test (6MWT) showed a desaturation to 88% while walking 1000 ft. Phenytoin was switched to zonisamide, and he was started on prednisone 40 mg orally daily, which was reduced to 20 mg daily after 4 weeks. After 2 months of phenytoin avoidance and steroid treatment, he reported less shortness of breath on exertion, and his lowest oxygen saturation on the 6MWT was 95%, while the distance walked improved to 1100 ft.
DISCUSSION An article published shortly after the introduction of phenytoin suggested that chest radiographic abnormalities occur in 87% of patients receiving phenytoin for at least 2 years.2 Moreover, abnormal PFT was found in 45% of patients receiving the drug for 2 or more years and
FIGURE 2. Video-assisted thoracic surgery (VATS) biopsy of lung showing (left, hematoxylin and eosin, 203) granulomatous vasculitis of muscular pulmonary artery with focal obliteration of the lumen. Slightly higher magnification (middle, hematoxylin and eosin, 1003) shows arteritis with mononuclear infiltrate and focal fibrinoid change. Higher magnification of another vessel (right, hematoxylin and eosin, 2003) showing smooth muscle arterial wall with adjacent infiltrate composed of lymphocytes and collections epithelioid histiocytes. American Journal of Therapeutics (2016) 23(1)
www.americantherapeutics.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Phenytoin-Associated Vasculitis
e313
FIGURE 3. Video-assisted thoracic surgery (VATS) biopsy of lung (left, hematoxylin and eosin, 403) muscular pulmonary artery with cellular myointimal hyperplasia and (right, hematoxylin and eosin, 1003) pulmonary artery with attenuated media obliteration with recanalization.
frequently in the absence of any symptoms or chest roentgenographic abnormalities.3 In contrast, another study of patients receiving phenytoin for at least 2 years found no abnormality in pulmonary functions among 43 patients and minimal radiological changes in two patients.4 Acute pulmonary disease caused by phenytoin has also been described,5 the patients presenting with fever, cough, dyspnea, hypoxemia, and bilateral radiographic infiltrates. Disease was reversible with cessation of the drug and treatment with corticosteroids. Phenytoin-induced lymphocytic interstitial pneumonitis, antineutrophilic cytoplasmic antibody-associated vasculitis, eosinophilic pneumonia, organizing pneumonia, and cavitary lung nodules have all been described in the literature.6–10 The mechanism of drug injury may involve drug-specific T cells,11 anticytochrome P450 antibodies,12 an inherited epoxide hydrolase deficiency,13 or polyclonal antibodies to phenytoin.14 Mosaic perfusion pattern may be seen when regions of higher attenuation are seen adjacent to regions of lower or normal attenuation of the lung. Such a pattern can be seen in parenchymal lung disease, airway abnormalities, and pulmonary vascular disease. In this case, the CT scan revealed mosaic perfusion pattern consistent with vascular abnormality. The lymphocyte transformation test (LTT) measures the proliferation of T cells to a drug in vitro and may be used to confirm a previous in vivo reaction because of sensitization. Phenytoin drug hypersensitivity can induce a positive LTT with a sensitivity of 60%–70% and specificity of 85%. However, vasculitis, caused by any drug exposure or toxicity, has only rarely (,10%) been found to be positive using the LTT.15 Although phenytoin might lead to a positive LTT with acceptable sensitivity www.americantherapeutics.com
and specificity, the test was not ordered for our patient since the yield is very low in the presence of vasculitis. Phenytoin-associated vasculitis is very rare and was reviewed in 2 case series published over 20 years ago. Gaffey et al16 reviewed 11 cases, of which 3 had disease limited only to the skin that was treated successfully with steroids. These 3 patients presented with a rash and systemic symptoms and skin biopsy showed vasculitis. All remaining 8 patients died, with postmortem studies showing severe diffuse granulomatous vasculitis in most organs. In addition, Yermakov et al17 reported 2 fatal cases of phenytoinassociated vasculitis with histology revealing necrotizing vasculitis in most organs. Our patient had evidence of granulomatous vasculitis that obliterated arterial lumina. Other muscular pulmonary arteries showed lymphohistiocytic vasculitis and focal fibrinoid change and myointimal hyperplasia. Some muscular pulmonary arteries showed recanalized lumens consistent with thromboembolic changes. In addition, our case differs from those reported in the literature where patients usually present with blood and tissue eosinophilia. Drugs associated with the development of small-vessel lung vasculitis and PH are shown in Table 1. Drugs that may cause pulmonary vasculitis. Antibacterials (sulfonamides, penicillin) Anticonvulsant (phenytoin) Cardiovascular agents (quinidine, hydralazine) Chemotherapeutic agents (all-trans-retinoic acid, busulfan, mitomycin) Thyroid blockers (thiouracil, propylthiouracil) Tranquilizers (phenothiazines) American Journal of Therapeutics (2016) 23(1)
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e314 Table 2. Drugs that may cause PH. Appetite suppressants (fenfluramine, dexfenfluramine) Illicit drugs (cocaine, heroin) Opiates (methadone) Interferon alpha Chemotherapeutic agents (busulfan, dasatinib, nitrosoureas) Psychostimulants (amphetamine, methylphenidate) Oral contraceptives
Tables 1 and 2, respectively.18,19 Diagnosis of drugassociated pulmonary vasculitis usually requires evidence of vasculitis on lung biopsy and a history of appropriate drug exposure. In our case, the pathology demonstrated granulomatous vasculitis with regional fibrinoid change without tissue eosinophilia, most probably related to drug ingestion. Ideally, follow-up echocardiography would be needed to confirm the improvement or nondeterioration of PH because of uncertain outcome even after withdrawal from phenytoin. Although the patient reported symptomatic improvement, he was unfortunately not able to afford any further testing including an echocardiography, PFT, or further imaging because of financial costs. Our patient reported an improvement of about 100 ft or 30.5 m. Mathai et al20 reported that the improvement in 6MWT of approximately 33 m is associated with improvement in quality-of-life measures and is a clinically meaningful measurement. The study subjects were retrospectively analyzed from the 16-week trial of PH response to Tadalafil trial. Although our patient had less than minimal important difference, he had a 6MWT at 2-month follow-up only. Unfortunately, we were unable to provide him any further testing because of his financial constraints. This case illustrates that drug reactions can mimic other pulmonary syndromes or diseases. Careful review of the patient’s medication history and up-todate knowledge about medication side effects were important in narrowing the differential diagnosis, planning subsequent investigations, establishing the diagnosis, and making important changes in the patient’s medication regimen. Treatment of druginduced pulmonary toxicity will require withdrawal of the offending agent and appropriate therapy.
REFERENCES 1. Vittorio CC, Muglia JJ. Anticonvulsant hypersensitivity syndrome. Arch Intern Med. 1995;155:2285–2290.
American Journal of Therapeutics (2016) 23(1)
Kheir et al 2. Moore MT. Pulmonary changes in hydantoin therapy. J Am Med Assoc. 1959;171:1328–1333. 3. Hazlett DR, Ward GW, Madison DS. Pulmonary function loss in diphenylhydantoin therapy. Chest. 1974;66: 660–664. 4. Livingston S, Whitehouse D, Pauli L. Study of the effects of diphenyl-hydantoin sodium on the lungs. N Engl J Med. 1961;264:648–651. 5. Michael JR, Rudin ML. Acute pulmonary disease caused by phenytoin. Ann Intern Med. 1981;95:452–454. 6. Chamberlain DW, Hyland RH, Ross DJ. Diphenylhydantoin induced lymphocytic interstitial pneumonia. Chest. 1986;90:458–460. 7. Mahatma M, Haponik EF, Nelson S, et al. Phenytoininduced acute respiratory failure with pulmonary eosinophilia. Am J Med. 1989;87:93–94. 8. Angle P, Thomas P, Chiu B, et al. Bronchiolitis obliterans with organizing pneumonia and cold agglutinin disease associated with phenytoin hypersensitivity syndrome. Chest. 1997;112:1697–1699. 9. Muren C, Strandberg O. Cavitary pulmonary nodules in atypical collagen disease and lupoid drug reaction. Report of two cases. Acta Radiol. 1989;30:281–284. 10. Merkel PA. Drug-induced vasculitis. Rheum Dis Clin North Am. 2001;27:849–862. 11. Mauri-Hellweg D, Bettens F, Mauri D, et al. Activation of drug-specific CD4+ and CD8+ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine. J Immunol. 1995;155:462–472. 12. Leeder JS, Riley RJ, Cook VA, et al. Human anti-cytochrome P450 antibodies in aromatic anticonvulsant-induced hypersensitivity reactions. J Pharmacol Exp Ther. 1992; 263:360–367. 13. Gennis MA, Vemuri R, Burns EA, et al. Familial occurrence of hypersensitivity to phenytoin. Am J Med. 1991; 91:631–634. 14. Kleckner HB, Yakulis V, Heller P. Severe hypersensitivity to diphenylhydantoin with circulating antibodies to the drug. Ann Intern Med. 1975;83:522–523. 15. Pichler WJ, Tilch J. The lymphocyte transformation test in the diagnosis of drug hypersensitivity. Allergy. 2004; 59:809–820. 16. Gaffey CM, Chun B, Harvey JC, Manz HJ. Phenytoin induced systemic granulomatous vasculitis. Arch Pathol Lab Med. 1986;110:131–135. 17. Yermakov VM, Hitti IF, Sutton AL. Necrotising vasculitis associated with diphenylhydantoin: two fatal cases. Hum Pathol. 1983;14:182–184. 18. Ozkan M, Dweik RA, Ahmad M. Drug-induced lung disease. Cleve Clin J Med. 2001;68:782–785, 789-95. 19. Schwarz MI, Fontenot AP. Drug-induced diffuse alveolar hemorrhage syndromes and vasculitis. Clin Chest Med. 2004;25:133–140. 20. Mathai SC, Puhan MA, Lam D, et al. The minimal important difference in the 6-minute walk test for patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:428–433.
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Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
