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Procainamide-induced pulmonary fibrosis after orthotopic heart transplantation: a case report and literature review
Cardiovascular Pathology 24 (2015) 250–253
Contents lists available at ScienceDirect
Cardiovascular Pathology
Clinical Case Report
Procainamide-induced pulmonary fibrosis after orthotopic heart transplantation: a case report and literature review Manoj Thangam a, Sriram Nathan a, Marija Petrovica a, Biswajit Kar a, Manish Patel a, Pranav Loyalka a, L. Maximilian Buja b, Igor D. Gregoric a,⁎ a
Center for Advanced Heart Failure, University of Texas Health Science Center at Houston/Memorial Hermann Hospital — Texas Medical Center, 6400 Fannin Street, Suite 2350, Houston, TX 77030, USA Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston/Memorial Hermann Hospital — Texas Medical Center, 6400 Fannin Street, Suite 2350, Houston, TX 77030, USA b
a r t i c l e
i n f o
Article history: Received 12 August 2014 Received in revised form 4 December 2014 Accepted 10 February 2015 Keywords: Procainamide Pulmonary fibrosis Heart transplantation
a b s t r a c t A 33-year-old African-American woman was bridged to heart transplantation with a left ventricular assist device. She had a 14-month history of heart failure secondary to viral cardiomyopathy. The patient's refractory ventricular tachycardia was treated with intravenous procainamide owing to the patient's history of amiodaroneinduced thyroiditis. After orthotopic cardiac transplant, she experienced prolonged respiratory failure. Serial computed tomography evaluation of the lung revealed diffuse bilateral ground-glass opacities and septal thickening. Bronchoscopies with tissue biopsies were performed with no conclusive results. Specimen samples displayed septal fibrosis with loose fibromyxoid tissue and some hobnail nodularities with no indication of granulomas, neutrophilic infiltration, malignancy, or fungal, viral, or bacterial growth. Histopathological evaluation of the lung wedge biopsy supported a diagnosis of pulmonary fibrosis and noted interstitial fibrosis with areas of focal alveolar hemorrhage and increased macrophage infiltration. Antinuclear body was found to be negative. After in-depth evaluation of the patient's medication history, procainamide was identified as the cause of the toxicity. As procainamide-induced lung fibrosis is relatively uncommon, we present this case to highlight procainamide's potential harm and the need for careful monitoring in postsurgical patients. © 2015 Elsevier Inc. All rights reserved.
1. Introduction
2. Case report
Since its approval by the Food and Drug Administration in 1950, procainamide has been frequently used to control atrial and ventricular arrhythmias [1,2]. Pulmonary accumulation of the drug was noted as early as 1951, and clinical associations with pulmonary toxicity were first described by Ladd in 1962 [2,3]. Procainamide-induced lung injury can take the form of a variety of complications involving any component of the lung and adjacent tissues. It is a dangerous toxicity that requires prompt identification and cessation of procainamide use to prevent morbidity and mortality. Among those affected, posttransplant patients are especially vulnerable to toxicities and may not be able to display early clinical symptoms because of their postsurgical state. Judicious procainamide use is critical in this population, and patients should be closely monitored for potential side effects. We present an interesting case of procainamide-associated pulmonary fibrosis that required prolonged intubation and hospitalization after a cardiac transplant.
A 33-year-old African-American woman presented to our clinic for a heart transplantation eligibility evaluation. Her past medical history included obesity, chronic anemia, pulmonary embolism necessitating long-term anticoagulation, and atrial fibrillation. Fourteen months earlier, she was diagnosed with sudden-onset heart failure during an evaluation for shortness of breath. At that time, a transthoracic echocardiogram revealed an ejection fraction of 16%. After extensive assessments to identify the etiology of her heart failure, she was determined to have viral cardiomyopathy secondary to environmental exposure as a child counselor. The patient underwent placement of an implantable cardioverter-defibrillator (ICD) for severe heart failure. Three months after ICD placement, she suffered cardiac arrest with ventricular tachycardia. Her defibrillator discharged during the subsequent month, which prompted another hospitalization. At that time, she had refractory ventricular tachycardia. Her arrhythmia was not amenable to an increased amiodarone or radiofrequency ablation. Furthermore, her ICD was replaced with a biventricular defibrillator. Her worsening cardiac function necessitated the implantation of a left ventricular assist device (LVAD). The patient arrived at our clinic 6 months after LVAD implantation to determine her candidacy for a heart transplant. Her heart failure status was New York Heart Association functional class II. She underwent a
Conflicts of interest and source of funding: None declared. Source of funding: None declared. ⁎ Corresponding author. 6400 Fannin Street, Suite 2350, Houston, TX 77030, USA. Tel.: +1-713-486-6704; fax: +1-713-486-6730. E-mail address: [email protected] (I.D. Gregoric). http://dx.doi.org/10.1016/j.carpath.2015.02.003 1054-8807/© 2015 Elsevier Inc. All rights reserved.
M. Thangam et al. / Cardiovascular Pathology 24 (2015) 250–253
heart transplant eligibility assessment that included endocrine evaluation of thyroid dysfunction as she had experienced amiodaroneinduced thyroiditis, electrophysiological evaluation, and right heart catheterizations revealing normal pressures. During her initial assessment (review of symptoms and physical exam) in our clinic, the patient was free of any known pulmonary abnormalities. While awaiting a donor heart, she was treated for refractory ventricular tachycardia with intravenous procainamide continuously for 64 days. She then underwent an uncomplicated orthotopic heart transplant. Posttransplant transesophageal and transthoracic echocardiograms revealed normal heart chamber sizes and function and an ejection fraction of 50–55%. Serial ventricular biopsies were negative for antibody- or cell-mediated organ rejection. Unfortunately, the patient endured a prolonged and arduous recovery. First, she suffered acute right ventricular failure with renal failure necessitating temporary continuous renal replacement therapy, ultrafiltration, and later hemodialysis. Second, she suffered respiratory failure after a successful postoperative extubation and required reintubation. Initially suspected to be a result of volume overload, the patient's respiratory failure was first treated with careful diuresis until she was normovolemic without improvement. She was weaned off the ventilator after 7 days of intubation, but she required high-flow oxygen supplementation to maintain adequate blood saturation. Serial computed tomography (CT) evaluation of the chest revealed diffuse bilateral lung ground-glass opacities and septal thickening that worsened acutely over 9 days (Fig. 1A and B). Initially suspected to have an infection, she was treated with antibiotics with little improvement. Several bronchoscopies with tissue biopsies were performed with no conclusive results. The transbronchial biopsy specimens displayed septal fibrosis and reactive epithelial changes with no indication of granulomas, neutrophilic infiltration, malignancy, or fungal, bacterial, or bacterial growth. An immunostain for cytomegalovirus was negative. With continued worsening of pulmonary function, the patient underwent an open lung wedge resection from the right lower lobe. Sections stained with hematoxylin and eosin and by the Movat method revealed an active pulmonary interstitial fibrosis with prominent proliferation of type II pneumocytes with areas of focal alveolar hemorrhage and collections of intraalveolar macrophages (Fig. 2A). A battery of immunohistochemical stains was performed using mouse monoclonal antibodies from Dako (CD68, SMA, and TTF-1) and Leica (CK pan) as the primary antibodies (Fig. 2B–E). The thickened alveolar septa contained foci of elongated smooth-muscle-like cells that stained positively for alpha smooth muscle actin. The proliferating type II pneumocytes stained positively for TTF-1 and pan CK [4]. The alveolar macrophages stained positively for CD68. The macrophages showed variable degrees of foamy cytoplasm. These macrophages stained only focally and weakly positive by Fontana-Masson silver stain in contrast to the inclusions in cases of amiodarone toxicity that stain strongly positive with Fontana-Masson silver stain [5,6] (Fig. 2F). After careful examination of the patient's medication history, we identified the 64-day course of intravenous procainamide as the most likely culprit for pulmonary toxicity. Antinuclear antibodies were found to be negative, and antihistone antibodies were not evaluated. She gradually improved with methylprednisolone therapy and was successfully extubated. Follow-up CT evaluation of lungs 6 months later showed a significant decrease in the size of ground-glass opacities confined to focal regions (Fig. 1C). She has been followed for 1 year in our clinic. The patient shows improvement in cardiac function as assessed by serial transthoracic echocardiograms with ejection fractions between 55% immediately posttransplant and 60% at 1 year postsurgery. She remains free of graft rejection and able to complete activities of daily living. 3. Discussion The transbronchial and wedge resection biopsies confirmed that the patient had developed pulmonary interstitial fibrosis in relationship to chronic procainamide therapy. The interstitial fibrosis was in an active
251
Fig. 1. CT scans. Widespread ground-glass opacities with septal thickening, more predominant on the right lung (A). Worsening of diffuse ground-glass opacities and septal thickening with increasing involvement of the left lung (B). Significant improvement in lung parenchyma and septum with noted airspace opacification in the lower lobe of left lung (C).
early stage with prominent proliferative smooth muscle and epithelial changes as well as accumulation of alveolar macrophages [4]. The alveolar macrophages showed variable degrees of foamy cytoplasm. These macrophages stained only focally and weakly positive by FontanaMasson silver stain in contrast to the inclusions in cases of amiodarone toxicity that stain strongly positive with Fontana-Masson silver stain. The patient had not received amiodarone for the last 6 months while she was receiving procainamide [5,6]. Procainamide-induced lung injury has a plethora of presentations ranging from cough and fatigue to hypoxia and respiratory failure [7,8]. Pleural involvement is commonly observed in these injuries and was originally described by Ladd as bilateral pleural effusions presenting with inspiratory chest pain [3]. Other manifestations include pulmonary infiltrates, pleural fibrosis, pleuritis, pulmonary fibrosis, respiratory muscle fatigue, and pulmonary thromboembolism [9–13]. Procainamideassociated lung injury has also been described independently and as part of a group of symptoms classified as drug-induced lupus (DIL) [3,10]. DIL differs significantly from systemic lupus erythematosus (SLE) and occurs in 20–30% of patients on long-term procainamide therapy [14,15]. Traditional cutaneous manifestations of lupus, such as malar
252
M. Thangam et al. / Cardiovascular Pathology 24 (2015) 250–253
Fig. 2. Photomicrographs of histopathological findings of wedge resection from right lower lobe. The lung exhibits an active pulmonary interstitial fibrosis with thickened septa lined by prominent proliferation of type II pneumocytes and with collections of intraalveolar macrophages (A, H&E, 20× lens). The thickened septa contain elongated smooth-muscle-like cells that stain intensely for smooth muscle actin (B, SMA, 20× lens). The thickened septa are lined by enlarged type II pneumocytes that stain intensely for TTF-1 and pan cytokeratin (C, TTF-1; D pan CK, 20× lens). The alveoli contain numerous CD68-positive macrophages with finely vacuolated cytoplasm (E, CD68, 40× lens). The intraalveolar macrophages exhibit weak staining of the cytoplasm with Fontana-Masson silver stain (F, FM, 40× lens).
rash, discoid rash, photosensitivity, alopecia, or mucosal ulcerations, are rarely encountered with DIL [13]. Also, DIL normally spares the kidneys, central nervous system, and hematopoietic system, which are often affected by SLE [16]. The most common manifestations of DIL are arthralgia and myalgia, which occur in up to 90% and 50% of patients, respectively [15]. Unfortunately, these are nonspecific symptoms that are very difficult to distinguish in postsurgical, intubated patients. Although diffuse organ involvement is possible, 50% of procainamide-induced DIL cases are limited to the pleura, pulmonary tissue, or pericardium [7]. Pulmonary fibrosis is a serious toxicity with the potential to devastate pulmonary function, prolong intubation, and complicate concomitant pathologies. Many early symptoms of lung injury are especially difficult to recognize in posttransplant patients. Delayed toxicity identification has the potential to significantly complicate the patient's condition and jeopardize recovery.
Procainamide-induced lung injury results from an autoimmune process involving dysregulation of genes. DNA methylation causes decreased gene transcription and expression [15–17]. Procainamide increases T cell activity and the related autoimmune response by decreasing DNA methylation in T cells and competitively inhibiting DNA methyltransferase, the enzyme responsible for DNA methylation [18,19]. Autoimmune manifestations, including pulmonary damage secondary to procainamide, result from this inhibition of T cell DNA methylation [20]. Also, hypomethylation enhances expression of genes that code for molecular mediators including IFN-y, IL-4, and CD70. These stimulatory molecules increase generation of autoimmune antibodies that produce inflammation and tissue damage [19–21]. Additionally, direct cytokine release has also been noted in patients treated with procainamide [21]. No specific criteria exist for the diagnosis of procainamide-induced pulmonary toxicity. The diagnosis is usually based on a history of recent
M. Thangam et al. / Cardiovascular Pathology 24 (2015) 250–253
procainamide use in patients experiencing pulmonary symptoms. Although the duration of procainamide therapy does not correlate with the drug's potential for toxicity, symptoms are in general suspected with a treatment course of 1 month. However, the full range of pulmonary toxicities has occurred with treatment durations ranging from days to years [13]. Two serologic markers are highly associated with procainamide-related DIL; antinuclear and antihistone antibodies are noted in 75–90% of suspected DIL patients [9,12]. Both DIL and direct procainamide-related pulmonary damage are generally reversible upon discontinuation of the drug [9,10]. Resolution of symptoms occurs in weeks to months after cessation of procainamide treatment [22]. Patients with severe pulmonary symptoms may benefit from corticosteroids, as in the case of our patient, who was treated with methylprednisolone. Persistent symptoms despite drug discontinuation suggest an underlying pathology, such as SLE or other autoimmune illness [22]. Pulmonary fibrosis can be evaluated with clinical examination and high-resolution CT. High-resolution CT may demonstrate reticular opacities, cystic airspaces, ground-glass opacities, pleural plaques, patchy consolidations, micronodules, air trapping, or a diffuse fibrotic appearance, as noted in our patient. Confirmation of the diagnosis is accomplished with the transbronchial and wedge resection biopsies [21]. Prompt identification of procainamide toxicity is critical to limit pulmonary damage and potentially reverse toxicities to expedite recovery. Procainamide use concurrent with pulmonary symptoms should prompt evaluation for procainamide-induced lung injury and drug cessation.
4. Conclusion Procainamide therapy is associated with a host of pulmonary side effects, including pulmonary fibrosis. Early manifestations of this pathology include symptoms such as cough, fatigue, myalgia, and arthralgia. These presentations are nonspecific and difficult to distinguish as signs of toxicity in patients after surgery. Procainamide-induced lung injury is an important differential diagnosis in any patient with pulmonary symptoms who has recently received the agent. Early cessation of the offending treatment combined with supportive therapy prevents worsening pulmonary function and allows recovery.
253
References [1] US Food and Drug Administration. Drugs at FDA: FDA Approved Drug Products. USA: US Food and Drug Administration (FDA); 2013[Retrieved 2013-12-25]. [2] Kayden H, Brodie B, Steele J. Procaine amide: a review. Circulation 1957;15:118–26. [3] Ladd A. Procainamide-induced lupus erythematosus. N Engl J Med 1962;267: 1357–8. [4] Balka G, Ladining A, Ritzmann M, Saalmuller A, Gerner W, Kaser T, et al. Immunohistochemical characterization of type II pneumocyte proliferation after challenge with type I porcine reproductive and respiratory syndrome virus. J Comp Pathol 2013; 149:322–30. [5] Kennedy JI, Myers JL, Plumb VJ, Fulmer JD. Amiodarone pulmonary toxicity: clinical, radiologic, and pathologic correlations. Arch Intern Med 1987;147:50–5. [6] Ming ME, Bhawan J, Stefanato CM, McCalmont TH, Cohen LM. Imipramine-induced hyperpigmentation: four cases and a review of the literature. J Am Acad Dermatol 1999;40:159–66. [7] Erasmus JJ, McAdams HP, Rossi SE. Drug-induced lung injury. Semin Roentgenol 2002;37(1):72–81. [8] Silva CI, Muller NL. Drug-induced lung diseases: most common reaction patterns and corresponding high-resolution CT manifestations. Semin Ultrasound CT MR 2006;27:111–6. [9] Sheikh S, Seggev JS. Procainamide-induced pleural fibrosis. Am J Med 1991;91(3): 313–5. [10] Rubin R. Drug-induced lupus. Toxicology 2005;209:135–47. [11] Pigakis K, Ferdoutsis M, Meletis G, Patsourakis G, Bachlitzanakis N. Pulmonary toxicity from cardiovascular drugs. Pneumonologia 2009;22(1):75–84. [12] Li F, Patterson AD, Krausz KW, Dick B, Frey FJ, Gonzalez FJ, et al. Metabolomics reveals the metabolic map of procainamide in humans and mice. Biochem Pharmacol 2012;83(10):1435–44. [13] Katz U, Zandman-Goddard G. Drug-induced lupus: an update. Autoimmun Rev 2010;10:46–50. [14] Birnbaum B, Sidhu GS, Smith RL, Pillinger MH, Tagoe CL. Fulminating hydralazineinduced lupus pneumonitis. Arthritis Rheum 2006;55(3):501–6. [15] Segal E, Barash I, Simon N, Friedman N, Koller D. From promoter sequence to expression: a probabilistic framework. Proceedings of the 6th International Conference on Computational Molecular Biology (RECOMB); 2002. [16] Kornberg D. The molecular basis of eukaryotic transcription. Proc Natl Acad Sci U S A 2007;104:12955–61. [17] Murakami K, Elmlund H, Kalisman N, Bushnell DA, Adams CM, Azubel M, et al. Architecture of an RNA polymerase II transcription pre-initiation complex. Science 2013; 342(6159):1238724. [18] Zhou Y, Lu Q. DNA methylation in T cells from idiopathic lupus and drug-induced lupus patients. Autoimmun Rev 2008;7:376–83. [19] Zhang Y, Zhao M, Sawalha AH, Richardson B, Lu Q. Impaired DNA methylation and its mechanisms in CD4+T cells of systemic lupus erythematosus. J Autoimmun 2013;41:92–9. [20] Delaunois L. Mechanisms in pulmonary toxicology. Clin Chest Med 2004;25:1–14. [21] Raghu G, Collard H, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/ JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2001;183(6):788–824. [22] Brochers A, Keen C, Gershwin M. Drug-induced lupus. Ann N Y Acad Sci 2007;1108: 166–82.
Contents lists available at ScienceDirect
Cardiovascular Pathology
Clinical Case Report
Procainamide-induced pulmonary fibrosis after orthotopic heart transplantation: a case report and literature review Manoj Thangam a, Sriram Nathan a, Marija Petrovica a, Biswajit Kar a, Manish Patel a, Pranav Loyalka a, L. Maximilian Buja b, Igor D. Gregoric a,⁎ a
Center for Advanced Heart Failure, University of Texas Health Science Center at Houston/Memorial Hermann Hospital — Texas Medical Center, 6400 Fannin Street, Suite 2350, Houston, TX 77030, USA Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston/Memorial Hermann Hospital — Texas Medical Center, 6400 Fannin Street, Suite 2350, Houston, TX 77030, USA b
a r t i c l e
i n f o
Article history: Received 12 August 2014 Received in revised form 4 December 2014 Accepted 10 February 2015 Keywords: Procainamide Pulmonary fibrosis Heart transplantation
a b s t r a c t A 33-year-old African-American woman was bridged to heart transplantation with a left ventricular assist device. She had a 14-month history of heart failure secondary to viral cardiomyopathy. The patient's refractory ventricular tachycardia was treated with intravenous procainamide owing to the patient's history of amiodaroneinduced thyroiditis. After orthotopic cardiac transplant, she experienced prolonged respiratory failure. Serial computed tomography evaluation of the lung revealed diffuse bilateral ground-glass opacities and septal thickening. Bronchoscopies with tissue biopsies were performed with no conclusive results. Specimen samples displayed septal fibrosis with loose fibromyxoid tissue and some hobnail nodularities with no indication of granulomas, neutrophilic infiltration, malignancy, or fungal, viral, or bacterial growth. Histopathological evaluation of the lung wedge biopsy supported a diagnosis of pulmonary fibrosis and noted interstitial fibrosis with areas of focal alveolar hemorrhage and increased macrophage infiltration. Antinuclear body was found to be negative. After in-depth evaluation of the patient's medication history, procainamide was identified as the cause of the toxicity. As procainamide-induced lung fibrosis is relatively uncommon, we present this case to highlight procainamide's potential harm and the need for careful monitoring in postsurgical patients. © 2015 Elsevier Inc. All rights reserved.
1. Introduction
2. Case report
Since its approval by the Food and Drug Administration in 1950, procainamide has been frequently used to control atrial and ventricular arrhythmias [1,2]. Pulmonary accumulation of the drug was noted as early as 1951, and clinical associations with pulmonary toxicity were first described by Ladd in 1962 [2,3]. Procainamide-induced lung injury can take the form of a variety of complications involving any component of the lung and adjacent tissues. It is a dangerous toxicity that requires prompt identification and cessation of procainamide use to prevent morbidity and mortality. Among those affected, posttransplant patients are especially vulnerable to toxicities and may not be able to display early clinical symptoms because of their postsurgical state. Judicious procainamide use is critical in this population, and patients should be closely monitored for potential side effects. We present an interesting case of procainamide-associated pulmonary fibrosis that required prolonged intubation and hospitalization after a cardiac transplant.
A 33-year-old African-American woman presented to our clinic for a heart transplantation eligibility evaluation. Her past medical history included obesity, chronic anemia, pulmonary embolism necessitating long-term anticoagulation, and atrial fibrillation. Fourteen months earlier, she was diagnosed with sudden-onset heart failure during an evaluation for shortness of breath. At that time, a transthoracic echocardiogram revealed an ejection fraction of 16%. After extensive assessments to identify the etiology of her heart failure, she was determined to have viral cardiomyopathy secondary to environmental exposure as a child counselor. The patient underwent placement of an implantable cardioverter-defibrillator (ICD) for severe heart failure. Three months after ICD placement, she suffered cardiac arrest with ventricular tachycardia. Her defibrillator discharged during the subsequent month, which prompted another hospitalization. At that time, she had refractory ventricular tachycardia. Her arrhythmia was not amenable to an increased amiodarone or radiofrequency ablation. Furthermore, her ICD was replaced with a biventricular defibrillator. Her worsening cardiac function necessitated the implantation of a left ventricular assist device (LVAD). The patient arrived at our clinic 6 months after LVAD implantation to determine her candidacy for a heart transplant. Her heart failure status was New York Heart Association functional class II. She underwent a
Conflicts of interest and source of funding: None declared. Source of funding: None declared. ⁎ Corresponding author. 6400 Fannin Street, Suite 2350, Houston, TX 77030, USA. Tel.: +1-713-486-6704; fax: +1-713-486-6730. E-mail address: [email protected] (I.D. Gregoric). http://dx.doi.org/10.1016/j.carpath.2015.02.003 1054-8807/© 2015 Elsevier Inc. All rights reserved.
M. Thangam et al. / Cardiovascular Pathology 24 (2015) 250–253
heart transplant eligibility assessment that included endocrine evaluation of thyroid dysfunction as she had experienced amiodaroneinduced thyroiditis, electrophysiological evaluation, and right heart catheterizations revealing normal pressures. During her initial assessment (review of symptoms and physical exam) in our clinic, the patient was free of any known pulmonary abnormalities. While awaiting a donor heart, she was treated for refractory ventricular tachycardia with intravenous procainamide continuously for 64 days. She then underwent an uncomplicated orthotopic heart transplant. Posttransplant transesophageal and transthoracic echocardiograms revealed normal heart chamber sizes and function and an ejection fraction of 50–55%. Serial ventricular biopsies were negative for antibody- or cell-mediated organ rejection. Unfortunately, the patient endured a prolonged and arduous recovery. First, she suffered acute right ventricular failure with renal failure necessitating temporary continuous renal replacement therapy, ultrafiltration, and later hemodialysis. Second, she suffered respiratory failure after a successful postoperative extubation and required reintubation. Initially suspected to be a result of volume overload, the patient's respiratory failure was first treated with careful diuresis until she was normovolemic without improvement. She was weaned off the ventilator after 7 days of intubation, but she required high-flow oxygen supplementation to maintain adequate blood saturation. Serial computed tomography (CT) evaluation of the chest revealed diffuse bilateral lung ground-glass opacities and septal thickening that worsened acutely over 9 days (Fig. 1A and B). Initially suspected to have an infection, she was treated with antibiotics with little improvement. Several bronchoscopies with tissue biopsies were performed with no conclusive results. The transbronchial biopsy specimens displayed septal fibrosis and reactive epithelial changes with no indication of granulomas, neutrophilic infiltration, malignancy, or fungal, bacterial, or bacterial growth. An immunostain for cytomegalovirus was negative. With continued worsening of pulmonary function, the patient underwent an open lung wedge resection from the right lower lobe. Sections stained with hematoxylin and eosin and by the Movat method revealed an active pulmonary interstitial fibrosis with prominent proliferation of type II pneumocytes with areas of focal alveolar hemorrhage and collections of intraalveolar macrophages (Fig. 2A). A battery of immunohistochemical stains was performed using mouse monoclonal antibodies from Dako (CD68, SMA, and TTF-1) and Leica (CK pan) as the primary antibodies (Fig. 2B–E). The thickened alveolar septa contained foci of elongated smooth-muscle-like cells that stained positively for alpha smooth muscle actin. The proliferating type II pneumocytes stained positively for TTF-1 and pan CK [4]. The alveolar macrophages stained positively for CD68. The macrophages showed variable degrees of foamy cytoplasm. These macrophages stained only focally and weakly positive by Fontana-Masson silver stain in contrast to the inclusions in cases of amiodarone toxicity that stain strongly positive with Fontana-Masson silver stain [5,6] (Fig. 2F). After careful examination of the patient's medication history, we identified the 64-day course of intravenous procainamide as the most likely culprit for pulmonary toxicity. Antinuclear antibodies were found to be negative, and antihistone antibodies were not evaluated. She gradually improved with methylprednisolone therapy and was successfully extubated. Follow-up CT evaluation of lungs 6 months later showed a significant decrease in the size of ground-glass opacities confined to focal regions (Fig. 1C). She has been followed for 1 year in our clinic. The patient shows improvement in cardiac function as assessed by serial transthoracic echocardiograms with ejection fractions between 55% immediately posttransplant and 60% at 1 year postsurgery. She remains free of graft rejection and able to complete activities of daily living. 3. Discussion The transbronchial and wedge resection biopsies confirmed that the patient had developed pulmonary interstitial fibrosis in relationship to chronic procainamide therapy. The interstitial fibrosis was in an active
251
Fig. 1. CT scans. Widespread ground-glass opacities with septal thickening, more predominant on the right lung (A). Worsening of diffuse ground-glass opacities and septal thickening with increasing involvement of the left lung (B). Significant improvement in lung parenchyma and septum with noted airspace opacification in the lower lobe of left lung (C).
early stage with prominent proliferative smooth muscle and epithelial changes as well as accumulation of alveolar macrophages [4]. The alveolar macrophages showed variable degrees of foamy cytoplasm. These macrophages stained only focally and weakly positive by FontanaMasson silver stain in contrast to the inclusions in cases of amiodarone toxicity that stain strongly positive with Fontana-Masson silver stain. The patient had not received amiodarone for the last 6 months while she was receiving procainamide [5,6]. Procainamide-induced lung injury has a plethora of presentations ranging from cough and fatigue to hypoxia and respiratory failure [7,8]. Pleural involvement is commonly observed in these injuries and was originally described by Ladd as bilateral pleural effusions presenting with inspiratory chest pain [3]. Other manifestations include pulmonary infiltrates, pleural fibrosis, pleuritis, pulmonary fibrosis, respiratory muscle fatigue, and pulmonary thromboembolism [9–13]. Procainamideassociated lung injury has also been described independently and as part of a group of symptoms classified as drug-induced lupus (DIL) [3,10]. DIL differs significantly from systemic lupus erythematosus (SLE) and occurs in 20–30% of patients on long-term procainamide therapy [14,15]. Traditional cutaneous manifestations of lupus, such as malar
252
M. Thangam et al. / Cardiovascular Pathology 24 (2015) 250–253
Fig. 2. Photomicrographs of histopathological findings of wedge resection from right lower lobe. The lung exhibits an active pulmonary interstitial fibrosis with thickened septa lined by prominent proliferation of type II pneumocytes and with collections of intraalveolar macrophages (A, H&E, 20× lens). The thickened septa contain elongated smooth-muscle-like cells that stain intensely for smooth muscle actin (B, SMA, 20× lens). The thickened septa are lined by enlarged type II pneumocytes that stain intensely for TTF-1 and pan cytokeratin (C, TTF-1; D pan CK, 20× lens). The alveoli contain numerous CD68-positive macrophages with finely vacuolated cytoplasm (E, CD68, 40× lens). The intraalveolar macrophages exhibit weak staining of the cytoplasm with Fontana-Masson silver stain (F, FM, 40× lens).
rash, discoid rash, photosensitivity, alopecia, or mucosal ulcerations, are rarely encountered with DIL [13]. Also, DIL normally spares the kidneys, central nervous system, and hematopoietic system, which are often affected by SLE [16]. The most common manifestations of DIL are arthralgia and myalgia, which occur in up to 90% and 50% of patients, respectively [15]. Unfortunately, these are nonspecific symptoms that are very difficult to distinguish in postsurgical, intubated patients. Although diffuse organ involvement is possible, 50% of procainamide-induced DIL cases are limited to the pleura, pulmonary tissue, or pericardium [7]. Pulmonary fibrosis is a serious toxicity with the potential to devastate pulmonary function, prolong intubation, and complicate concomitant pathologies. Many early symptoms of lung injury are especially difficult to recognize in posttransplant patients. Delayed toxicity identification has the potential to significantly complicate the patient's condition and jeopardize recovery.
Procainamide-induced lung injury results from an autoimmune process involving dysregulation of genes. DNA methylation causes decreased gene transcription and expression [15–17]. Procainamide increases T cell activity and the related autoimmune response by decreasing DNA methylation in T cells and competitively inhibiting DNA methyltransferase, the enzyme responsible for DNA methylation [18,19]. Autoimmune manifestations, including pulmonary damage secondary to procainamide, result from this inhibition of T cell DNA methylation [20]. Also, hypomethylation enhances expression of genes that code for molecular mediators including IFN-y, IL-4, and CD70. These stimulatory molecules increase generation of autoimmune antibodies that produce inflammation and tissue damage [19–21]. Additionally, direct cytokine release has also been noted in patients treated with procainamide [21]. No specific criteria exist for the diagnosis of procainamide-induced pulmonary toxicity. The diagnosis is usually based on a history of recent
M. Thangam et al. / Cardiovascular Pathology 24 (2015) 250–253
procainamide use in patients experiencing pulmonary symptoms. Although the duration of procainamide therapy does not correlate with the drug's potential for toxicity, symptoms are in general suspected with a treatment course of 1 month. However, the full range of pulmonary toxicities has occurred with treatment durations ranging from days to years [13]. Two serologic markers are highly associated with procainamide-related DIL; antinuclear and antihistone antibodies are noted in 75–90% of suspected DIL patients [9,12]. Both DIL and direct procainamide-related pulmonary damage are generally reversible upon discontinuation of the drug [9,10]. Resolution of symptoms occurs in weeks to months after cessation of procainamide treatment [22]. Patients with severe pulmonary symptoms may benefit from corticosteroids, as in the case of our patient, who was treated with methylprednisolone. Persistent symptoms despite drug discontinuation suggest an underlying pathology, such as SLE or other autoimmune illness [22]. Pulmonary fibrosis can be evaluated with clinical examination and high-resolution CT. High-resolution CT may demonstrate reticular opacities, cystic airspaces, ground-glass opacities, pleural plaques, patchy consolidations, micronodules, air trapping, or a diffuse fibrotic appearance, as noted in our patient. Confirmation of the diagnosis is accomplished with the transbronchial and wedge resection biopsies [21]. Prompt identification of procainamide toxicity is critical to limit pulmonary damage and potentially reverse toxicities to expedite recovery. Procainamide use concurrent with pulmonary symptoms should prompt evaluation for procainamide-induced lung injury and drug cessation.
4. Conclusion Procainamide therapy is associated with a host of pulmonary side effects, including pulmonary fibrosis. Early manifestations of this pathology include symptoms such as cough, fatigue, myalgia, and arthralgia. These presentations are nonspecific and difficult to distinguish as signs of toxicity in patients after surgery. Procainamide-induced lung injury is an important differential diagnosis in any patient with pulmonary symptoms who has recently received the agent. Early cessation of the offending treatment combined with supportive therapy prevents worsening pulmonary function and allows recovery.
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