Bayford D. An account of a singular case of obstructed deglutition. Memoirs Med Soc London 1794; 275-86 5 Austin EH, Wolfe WG. Aneurysm of aberrant subclavian artery with a review of the literature. J Vase Surg 1985; 2:571-77 6 Kommerell B. Verlagerung des osophagus durch eine abnorm 4 Key words: anemia; bronchiolitis obliterans organizing pneumo¬ nia; hemolysis; hypersensitivity; phenytoin Abbreviations: BOOP=bronchiolitis obliterans organizing pneumonia; PHS=phenytoin h)persensitivity syndrome verlaufende arteria subclavia dextra (arteria lusoria). Fortschr Geb Roentgenstr Nuklearmed 1936 54:590-95 7 Felson B. Ruptured anomalous right subclavian artery: aneu¬ rysm or diverticulum? Semin Roentgenol 1989; 24:122-26 8 Roberts CS, Otherson HB, Sade RM, et al. Tracheoesophageal compression from aortic arch anomalies: analysis of 30 operatively treated children. J Pediatr Surg 1994; 29:334-37 9 Gobel JW, Pierpont ME, Moller JH, et al. Familial interrup¬ tion ofthe aortic arch. Pediatric Cardiol 1993; 14:110-15 10 Dartevelle P, Bouquet P, Planche C, et al. Aneurysme atheromateux d'ine artere sous claviere droit aberrante: a propos d'un cas revele par une dysphagie et opere chez une femme de 73 ans. Chirurgie 1978; 104:141-47 11 Kiernan P, Dearani J, Byrne W, et al. Aneurysm of an aberrant right subclavian artery: case report and review of the literature. Mayo Clinic Proc 1993; 68:468-74 12 Bower TC, Pairolero PC, Hallett JW, et al. Brachiocephalic aneurysm: the case for early recognition and repair. Ann Vase 13 Surg 1991; 5:125-32 Campbell CF. Repair of an aneurysm of an aberrant retroesophageal right subclavian artery arising from Kommerell's diverticulum. J Thorac Cardiovasc Surg 1971; 62:330-34 Bronchiolitis Obliterans With Organizing Pneumonia and Cold Agglutinin Disease Associated With Phenytoin Hypersensitivity Syndrome* Pamela Angle, MD; Peter Thomas, MD, FCCP; Chiu, MD; and John Freedman, MD Brian Phenytoin hypersensitivity syndrome (PHS) is a rare delayed hypersensitivity reaction which oc¬ curs following exposure to phenytoin sodium. Pul¬ monary involvement is uncommonly described. Herein is reported the first case of histopathologic bronchiolitis obliterans organizing pneumonia (BOOP) found on open-lung biopsy in a patient with severe PHS. New onset, clinically significant, cold agglutinin disease was also documented. He¬ modynamic parameters mimicking sepsis were present in the absence of significant clinical infec¬ tion. Rapid, dramatic improvement followed highdose steroid therapy. (CHEST 1997; 112:1697-99) Departments of Anaesthesia (Dr. Angle), Respirology (Dr. Thomas), Pathology (Dr. Chiu), and Transfusion Medicine and Blood Bank (Dr. Freedman), St. Michael's Hospital, Uni¬ versity of Toronto, Ontario, Canada. *From the Manuscript received December 10, 1996; revision accepted March 2, 1997. Reprint requests: Pamela Angle, MD, Women's College Hospital, 76 Grenville St, Toronto, Ontario, Canada M5S 1B2 "D rovided here is the first description of histopathologic bronchiolitis obliterans with organizing pneumonia (BOOP) in a patient with severe phenytoin hypersensitiv¬ ity syndrome (PHS). The presence of cold hemagglutinin disease was also documented for the first time. The patient ¦*¦ showed dramatic therapy. In September improvement with high-dose steroid Case Report 1994, a 40-year-old black man underwent craniotomy and started receiving therapy with phenytoin sodium (Dilantin; Parke-Davis; Morris Plains, NJ), 300 mg daily. A medical history revealed chronic use of tobacco, crack cocaine, and alcohol. Results of a lung examination and a chest x-ray film showed no abnormalities. Four weeks following phenytoin ther¬ apy, clear rhinorrhea, myalgia, high fever, diffusely spreading pruritic maculopapular rash, and dry cough developed. The cough became productive and was associated with dyspnea. Six weeks after phenytoin therapy was initiated, the patient was readmitted to the hospital. Vital signs were as follows: respiratory rate, 24 breaths per minute; heart rate, 112 beats per minute; BP, 100/60 mm Hg; and temperature, 38°C. Examination revealed diffuse skin exfoliation; conjunctivitis; facial edema; tender, en¬ larged lymph nodes; decreased breath sounds bilaterally with diffuse inspiratoiy crackles; mild right upper quadrant tender¬ ness; and hepatomegaly. Laboratory7 findings included a fall in hemoglobin level from 155 g/L (noted 6 weeks earlier prior to phenytoin treatment) to 133 g/L; WBC count, 29X109/L (35% eosinophils); subtherapeu- phenytoin level; mildly elevated liver function tests; while breathing room air, arterial blood gas values showed mild hypoxia; and chest radiograph, diffuse, patchy, asymmetric, reticulonodular infiltrates. Administration of broad-spectrum anti¬ biotics and prednisone, 50 mg daily, was started. Phenytoin treatment was discontinued. Tests for cold agglutinins were positive. The Mantoux test and tests for HIV, heterophile agglutination, antinuclear antibody, rheumatoid factor, Legio¬ nella, and sputum cultures for bacteria, fungi, acid-fast bacilli, and Pneumocystis carinii pneumonia were negative. A skin biopsy specimen showed a drug eruption. Serological tests for Mycoplasma, adenovirus, influenza A and B, herpes simplex, cytomegalovirus, and hepatitis A, B, and C were negative. Spiking fevers, marked eosinophilia, and deterioration of liver function tests continued (aspartate aminotransferase, 214 U/L [normal, <40 U/L]; alanine aminotransferase, 247 U/L [normal, <35 U/L]; lactate dehydrogenase, 435 U/L [normal, <260 U/L]; alkaline phosphatase, 237 U/L [normal, <35 to 125 U/L]). The admission hemoglobin level of 133 g/L dropped to 101 g/L within 48 h of hospitalization, and a mild coagulopathy developed. Respiratory7 insufficiency culminated in ICU admission and intu¬ bation. A chest x-ray film revealed asymmetric patchy infiltrates at lung bases (Fig 1). Sepsis-like hemodynamics developed with hypotension; tachycardia (heart rate, 120 to 140 beats per minute); cardiac output, 10 to 17.5 L/min; and systemic vascular resistance, 300 to 500 dyne-s*cm~5 (normal, 770 to 1,500 dyneS'cm-5) requiring inotropic and fluid support. Bronchoscopy, BAL stains, cultures, and cytologic studies were negative for organisms. Urine was treated for a Staphylococcus aureus infec¬ tion. All other cultures tic remained negative for organisms. CHEST/ 112/6 /DECEMBER, 1997 Downloaded From: http://publications.chestnet.org/ on 12/22/2014 1697 showing status after intubation in at bilateral (right greater than left) lung bases. Figure 1. Chest x-ray film ICU; of note are diffuse patchy interstitial and alveolar infiltrates hemoglobin level dropping g/L. negative prior to phenytoin treatment, were positive with anticomplement C3d and negative with anti-IgG. Saline-reactive cold agglutinins with anti-I specificity of low-titer, high thermal amplitude were The anemia continued to 70 to worsen with the Direct and indirect antiglobulin tests, present, reacting in saline with adult RBCs at a titer of 1:512 at 4°C and 1:4 at 30°C; with albumin, the titer was 1:8 at 30°C. Nucleated RBCs, occasional cell fragments and spherocytes, and 1 to 2% atypical lymphocytes were found on a smear. Transfusion of packed RBCs following crossmatch by prewarm technique failed to show the appropriate rise in hemoglobin and was followed by further transfusion. The coagulopathy worsened (prothrombin time, 20 s; partial thromboplastin time, 35 s; international normalized ratio, 3.0) and was unresponsive to vitamin K, but did improve following administration of fresh-frozen plasma. Factor analysis showed hep¬ atocellular injury. An open-lung biopsy specimen showed myxoid organizing granulation tissue present in bronchioles,inwhich was consistent with BOOP (Fig 2, top). A mild increase eosinophils within a chronic mononuclear inflammatory infiltrate was present in the alveolar exudate (Fig 2, bottom). Lung tissue was negative for acid-fast bacilli, fungi, P carinii pneumonia, vasculitis, or granu¬ lomata. Electron microscopy was negative for viral inclusions. BAL culture later grew rhinovirus. Methylprednisolone sodium succinate (Solu-Medrol), 60 mg, was administered intravenously every 6 h for 48 h and then followed by a slow intravenous taper over 1 week. This was followed by high-dose treatment with prednisone (1 mg/kg) for 3 months, followed by a very slow taper for a total steroid course of 1 year. Pulmonar)7 function tests done 10, 21, and 42 days after steroid administration showed a resolving restrictive lung defect and reduced diffusing capacity of carbon monoxide. A chest x-ray film, liver function, and all hematologic abnormalities resolved. PHS is rare Discussion with few reports describing pulmonary in¬ volvement. Fever, cough, dyspnea, hypoxemia, and bilateral infiltrates on a chest x-ray film in the setting of a more generalized hypersensitivity reaction are typical.1 Herein is the first description of BOOP in PHS. BOOP is character¬ ized by ingrowth of polypoid fibroinflammatory granulation tissue from bronchioles into adjacent alveoli where an orga¬ nizing pneumonia forms. The infiltrate is predominantly 1698 Downloaded From: http://publications.chestnet.org/ on 12/22/2014 Top: histopathologic findings of open-lung biopsy specimen showing myxoid granulation tissues in bronchioles, alveolar ducts and alveoli with confluent areas extending to consistent with BOOP. Both the pleura (p) and (arrowheads) lobular septum (s) are congested and edematous (hematoxylineosin, original X25). Bottom: higher magnification of Figure 2, top, showing chronic inflammatory cellular infiltrate with a few (arrowheads). Asterisk indicates myxoid connective eosinophils tissue background (original X250). Figure 2. mononuclear, patchy, and thought to be part of the lung's reparative process after insults, including hypersensitivity reactions. Commonly, BOOP is sensitive to steroid therapy,2 associated with a restrictive lung defect and decreased carbon monoxide diffusing capacity7. X-ray film findings vary and often show multiple, patchy interstitial-alveolar infiltrates like those described here. Use of crack cocaine, implicated in one case of BOOP,3 was not thought significant here since this patient ceased cocaine use after his first hospital discharge and clearly suffered from a generalized hypersensitivity syn¬ drome, a finding not associated with cocaine. Rhinovirus found on BAL culture was likely the result of upper airway contamination during bronchoscopy. The clear rhinorrhea at illness onset, multiple other case reports sug¬ gesting concomitant respiratory tract infections, and the reported seasonal variation of phenytoin hypersensitivity7 reactions4 suggest a role for concurrent infection in triggering or intensifying the syndrome or, conversely, infections may be the result of phenytoin's effect on immune function. Sepsis-like hemodynamics, responsive to steroids, have been described rarely in PHS.5 Coombs'-negative hemolytic anemia has been repeat¬ edly noted in PHS. Coombs'-positive hemolysis, however, was mentioned only once in the present review of the literature.6 Here is provided the first full description of acute cold hemagglutinin disease in PHS. Clear evidence of new onset cold hemagglutinins with a positive direct Selected Reports antiglobulin test for of complement only and presence IgM anti-I autoantibodies of high enough thermal ampli¬ tude and titer to produce a clinical picture consistent with both intravascular and extravascular hemolysis were found. Such low-titer, high thermal amplitude-type cold are responsive to high-dose steroids.7 Cur¬ agglutinins no consensus exists regarding the optimal dose or rently, treatment duration of corticosteroids for BOOP, nor are there guidelines for steroid use in PHS. This patient's response to intravenously administered methylpred¬ nisolone, 60 mg every 6 h for 48 h with a slow intravenous taper over a week, was followed by the regimen suggested and Colby8 for BOOP: prednisone, 1 mg/kg for 3 by Eplerwith a subsequent slow drug taper so that steroid months This proved to therapy was used for a total of 12 months. be satisfactory for the patient reported herein. ACKNOWLEDGMENT: Drs. Victor Hoffstein and Halpern assisted in the preparation of this paper. JR, Rudin ML. Acute pulmonary disease caused by phenytoin. Ann Intern Med 1981; 95:452-54 Epler GR. Bronchiolitis obliterans organizing pneumonia: defi¬ and clinical features. Chest 1992; improved, and the IgA contributed vasculitis. to both the bronchial disease and (CHEST 1997; 112:1699-1701) Keywords: arantitrypsin deficiency; antineutrophil cytoplasmic bactericidal/permeability-increasing protein; bronchi¬ antibody; ectasis a1-AT=a1-antitrypsin; ANCA=antineutrophil cytoplasmic antibody; BPI=bactericidaPpermeability-increasing protein; LPS=lipopolysaccharide; LBP=LPS binding protein Abbreviations: associated with chronic suppurative lung Vasculitis diseases, such bronchiectasis and cystic fibrosis, researchers.12 has been as 1 Michael nition chial disease and vasculitis anti-BPI titer fell after antipseudomonal treatment. This raises the possibility that anti-BPI antibodies Stephen References 2 detected, which produced granular cytoplasmic staining by indirect immunofluorescence with specifi¬ city for a newly characterized antigen: bactericidal/ permeability-increasing protein (BPI). The bron¬ 102(suppl 1):2-6S 3 Patel RC, Dutta D, Schonfeld SA. Free-base cocaine use associated with bronchiolitis obliterans organizing pneumo¬ nia. Ann Intern Med 1987; 107:186-87 4 Leppik IE, Lapora JK, Lowenson R. Seasonal incidence of phenytoin allergy unrelated to plasma levels. Arch Neurol 1985;42:120-22 DiGregorio F, Stiff M, et al. Dilantin hypersensi¬ tivity syndrome imitating staphylococcal toxic shock. Arch 5 Potter T, Dermatol 1994; 130:856-58 Spielberg SP. Anticonvulsant hypersensitivity syndrome: an in vitro assessment of risk. J Clin Invest 1988; 6 Shear NH, 82:1826-32 7 Schreiber AD, Herskovitz BS, Goldwein M. Low-titer coldof hemolysis and response to mechanism disease: agglutmin corticosteroids. N Engl J Med 1977; 296:1490-94 8 Epler GR, Colby TV. The spectrum of bronchiolitis obliterans [editorial]. Chest 1983; 83:161-62 Antineutrophil reported by marker for cytoplasmic antibody (ANCA), ahasserologic been detected in some small-vessel vasculitides, some series12 but without a defined antigen specificity or a clear relationship to disease. Bactericidal/perme¬ ability-increasing (BPI) protein is an important host defense mechanism against lipopolysaccharide (LPS). Autoantibodies directed against this protein recently have been recognized to be associated with vasculitis, cystic fibrosis, and inflammatory bowel disease.3-5 Herein is the report of a case of bronchiectasis and a]_-antitrypsin (arAT) deficiency in whom infection with Pseudomonas aeruginosa was closely related to the development of recurrent vasculitis, worsening bron¬ chial disease, and raised levels of anti-BPI antibodies. Treatment with antibiotics produced a clinical improve¬ ment and was accompanied by a fall in the level of IgA anti-BPI autoantibodies. Findings in this index patient linking infection, autoim-of provide further information and and vasculitis suggest an etiologic role munity, infection in certain vasculitides. Vasculitis and Bronchiectasis in a Patient With Antibodies to Bactericidal/PermeabilityIncreasing Protein and a!-Antitrypsin Deficiency* Ravi Mahadeva, MD; Ming Hui Zhao, MD, Susan Stewart, MD; Nathaniel Cary, MD; Christopher Flower, MD; Martin Lockwood, MD; and John Shneerson, MD A patient with a^-antitrypsin deficiency is reported herein; this subject developed aggressive bronchial disease and recurrent cutaneous vasculitis after pul¬ monary infection with Pseudomonas aeruginosa, Au¬ toantibodies to neutrophil cytoplasmic antigens were Case Report a nonsmoker, presented with a 4-month A 59-year-old man, history of daily sputum production, hemoptysis, and a 5-kg weight loss. These symptoms were unresponsive to treatment with clarithromycin and doxycycline (Vibramycin). Examination re¬ vealed widespread expiratory wheezes and coarse crackles at both bases. Spirometry showed an obstructive defect; FEVj was 1.1 L (predicted, 2.6 L) and FVC was 3.1 L (predicted, 3.3 L). Investigations revealed arAT level to be 0.3 g/L (normal range, 0.9 to 1.8 g/L); phenotype Z; cytoplasmic staining of ANCA, *From the Departments of Respiratory Medicine (Drs. Ma¬ hadeva and Shneerson), Medicine (Drs. Zhao and Lockwood), and Radiology (Dr. Flower), Addenbrooke's Hospital, and the Department of Pathology (Dr. Stewart), Papworth Hospital, Cambridge, UK. received November 13, 1996; revision accepted April Manuscript 18, 1997. MD, Department of HaemaReprint requests: Ravi Mahadeva, MRC Centre, Addenbrooke's of Cambridge, tology, University Hospital, Hills Road, Cambridge CB2 2QH, UK CHEST/112/6/DECEMBER, 1997 Downloaded From: http://publications.chestnet.org/ on 12/22/2014 1699
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