Successful Lung Retransplantation in a Patient With Acute Fibrinous and Organizing Pneumonia: A Case Report B. Renaud-Picarda, T. Dégota, D. Biondinia, N. Weingertnerb, J. Reebc, M.P. Chenardb, and R. Kesslera,* a Department of Pneumology, bDepartment of Pathology, and cDepartment of Thoracic Surgery, University Hospital of Strasbourg, Strasbourg, France
ABSTRACT Acute fibrinous and organizing pneumonia (AFOP) is an unusual histopathologic pattern characterized by the formation of intra-alveolar plugs of fibrin deposition and associated organizing pneumonia. AFOP is considered to be a form of rejection and portends a dismal prognosis. Here, we present the case of a young male patient who initially underwent a double lung transplantation for cystic fibrosis. After 42 months of regular follow-up, he experienced rapidly progressive respiratory failure. Acute rejection and opportunistic lung infections were suspected. The clinical conditions rapidly deteriorated despite treatment with broad-spectrum antibiotics and high-dose steroids. Therefore, AFOP was suspected owing to: 1) acute clinical presentation; 2) pulmonary computerized tomographic data; 3) typical histopathologic findings on transbronchial biopsieseconds, and 4) lack of response to different treatments. The patient required an emergency bilateral lung retransplantation 44 months after the initial transplantation. The histopathologic analysis of the explanted lungs confirmed the diagnosis of AFOP. Two years after the 2nd transplant, the patient is alive and well. To the best of our knowledge, this is the 1st case of a patient experiencing AFOP following lung transplantation who was successfully rescued by a 2nd bilateral lung retransplantation.
A
CUTE FIBRINOUS AND ORGANIZING PNEUMONIA (AFOP) is an unusual histopathologic pattern which was initially described in 2002 by Beasley et al [1]. Although the majority of cases are idiopathic, AFOP has been associated with a number of different conditions, including systemic diseases (eg, systemic lupus erythematosus) [2], collagen vascular disorders [3], hematopoietic stem cell transplantation [4], infections of bacterial [5] or viral [6] origin, acute respiratory distress syndrome [7], exposure to certain drugs (eg, amiodarone, statins, abacavir) [7], and following lung transplantation [6,8]. To date, there is no clear consensus on the main predisposing factors. The histopathologic pattern is characterized by the presence of intra-alveolar fibrinous deposits that involve 25%e90% of the alveolar spaces in a patchy distribution, accompanied by areas of organizing pneumonia. Other common findings include interstitial acute and/or chronic inflammatory changes, type II pneumocytes hyperplasia, and alveolar septal expansion. A diagnosis of AFOP is defined by the absence of hyaline membranes, absent or scarce eosinophilic infiltration, and lack of extensive bronchopneumonia, 0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.08.039
182
granulomas, and/or abscess formation. The main differential diagnoses include diffuse alveolar damage, bronchiolitis obliterans organizing pneumonia, and eosinophilic pneumonia. Chest X-ray findings are not specific, but the usual appearance consists of bilateral basal alveolar opacities. CT scans are generally characterized by areas of consolidation, extensive patchy ground glass opacities, bilateral diffuse infiltrates, and reticulations. Clinically, AFOP is characterized by 2 main presentations: 1) a rare fulminant form where symptoms are accompanied by respiratory distress and can rapidly progress to death; and 2) a more common subacute form characterized by a better prognosis and recovery within a few months. Here, we present the case of 22-year-old male patient who underwent a double lung transplantation for end-stage lung disease due to cystic fibrosis in 2008. He subsequently
*Address correspondence to Prof Romain Kessler, Service de pneumologie, Nouvel Hôpital Civil, 1 place de l’hôpital, 67000 Strasbourg, France. E-mail: [email protected] ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 182e185 (2015)
SUCCESSFUL LUNG RETRANSPLANTATION
experienced an acute respiratory distress syndrome characterized by rapid clinical progression. A diagnosis of AFOP was made and the patient required an emergency bilateral lung retransplantation 44 months after the initial transplantation. Such an approach was successful and the patient is currently alive and well. To the best of our knowledge, this is the 1st case of a patient experiencing AFOP following an initial lung transplantation who was successfully rescued by a 2nd bilateral transplant. CASE REPORT A 22-year-old male patient with cystic fibrosis diagnosed at birth was regularly followed in our specialized unit. He suffered from chronic respiratory failure, recurrent respiratory exacerbations due to chronic Stenotrophomonas maltophilia infection, denutrition, and glucose intolerance. In October 2008, he underwent a bilateral lung transplantation which had a favorable clinical course. At 7 months after surgery, a right cervicolateral adenopathy was clinically detected during a regular follow-up visit. Biopsy findings revealed a B-cell Epstein-Barr virus (EBV)epositive polymorphic post-transplantation lymphoproliferative disorder. No other locations of the lymphoproliferative disorder were identified on positron-emission tomographyecomputerized tomography (CT) images. Treatment consisted of complete surgical resection of the cervical lymphadenopathy accompanied by a reduction in immunosuppression (tacrolimus target through levels, 5e7 mg/L; mycophenolate mofetil, 1 g/d). Thereafter, his clinical conditions and respiratory lung function remained stable for 23 months. In March 2012, the patient’s respiratory conditions rapidly worsened and hospitalization was required. The patient was afebrile but presented with severe shortness of breath, loss of appetite, and bilateral crackles on the lung bases. At admission, chest X-ray showed ground-glass opacifications with basal predominance. A CT scan confirmed the presence of a multifocal diffuse ground-glass pattern, associated with centrilobular micronodules and bilateral traction bronchiectasis. Opacities were present in every lobe but showed a basal predominance. We also observed some areas of air trapping and a few mediastinal centimetric adenopathies. Bilateral infectious pneumonia, cryptogenic organizing pneumonia, acute rejection, or pulmonary lymphoma were initially suspected. Bronchial endoscopy did not show any endobronchial abnormality. The bronchoalveolar lavage fluid had a normal cellularity and formula. Blood samples were positive for Candida antigenemia (25.34 U/mL), and the polymerase chain reaction for EBV infection yielded positive results (2.85 log). Other microbiologic tests were negative. The histopathologic examination of transbronchial biopsies did not
183 reveal signs of cellular or CD4 humoral lung transplant rejection. However, the pattern was consistent with an organizing pneumonia. The anti-HLA antibodies were negative on the Luminex assay. Treatment consisted of antibiotics (intravenous ceftazidime and oral levofloxacin) and an antifungal agent (intravenous caspofungin). Other drugs (valganciclovir, sulfamethoxazole-trimethroprim) were administered for preventing additional infections. Despite the lack of histologic evidence, an acute rejection of the lungs was suspected. Consequently, corticosteroids at a dose of 750 mg were administered in bolus for 3 days, followed by progressive tapering. Unfortunately, the patient’s clinical conditions did not improve significantly. A novel chest CT scan carried out on April 24, 2012, identified extensive ground-glass opacities, fine-mesh reticulations, and bronchiectasis by traction. Such lesions were much more evident than in the previous scan, especially in the upper lobes (Fig 1). Based on these findings, AFOP was suspected because of: 1) acute clinical presentation; 2) pulmonary CT data; 3) typical histopathologic findings on transbronchial biopsies; and 4) lack of response to different treatments (broad-spectrum antibiotics, high-dose steroids). Owing to the patient’s worsening respiratory conditions, he was placed on the lung transplant emergency waiting list. He was then transferred to the Intensive Care Unit (ICU) because of acute severe respiratory failure. On admission, arterial blood gases measured under nasal oxygenation revealed respiratory acidosis (pH, 7.12; paO2, 147 mm Hg; paCO2, 111 mm Hg; bicarbonates, 34.2 mmol/L). The patient was intubated and artificial ventilation started. Bilateral pulmonary transplantation was performed on May 18, 2012, under extracorporeal circulation. The donor was a 58-year-old man who died of stroke. The histopathologic analysis of the explanted lungs revealed an identical pattern bilaterally. The main finding in the explanted lungs was the presence of fibrinous balls located in the alveolar spaces, which were predominant in the peripheral subpleural areas. Classic hyaline membranes were not observed. The fibrin deposits filled w30%e40% of the alveolar space in different lobes bilaterally. In specific areas, fibrinoid deposits were organized and resulted in intra-alveolar fibrous obliterations. The alveolar walls in such locations were characterized by a moderate lymphoplasmocytic infiltrate without eosinophils and granulomas. Only small areas of normal lung parenchyma were detected, and no signs of bronchiolitis obliterans were detected. Several vessels had intimal hyperplasia, and some contained fibrinoid deposits. This pattern was highly suggestive of AFOP (Fig 2). After surgery and 3 failed attempts to extubate the patient, percutaneous tracheotomy was performed under general anesthesia on June 7, 2012. After 30 days of ICU stay, the patient was discharged to the pneumology unit. His respiratory conditions gradually improved, ultimately allowing decanulation of the tracheotomy tube. A bronchial fibroscopy performed on July 3, 2012, did not reveal any
Fig 1. A computerized tomographic (CT) scan performed on April 24, 2012, revealed extensive ground-glass opacities, nodules, and micronodules with a patchy distribution, traction bronchiectasis, and some reticular abnormalities. (A) CT scan at mid thoracic level, and (B) CT scan at lung bases.
184 major endoscopic abnormalities. The bronchoalveolar lavage yielded normal findings (macrophages, 96%; lymphocytes, 3%; neutrophils, 1%). Similarly, a thoracic CT scan (on July 12, 2012) was normal. The clinical course was subsequently complicated by the persistence of critical illness polyneuropathy and myopathy, left pneumothorax, acquired factor XII deficiency, steroid-induced diabetes, regular sinus tachycardia, and severe malnutrition requiring a gastrostomy for enteral feeding. The patient’s general and respiratory conditions improved progressively, and he was finally discharged 2 months after lung transplantation. At 24 months after the retransplantation, he is currently well at home and conducts a normal life.
DISCUSSION
Lung transplantation is a key treatment option for patients with end-stage lung disease, of which cystic fibrosis remains one of the major causes. Post-transplantation morbidity and mortality can be often attributed to acute (cellular or humoral) or chronic rejection. Chronic lung allograft dysfunction is mainly due to obliterans bronchiolitis (an obstructive ventilatory defect characterized by a progressive decrease of the 1-second forced expiratory volume) ordless frequentlydby restrictive lung allograft syndrome [8]. AFOP has recently been described as a novel form of chronic lung allograft dysfunction [9]. The original study cohort consisted of 194 patients who received bilateral lung transplantation [9]. Of the 78 patients who developed a chronic lung allograft dysfunction, 22 were categorized as having AFOP. However, the clinical course of AFOP cases was invariably acute or subacute, not chronic, with all of the patients dying after a median 101 days. Of the 22 AFOP patients, only 3 presented an obstructive ventilatory defect, whereas 12 showed a nonobstructive pattern. Sufficient spirometric data were lacking for 7 patients. In that study, the diagnosis of AFOP was made with the use of histopathologic analysis of explanted postmortem lung transplants or transbronchial biopsy (TBB). However, TBB was unsuccessfully used in other reports [1,3,6e8]. Compared with obliterans bronchiolitis, the mean delay between the onset of symptoms and the decline of lung function was shorter in AFOP cases. Moreover, the evolution was rapidly fatal in all patients (median survival after diagnosis, 94 days). Notably, the mortality rate was significantly higher in patients with AFOP than in those with obliterans bronchiolitis during the study period (95%
Fig 2. (A) Prominent intra-alveolar fibrin deposition (fibrin balls) (hematoxylin-eosin stain; original magnification, 200). (B) Intra-alveolar fibrin deposition and patchy-distributed organizing pneumonia (Masson trichrome stain; original magnification, 200).
RENAUD-PICARD, DÉGOT, BIONDINI ET AL
vs 54%, respectively). Because most cases of AFOP occurred during the winter period, a possible viral infection as a triggering factor was suggested, although definite microbiologic evidence was lacking [9]. Different treatments have been proposed for improving respiratory function in AFOP patients, including immunosuppressive drugs at high doses, bolus corticosteroids, intravenous immunoglobulins, antibiotics, and antiviral agents. Unfortunately, all of these approaches were ineffective and the clinical course invariably unfavorable. Lee et al [4] previously reported the occurrence of AFOP following allogenic hematopoietic stem cell transplantation for the treatment of acute myeloid leukemia. Specifically, AFOP developed after 2 courses of induction chemotherapy and a complete remission. The symptoms presented 4 months after transplantation, starting with cough, sputum, and dyspnea [4]. The initial chest radiograph demonstrated diffuse haziness and miliary nodules in both lungs and right pleural effusion. High-resolution chest CT showed diffuse miliary nodules and ground-glass opacities in both lungs, patchy consolidation in the left lower lobe, and right pleural effusion. Pulmonary function tests revealed a severe restrictive pulmonary defect and decreased transfer factor of the lung for carbon monoxide. The diagnosis of AFOP was obtained with the use of TBB. Despite different therapeutic attempts (broad-spectrum antibiotics, methylprednisolone pulse therapy), the patient died of respiratory failure after 61 days. Otto et al [6] reported a case of AFOP with concomitant influenza A/H1N1 pneumonia following lung transplantation. The patient suffered from end-stage pulmonary fibrosis and had received a double-lung transplantation. Four months after transplantation, she started complaining about persistent cough. Intubation was required owing to the rapid worsening of her respiratory conditions. A CT scan revealed bronchiectasis, consolidation, and increased bilateral diffuse pulmonary infiltrates with a ground-glass pattern in both lungs. Nasotracheal swabs were positive for viral influenza A/ H1N1 RNA according to reverse-transcription polymerase chain reaction results. Despite repeated therapeutic attempts (antibiotics, oseltamivir switched to zanamavir, prednisolone, and mycophenolate-mofetil), the patient developed acute renal failure and suspected heparin-induced thrombocytopenia type II. She ultimately died owing to
SUCCESSFUL LUNG RETRANSPLANTATION
rapidly progressive respiratory failure. The postmortem examination of the transplanted lungs revealed typical microscopic features of AFOP, which were especially evident in the lower parts. In the present case report, the patient presented with rapidly worsening dyspnea and an abrupt decline in lung function. To our knowledge, this is the 1st case of AFOP successfully treated with lung retransplantation. In our patient, the use of TBB did not allow a definite diagnosis of AFOP even though the pattern was consistent with organizing pneumonia. Nonetheless, organizing pneumonia with a patchy distribution is a typical AFOP-associated feature. Organizing pneumonia is characterized by the presence of endoluminal buds of granulation tissue (known as Masson bodies) which fill the alveoli and spread to the alveolar ducts and terminal bronchioles. However, the hallmark of AFOP is represented by the presence of intraalveolar plugs of fibrin deposition. In this scenario, it is possible that a definite diagnosis of AFOP can be obtained only by means of a surgical lung biopsy and/or histologic examination of the explanted lungs (as in our case). Beasley et al [1] initially described 2 distinct subtypes of AFOP: 1) a malignant form characterized by an aggressive clinical course, resistance to medical therapy, and a dismal prognosis; and 2) a subacute form associated with a more favorable clinical outcome. In our case, we faced the former subtype and lung retransplantation was required. AFOP is currently recognized as a specific histopathologic entity and has been included in the latest international classification of Idiopathic Interstitial Pneumonia released by the American Thoracic Society and the European Respiratory Society in 2013 [10]. It is classified as a rare idiopathic interstitial pneumonia with a typical histologic pattern. Despite some recent advances, AFOP remains a poorly understood condition that portends a dismal prognosis when presenting in its fulminant form. Some of such severe cases can complicate the clinical course of lung transplant recipients. Nonetheless, the
185
question as to whether AFOP may be a manifestation of acute lung rejection remains open. The present case demonstrates the feasibility of lung retransplantation in selected patients with fulminant AFOP. It should be noted, however, that our patient was young and in good general condition before the onset of this condition.
REFERENCES [1] Beasley MB, Franks TJ, Galvin JR, et al. Acute fibrinous and organizing pneumonia: a histological pattern of lung injury and possible variant of diffuse alveolar damage. Arch Pathol Lab Med 2002;126:1064e70. [2] Hariri LP, Unizony S, Stone J, Mino-Kenudson M, et al. Acute fibrinous and organizing pneumonia in systemic lupus erythematosus: a case report and review of the literature. Pathol Int 2010;60:755e9. [3] Valim V, Rocha RH, Couto RB, et al. Acute fibrinous and organizing pneumonia and undifferentiated connective tissue disease: a case report. Case Rep Rheumatol 2012;2012:549298. [4] Lee SM, Park JJ, Sung SH, et al. Acute fibrinous and organizing pneumonia following hematopoietic stem cell transplantation. Korean J Intern Med 2009;24:156e9. [5] Mittal V, Kulshrestha R, Arya A, et al. Acute fibrinous and organizing pneumonia presenting as complete lung consolidation. Singapore Med J 2011;52:e88. [6] Otto C, Huzly D, Kemna L, et al. Acute fibrinous and organizing pneumonia associated with influenza A/H1N1 pneumonia after lung transplantation. BMC Pulm Med 2013;13:30. [7] López-Cuenca S, Morales-García S, Martín-Hita A, et al. Severe acute respiratory failure secondary to acute fibrinous and organizing pneumonia requiring mechanical ventilation: a case report and literature review. Respir Care 2012;57:1337e41. [8] Sato M, Waddell TK, Wagnetz U, et al. Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction. J Heart Lung Transplant 2011;30:735e42. [9] Paraskeva M, McLean C, Ellis S, et al. Acute fibrinoid organizing pneumonia after lung transplantation. Am J Respir Crit Care Med 2013;187:1360e8. [10] Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013;188:733e4.
ABSTRACT Acute fibrinous and organizing pneumonia (AFOP) is an unusual histopathologic pattern characterized by the formation of intra-alveolar plugs of fibrin deposition and associated organizing pneumonia. AFOP is considered to be a form of rejection and portends a dismal prognosis. Here, we present the case of a young male patient who initially underwent a double lung transplantation for cystic fibrosis. After 42 months of regular follow-up, he experienced rapidly progressive respiratory failure. Acute rejection and opportunistic lung infections were suspected. The clinical conditions rapidly deteriorated despite treatment with broad-spectrum antibiotics and high-dose steroids. Therefore, AFOP was suspected owing to: 1) acute clinical presentation; 2) pulmonary computerized tomographic data; 3) typical histopathologic findings on transbronchial biopsieseconds, and 4) lack of response to different treatments. The patient required an emergency bilateral lung retransplantation 44 months after the initial transplantation. The histopathologic analysis of the explanted lungs confirmed the diagnosis of AFOP. Two years after the 2nd transplant, the patient is alive and well. To the best of our knowledge, this is the 1st case of a patient experiencing AFOP following lung transplantation who was successfully rescued by a 2nd bilateral lung retransplantation.
A
CUTE FIBRINOUS AND ORGANIZING PNEUMONIA (AFOP) is an unusual histopathologic pattern which was initially described in 2002 by Beasley et al [1]. Although the majority of cases are idiopathic, AFOP has been associated with a number of different conditions, including systemic diseases (eg, systemic lupus erythematosus) [2], collagen vascular disorders [3], hematopoietic stem cell transplantation [4], infections of bacterial [5] or viral [6] origin, acute respiratory distress syndrome [7], exposure to certain drugs (eg, amiodarone, statins, abacavir) [7], and following lung transplantation [6,8]. To date, there is no clear consensus on the main predisposing factors. The histopathologic pattern is characterized by the presence of intra-alveolar fibrinous deposits that involve 25%e90% of the alveolar spaces in a patchy distribution, accompanied by areas of organizing pneumonia. Other common findings include interstitial acute and/or chronic inflammatory changes, type II pneumocytes hyperplasia, and alveolar septal expansion. A diagnosis of AFOP is defined by the absence of hyaline membranes, absent or scarce eosinophilic infiltration, and lack of extensive bronchopneumonia, 0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.08.039
182
granulomas, and/or abscess formation. The main differential diagnoses include diffuse alveolar damage, bronchiolitis obliterans organizing pneumonia, and eosinophilic pneumonia. Chest X-ray findings are not specific, but the usual appearance consists of bilateral basal alveolar opacities. CT scans are generally characterized by areas of consolidation, extensive patchy ground glass opacities, bilateral diffuse infiltrates, and reticulations. Clinically, AFOP is characterized by 2 main presentations: 1) a rare fulminant form where symptoms are accompanied by respiratory distress and can rapidly progress to death; and 2) a more common subacute form characterized by a better prognosis and recovery within a few months. Here, we present the case of 22-year-old male patient who underwent a double lung transplantation for end-stage lung disease due to cystic fibrosis in 2008. He subsequently
*Address correspondence to Prof Romain Kessler, Service de pneumologie, Nouvel Hôpital Civil, 1 place de l’hôpital, 67000 Strasbourg, France. E-mail: [email protected] ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 182e185 (2015)
SUCCESSFUL LUNG RETRANSPLANTATION
experienced an acute respiratory distress syndrome characterized by rapid clinical progression. A diagnosis of AFOP was made and the patient required an emergency bilateral lung retransplantation 44 months after the initial transplantation. Such an approach was successful and the patient is currently alive and well. To the best of our knowledge, this is the 1st case of a patient experiencing AFOP following an initial lung transplantation who was successfully rescued by a 2nd bilateral transplant. CASE REPORT A 22-year-old male patient with cystic fibrosis diagnosed at birth was regularly followed in our specialized unit. He suffered from chronic respiratory failure, recurrent respiratory exacerbations due to chronic Stenotrophomonas maltophilia infection, denutrition, and glucose intolerance. In October 2008, he underwent a bilateral lung transplantation which had a favorable clinical course. At 7 months after surgery, a right cervicolateral adenopathy was clinically detected during a regular follow-up visit. Biopsy findings revealed a B-cell Epstein-Barr virus (EBV)epositive polymorphic post-transplantation lymphoproliferative disorder. No other locations of the lymphoproliferative disorder were identified on positron-emission tomographyecomputerized tomography (CT) images. Treatment consisted of complete surgical resection of the cervical lymphadenopathy accompanied by a reduction in immunosuppression (tacrolimus target through levels, 5e7 mg/L; mycophenolate mofetil, 1 g/d). Thereafter, his clinical conditions and respiratory lung function remained stable for 23 months. In March 2012, the patient’s respiratory conditions rapidly worsened and hospitalization was required. The patient was afebrile but presented with severe shortness of breath, loss of appetite, and bilateral crackles on the lung bases. At admission, chest X-ray showed ground-glass opacifications with basal predominance. A CT scan confirmed the presence of a multifocal diffuse ground-glass pattern, associated with centrilobular micronodules and bilateral traction bronchiectasis. Opacities were present in every lobe but showed a basal predominance. We also observed some areas of air trapping and a few mediastinal centimetric adenopathies. Bilateral infectious pneumonia, cryptogenic organizing pneumonia, acute rejection, or pulmonary lymphoma were initially suspected. Bronchial endoscopy did not show any endobronchial abnormality. The bronchoalveolar lavage fluid had a normal cellularity and formula. Blood samples were positive for Candida antigenemia (25.34 U/mL), and the polymerase chain reaction for EBV infection yielded positive results (2.85 log). Other microbiologic tests were negative. The histopathologic examination of transbronchial biopsies did not
183 reveal signs of cellular or CD4 humoral lung transplant rejection. However, the pattern was consistent with an organizing pneumonia. The anti-HLA antibodies were negative on the Luminex assay. Treatment consisted of antibiotics (intravenous ceftazidime and oral levofloxacin) and an antifungal agent (intravenous caspofungin). Other drugs (valganciclovir, sulfamethoxazole-trimethroprim) were administered for preventing additional infections. Despite the lack of histologic evidence, an acute rejection of the lungs was suspected. Consequently, corticosteroids at a dose of 750 mg were administered in bolus for 3 days, followed by progressive tapering. Unfortunately, the patient’s clinical conditions did not improve significantly. A novel chest CT scan carried out on April 24, 2012, identified extensive ground-glass opacities, fine-mesh reticulations, and bronchiectasis by traction. Such lesions were much more evident than in the previous scan, especially in the upper lobes (Fig 1). Based on these findings, AFOP was suspected because of: 1) acute clinical presentation; 2) pulmonary CT data; 3) typical histopathologic findings on transbronchial biopsies; and 4) lack of response to different treatments (broad-spectrum antibiotics, high-dose steroids). Owing to the patient’s worsening respiratory conditions, he was placed on the lung transplant emergency waiting list. He was then transferred to the Intensive Care Unit (ICU) because of acute severe respiratory failure. On admission, arterial blood gases measured under nasal oxygenation revealed respiratory acidosis (pH, 7.12; paO2, 147 mm Hg; paCO2, 111 mm Hg; bicarbonates, 34.2 mmol/L). The patient was intubated and artificial ventilation started. Bilateral pulmonary transplantation was performed on May 18, 2012, under extracorporeal circulation. The donor was a 58-year-old man who died of stroke. The histopathologic analysis of the explanted lungs revealed an identical pattern bilaterally. The main finding in the explanted lungs was the presence of fibrinous balls located in the alveolar spaces, which were predominant in the peripheral subpleural areas. Classic hyaline membranes were not observed. The fibrin deposits filled w30%e40% of the alveolar space in different lobes bilaterally. In specific areas, fibrinoid deposits were organized and resulted in intra-alveolar fibrous obliterations. The alveolar walls in such locations were characterized by a moderate lymphoplasmocytic infiltrate without eosinophils and granulomas. Only small areas of normal lung parenchyma were detected, and no signs of bronchiolitis obliterans were detected. Several vessels had intimal hyperplasia, and some contained fibrinoid deposits. This pattern was highly suggestive of AFOP (Fig 2). After surgery and 3 failed attempts to extubate the patient, percutaneous tracheotomy was performed under general anesthesia on June 7, 2012. After 30 days of ICU stay, the patient was discharged to the pneumology unit. His respiratory conditions gradually improved, ultimately allowing decanulation of the tracheotomy tube. A bronchial fibroscopy performed on July 3, 2012, did not reveal any
Fig 1. A computerized tomographic (CT) scan performed on April 24, 2012, revealed extensive ground-glass opacities, nodules, and micronodules with a patchy distribution, traction bronchiectasis, and some reticular abnormalities. (A) CT scan at mid thoracic level, and (B) CT scan at lung bases.
184 major endoscopic abnormalities. The bronchoalveolar lavage yielded normal findings (macrophages, 96%; lymphocytes, 3%; neutrophils, 1%). Similarly, a thoracic CT scan (on July 12, 2012) was normal. The clinical course was subsequently complicated by the persistence of critical illness polyneuropathy and myopathy, left pneumothorax, acquired factor XII deficiency, steroid-induced diabetes, regular sinus tachycardia, and severe malnutrition requiring a gastrostomy for enteral feeding. The patient’s general and respiratory conditions improved progressively, and he was finally discharged 2 months after lung transplantation. At 24 months after the retransplantation, he is currently well at home and conducts a normal life.
DISCUSSION
Lung transplantation is a key treatment option for patients with end-stage lung disease, of which cystic fibrosis remains one of the major causes. Post-transplantation morbidity and mortality can be often attributed to acute (cellular or humoral) or chronic rejection. Chronic lung allograft dysfunction is mainly due to obliterans bronchiolitis (an obstructive ventilatory defect characterized by a progressive decrease of the 1-second forced expiratory volume) ordless frequentlydby restrictive lung allograft syndrome [8]. AFOP has recently been described as a novel form of chronic lung allograft dysfunction [9]. The original study cohort consisted of 194 patients who received bilateral lung transplantation [9]. Of the 78 patients who developed a chronic lung allograft dysfunction, 22 were categorized as having AFOP. However, the clinical course of AFOP cases was invariably acute or subacute, not chronic, with all of the patients dying after a median 101 days. Of the 22 AFOP patients, only 3 presented an obstructive ventilatory defect, whereas 12 showed a nonobstructive pattern. Sufficient spirometric data were lacking for 7 patients. In that study, the diagnosis of AFOP was made with the use of histopathologic analysis of explanted postmortem lung transplants or transbronchial biopsy (TBB). However, TBB was unsuccessfully used in other reports [1,3,6e8]. Compared with obliterans bronchiolitis, the mean delay between the onset of symptoms and the decline of lung function was shorter in AFOP cases. Moreover, the evolution was rapidly fatal in all patients (median survival after diagnosis, 94 days). Notably, the mortality rate was significantly higher in patients with AFOP than in those with obliterans bronchiolitis during the study period (95%
Fig 2. (A) Prominent intra-alveolar fibrin deposition (fibrin balls) (hematoxylin-eosin stain; original magnification, 200). (B) Intra-alveolar fibrin deposition and patchy-distributed organizing pneumonia (Masson trichrome stain; original magnification, 200).
RENAUD-PICARD, DÉGOT, BIONDINI ET AL
vs 54%, respectively). Because most cases of AFOP occurred during the winter period, a possible viral infection as a triggering factor was suggested, although definite microbiologic evidence was lacking [9]. Different treatments have been proposed for improving respiratory function in AFOP patients, including immunosuppressive drugs at high doses, bolus corticosteroids, intravenous immunoglobulins, antibiotics, and antiviral agents. Unfortunately, all of these approaches were ineffective and the clinical course invariably unfavorable. Lee et al [4] previously reported the occurrence of AFOP following allogenic hematopoietic stem cell transplantation for the treatment of acute myeloid leukemia. Specifically, AFOP developed after 2 courses of induction chemotherapy and a complete remission. The symptoms presented 4 months after transplantation, starting with cough, sputum, and dyspnea [4]. The initial chest radiograph demonstrated diffuse haziness and miliary nodules in both lungs and right pleural effusion. High-resolution chest CT showed diffuse miliary nodules and ground-glass opacities in both lungs, patchy consolidation in the left lower lobe, and right pleural effusion. Pulmonary function tests revealed a severe restrictive pulmonary defect and decreased transfer factor of the lung for carbon monoxide. The diagnosis of AFOP was obtained with the use of TBB. Despite different therapeutic attempts (broad-spectrum antibiotics, methylprednisolone pulse therapy), the patient died of respiratory failure after 61 days. Otto et al [6] reported a case of AFOP with concomitant influenza A/H1N1 pneumonia following lung transplantation. The patient suffered from end-stage pulmonary fibrosis and had received a double-lung transplantation. Four months after transplantation, she started complaining about persistent cough. Intubation was required owing to the rapid worsening of her respiratory conditions. A CT scan revealed bronchiectasis, consolidation, and increased bilateral diffuse pulmonary infiltrates with a ground-glass pattern in both lungs. Nasotracheal swabs were positive for viral influenza A/ H1N1 RNA according to reverse-transcription polymerase chain reaction results. Despite repeated therapeutic attempts (antibiotics, oseltamivir switched to zanamavir, prednisolone, and mycophenolate-mofetil), the patient developed acute renal failure and suspected heparin-induced thrombocytopenia type II. She ultimately died owing to
SUCCESSFUL LUNG RETRANSPLANTATION
rapidly progressive respiratory failure. The postmortem examination of the transplanted lungs revealed typical microscopic features of AFOP, which were especially evident in the lower parts. In the present case report, the patient presented with rapidly worsening dyspnea and an abrupt decline in lung function. To our knowledge, this is the 1st case of AFOP successfully treated with lung retransplantation. In our patient, the use of TBB did not allow a definite diagnosis of AFOP even though the pattern was consistent with organizing pneumonia. Nonetheless, organizing pneumonia with a patchy distribution is a typical AFOP-associated feature. Organizing pneumonia is characterized by the presence of endoluminal buds of granulation tissue (known as Masson bodies) which fill the alveoli and spread to the alveolar ducts and terminal bronchioles. However, the hallmark of AFOP is represented by the presence of intraalveolar plugs of fibrin deposition. In this scenario, it is possible that a definite diagnosis of AFOP can be obtained only by means of a surgical lung biopsy and/or histologic examination of the explanted lungs (as in our case). Beasley et al [1] initially described 2 distinct subtypes of AFOP: 1) a malignant form characterized by an aggressive clinical course, resistance to medical therapy, and a dismal prognosis; and 2) a subacute form associated with a more favorable clinical outcome. In our case, we faced the former subtype and lung retransplantation was required. AFOP is currently recognized as a specific histopathologic entity and has been included in the latest international classification of Idiopathic Interstitial Pneumonia released by the American Thoracic Society and the European Respiratory Society in 2013 [10]. It is classified as a rare idiopathic interstitial pneumonia with a typical histologic pattern. Despite some recent advances, AFOP remains a poorly understood condition that portends a dismal prognosis when presenting in its fulminant form. Some of such severe cases can complicate the clinical course of lung transplant recipients. Nonetheless, the
185
question as to whether AFOP may be a manifestation of acute lung rejection remains open. The present case demonstrates the feasibility of lung retransplantation in selected patients with fulminant AFOP. It should be noted, however, that our patient was young and in good general condition before the onset of this condition.
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