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Recurrent Alveolar Proteinosis Following Double Lung Transplantation
early afterde polarizations. In cellular preparations , as well as with monophasic action potential recordings, magnesium administration h as been reported to suppress such activity. 6 In conclusion, proarrhythmic actions may occur with use of amiodarone. Should polymorphous ventricular tachycardia develop in association with its use, the drug should be discontinued, ele ctrolyte imbalances should be corrected, and pacing should be considered if necessary. Concomitantly, an infusion of intravenous magnesium sulfate should be administered until an adequate period of time has passed. REFERENCES 1 Hohnloser SH, Khngenheben T , Singh BH. Amiodarone-associated proarrhythmic effects: a review with special reference to torsades de pointes. Ann Intern Med 1994; 121:529-35 2 Churn SH, Sager PT, Stevenson WG, et a!. Long term efficacy of amiodarone for the maintenance of sinus rhythm in patients with refractory atrial fibrillation or flutter. Am J Cardiol1995; 76:47-50 3 Middlekauff HR, Stevenson WG, Saxon LA, e t !a. Amiodarone and torsades de pointes in patients with advanced heart h1ilure. Am J Cardiol 1995; 76:499-502 4 Singh BH, Venkatesh N, Nadamanee K, eta!. The historical development, cellular electrophysiology and pharmacology of amiodarone. Prog Cardiovasc Dis 1989; 31:249-80 5 Keren A, Tzivoni D. Torsades de pointes: prevention and therapy. Cardiovasc Drugs Ther 1991; 5:509-13 6 Vos MA, Verduyn SC, Anton PM , et al. Reproducible induction of early afterdepolarizations and torsade de pointes arrhythmias by d-sotalol and pacing in dogs with chronic atrioventricular block. Circulation 1995; 91:864-72
Recurrent Alveolar Proteinosis Following Double Lung Transplantation* L. Alden Parker, MD; and Debra B. Novotny, MD
We present a case of recurrent alveolar proteinosis following double lung transplantation. (CHEST 1997; 111:1457-58) Key words: alveolar proteinosis; lung transplantation Abbreviations: PAP=pulmonary alveolar proteinosis
p ulmonmy alveolar proteinosis
(PAP) is a disorder characterized by excessive accumulation of surfactantlike material within the alveoli. Traditional management has been with bronchopulmonary lavage as needed for
*From the University of North Carolina School of Medicine, Chapel Hill. Manuscript received August 14, 1996; revision accepted S eptember 26.
Reprint ·requests: Dr. Parker, CB# 7510, Second Floor Old Clinic Bldg., The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7510
FIGURE l. Preoperative chest radiograph showing reduced lung volumes and coarse reticular and nodular shadows.
symptomatic relief. Progression to pulmonary fibrosis is rare.l We present a case of a patient with PAP who progresse d to pulmonary fibrosis (end-stage lung disease) treated with double lung transplantation who developed recurrent PAP in the transplanted lungs within 3 years of transplantation. CASE REPORT A 41-year-old woman was evaluated for lung transplantation because of end-stage lung seconda1y to PAP (Fig 1). H er disease had been diagnosed at age 27 years, and she had been treated with bronchopulmonmy lavage (12 episodes) with initial good results but had a slowly declining course. Then, 8 years after diagnosis, she was referred to a major transplantation center for possible heart-lung transplantation. However, she experienced a spontaneous regression of symptoms and was not evaluated further. Approximately 6 years later, she was referred to our institution with worsening symptoms. On presentation, her FVC was 30% of predicted, her FEV1 was 35% of predicted, and her arterial blood oxygen saturation was 81% while breathing room air. During the ensuing 7 months, her condition steadily deteriorated and she unde1went double lung transplantation. Postoperatively she did well. Routine follow-up was with chest radiography, pulmonary function tests, and surveillance bronchoscopic evaluation with transbronchial biopsy. Over the next 2 years, she experienced periodic episodes of bronchitis and developed mild obliterative bronchiolitis with concomitant decrease in pulmonmy performance. A little over 3 years after transplantation, she had a transbronchial biopsy of the right upper ol be to evaluate a new infiltrate seen on the chest radiograph (Fig 2). Specimens were negative for rejection or infection with fungus or a mycobacterial species. She returned in 2 months complaining of increasing fatigue and dyspnea on exertion . Another BAL and transbronchial biopsy were performed. Histologic sections fi·om the transbronchial lung biopsy reCHEST I 111 I 5 I MAY, 1997
1457
FIGURE 2. Diffuse involvement of both lungs with small rounded opacities representing airspace fillin g with li poproteinaceous material. vealed alveolar spaces filled with eosinophilic, dense flocculent material (F ig 3). Scattered foam y macrophages and cholesterol crystal clefts also were present. Type 2 pneumocyte hyperplasia was conspicuous, and alveolar walls and interstitium were slightly expanded b y apparent edema flui d. The intra-alveolar granular and fl occulent material was intensely positive with periodic acid-Schiff digest stains. Similar alveolar accumu lations were focall y observed in the transbronchial biopsy obtained 2 months previously. An electron microscopic examination was then perform ed on a specimen obtained during the previous biopsy, and this confirmed the presence of surfactant accu mulation characteristic of PAP. DISCUSSION
PAP is a disease entity characterized by accumulation of phospholipoproteinaceous material \vithin the alveoli. Ra-
F IGURE 3. Histologic section reveals an alveolus filled with granular and flocculent material (large arrows) and lined b y reactive type 2 pneumocytes (small arrows) (hematoxylin -eosin, original X400). 1458
diographically, it is characterized by a symmehic pattern of alveolar filling bilaterally that is similar in appearance to pulmonary edema. Early in the disease process, discrete acinar shadows may be apparent that become more confluent and eventually lead to diffuse a reas of parenchymal consolidation. 2 High-resolution computed tomography has been used to demonstrate the interstitial involvement that is usually not apparent on the chest radiograph.3 Rarely, the process may progress to radiographically apparent interstitial involvement.l·4 However, progression to severe pulmonary fibrosis, or "end-stage lung disease," is distinctly uncommon' and is one of the interesting features of this case. The cause of alveolar proteinosis has been atttibuted to various factors including inhaled agents , altered immunity,5 or locally produced toxic agents. 6 Overproduction of surfactant-like material by the type 2 pneumocytes was considered to be the source of the lipoproteinaceous material filling the alveoli. 5 Recent work has shown that it is more likely to be the result of defective clearance of the material by alveolar macrophages,5·6 and this can be shown experimentally in laboratory animals. 7 This case is of interest not only because of the unusual course of disease leading to pulmonary fibrosis , but also because of the recurrence of the disease in the transplanted lung in tl1 e absence of exposure to a toxic agent supports the theo1y of reduced alveolar clearance secondary to diminished macrophage activity. It may well be that the underlying defect exists in circulating monocytes. Experimentally, macrophage dysfunction can be induced in normal human monocytes after exposure to the lipoproteinaceous material that fills the alveoli. 8 More work needs to be done to elucidate the fundam ental cellular alteration responsible. Radiologists and pulmonologists need to beaware that this entity may rarely progress to pulmonary fibrosis. Physicians involved in lung transplantation programs should be informed that PAP can recur in the transplanted lungs and may be heralded by the appearance of small rounded opacities seen on the c hest radiograph (Fig 3). REFERENCES
1 Clague HW, Wallace AC, Morgan WKC . Pulmonmy interstitial fibrosis associated with alveolar proteinosis. Thorax 1983; 38:865-66 2 Fraser RS, Pare JAP, Fraser RG, eta!. Synopsis of diseases of the chest. 2nd ed. Philadelphia: WB Saunders 1994:815-19 3 Webb WR, Mi.iller NL, aidich DP. High-resolution CT of the lung. 2nd eel. New York: Raven Press, 1996:202-06 4 Miller PA, Ravin CE, Walker Smith GJ, et !.a Pulmonmy alveolar proteinosis with interstitial involvement. AJR 1981; 137:1069-71 5 Dail DH, Ham mar SP. Pulmonary pathology, 2nd ed. ew York: Springer-Verlag, 1994:745-51 6 Gonzalez-Rothi RJ, Banis JO. Pulmonary alveolar proteinosis: furth er evaluation of abnormal alveolar macrophages. Chest 1986; 90:656-61 7 Murata Y, Emi Y, Denda A, et a!. Ultrastructural analysis of pulmonary alveolar proteinosis induced b y methylnaphthalene in mice. Exp Toxic Pathol1992; 44:47-54 8 Golde DW, Territo M, Finely TN , et la. Defective lung macrophages in pulmonary alveolar proteinosis. Ann Intern Med 1976; 85:304-09 Selected Reports
Recurrent Alveolar Proteinosis Following Double Lung Transplantation* L. Alden Parker, MD; and Debra B. Novotny, MD
We present a case of recurrent alveolar proteinosis following double lung transplantation. (CHEST 1997; 111:1457-58) Key words: alveolar proteinosis; lung transplantation Abbreviations: PAP=pulmonary alveolar proteinosis
p ulmonmy alveolar proteinosis
(PAP) is a disorder characterized by excessive accumulation of surfactantlike material within the alveoli. Traditional management has been with bronchopulmonary lavage as needed for
*From the University of North Carolina School of Medicine, Chapel Hill. Manuscript received August 14, 1996; revision accepted S eptember 26.
Reprint ·requests: Dr. Parker, CB# 7510, Second Floor Old Clinic Bldg., The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7510
FIGURE l. Preoperative chest radiograph showing reduced lung volumes and coarse reticular and nodular shadows.
symptomatic relief. Progression to pulmonary fibrosis is rare.l We present a case of a patient with PAP who progresse d to pulmonary fibrosis (end-stage lung disease) treated with double lung transplantation who developed recurrent PAP in the transplanted lungs within 3 years of transplantation. CASE REPORT A 41-year-old woman was evaluated for lung transplantation because of end-stage lung seconda1y to PAP (Fig 1). H er disease had been diagnosed at age 27 years, and she had been treated with bronchopulmonmy lavage (12 episodes) with initial good results but had a slowly declining course. Then, 8 years after diagnosis, she was referred to a major transplantation center for possible heart-lung transplantation. However, she experienced a spontaneous regression of symptoms and was not evaluated further. Approximately 6 years later, she was referred to our institution with worsening symptoms. On presentation, her FVC was 30% of predicted, her FEV1 was 35% of predicted, and her arterial blood oxygen saturation was 81% while breathing room air. During the ensuing 7 months, her condition steadily deteriorated and she unde1went double lung transplantation. Postoperatively she did well. Routine follow-up was with chest radiography, pulmonary function tests, and surveillance bronchoscopic evaluation with transbronchial biopsy. Over the next 2 years, she experienced periodic episodes of bronchitis and developed mild obliterative bronchiolitis with concomitant decrease in pulmonmy performance. A little over 3 years after transplantation, she had a transbronchial biopsy of the right upper ol be to evaluate a new infiltrate seen on the chest radiograph (Fig 2). Specimens were negative for rejection or infection with fungus or a mycobacterial species. She returned in 2 months complaining of increasing fatigue and dyspnea on exertion . Another BAL and transbronchial biopsy were performed. Histologic sections fi·om the transbronchial lung biopsy reCHEST I 111 I 5 I MAY, 1997
1457
FIGURE 2. Diffuse involvement of both lungs with small rounded opacities representing airspace fillin g with li poproteinaceous material. vealed alveolar spaces filled with eosinophilic, dense flocculent material (F ig 3). Scattered foam y macrophages and cholesterol crystal clefts also were present. Type 2 pneumocyte hyperplasia was conspicuous, and alveolar walls and interstitium were slightly expanded b y apparent edema flui d. The intra-alveolar granular and fl occulent material was intensely positive with periodic acid-Schiff digest stains. Similar alveolar accumu lations were focall y observed in the transbronchial biopsy obtained 2 months previously. An electron microscopic examination was then perform ed on a specimen obtained during the previous biopsy, and this confirmed the presence of surfactant accu mulation characteristic of PAP. DISCUSSION
PAP is a disease entity characterized by accumulation of phospholipoproteinaceous material \vithin the alveoli. Ra-
F IGURE 3. Histologic section reveals an alveolus filled with granular and flocculent material (large arrows) and lined b y reactive type 2 pneumocytes (small arrows) (hematoxylin -eosin, original X400). 1458
diographically, it is characterized by a symmehic pattern of alveolar filling bilaterally that is similar in appearance to pulmonary edema. Early in the disease process, discrete acinar shadows may be apparent that become more confluent and eventually lead to diffuse a reas of parenchymal consolidation. 2 High-resolution computed tomography has been used to demonstrate the interstitial involvement that is usually not apparent on the chest radiograph.3 Rarely, the process may progress to radiographically apparent interstitial involvement.l·4 However, progression to severe pulmonary fibrosis, or "end-stage lung disease," is distinctly uncommon' and is one of the interesting features of this case. The cause of alveolar proteinosis has been atttibuted to various factors including inhaled agents , altered immunity,5 or locally produced toxic agents. 6 Overproduction of surfactant-like material by the type 2 pneumocytes was considered to be the source of the lipoproteinaceous material filling the alveoli. 5 Recent work has shown that it is more likely to be the result of defective clearance of the material by alveolar macrophages,5·6 and this can be shown experimentally in laboratory animals. 7 This case is of interest not only because of the unusual course of disease leading to pulmonary fibrosis , but also because of the recurrence of the disease in the transplanted lung in tl1 e absence of exposure to a toxic agent supports the theo1y of reduced alveolar clearance secondary to diminished macrophage activity. It may well be that the underlying defect exists in circulating monocytes. Experimentally, macrophage dysfunction can be induced in normal human monocytes after exposure to the lipoproteinaceous material that fills the alveoli. 8 More work needs to be done to elucidate the fundam ental cellular alteration responsible. Radiologists and pulmonologists need to beaware that this entity may rarely progress to pulmonary fibrosis. Physicians involved in lung transplantation programs should be informed that PAP can recur in the transplanted lungs and may be heralded by the appearance of small rounded opacities seen on the c hest radiograph (Fig 3). REFERENCES
1 Clague HW, Wallace AC, Morgan WKC . Pulmonmy interstitial fibrosis associated with alveolar proteinosis. Thorax 1983; 38:865-66 2 Fraser RS, Pare JAP, Fraser RG, eta!. Synopsis of diseases of the chest. 2nd ed. Philadelphia: WB Saunders 1994:815-19 3 Webb WR, Mi.iller NL, aidich DP. High-resolution CT of the lung. 2nd eel. New York: Raven Press, 1996:202-06 4 Miller PA, Ravin CE, Walker Smith GJ, et !.a Pulmonmy alveolar proteinosis with interstitial involvement. AJR 1981; 137:1069-71 5 Dail DH, Ham mar SP. Pulmonary pathology, 2nd ed. ew York: Springer-Verlag, 1994:745-51 6 Gonzalez-Rothi RJ, Banis JO. Pulmonary alveolar proteinosis: furth er evaluation of abnormal alveolar macrophages. Chest 1986; 90:656-61 7 Murata Y, Emi Y, Denda A, et a!. Ultrastructural analysis of pulmonary alveolar proteinosis induced b y methylnaphthalene in mice. Exp Toxic Pathol1992; 44:47-54 8 Golde DW, Territo M, Finely TN , et la. Defective lung macrophages in pulmonary alveolar proteinosis. Ann Intern Med 1976; 85:304-09 Selected Reports