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Jan 10, 2011 - infectious etiologies, idiopathic pneumonia syndrome and diffuse alveolar hemorrhage, have been ruled out. This case also suggests particular ...

Bone Marrow Transplantation (2011) 46, 1480–1483 & 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11



Pulmonary alveolar proteinosis following allogeneic hematopoietic cell transplantation Bone Marrow Transplantation (2011) 46, 1480–1483; doi:10.1038/bmt.2010.321; published online 10 January 2011 Pulmonary alveolar proteinosis (PAP) is a rare diffuse pulmonary disease characterized by the accumulation of periodic acid-Schiff (PAS)-positive lipoproteinaceous material, primarily phospholipid surfactant and surfactant apoproteins in the distal air spaces.1 The underlying etiopathogenesis is incompletely elucidated, but evidence suggests a central role for GM-CSF and macrophage function.2–7 Congenital, autoimmune and secondary forms have been described. Congenital PAP has been described to result from inherited mutations in genes for surfactant, or the GM-CSF receptor. An autoimmune form has been attributed to anti-GM-CSF Abs that undermine macrophage function.8 Finally, secondary PAP has been reported following diverse conditions, including toxic inhalation and associated pneumoconioses, infections such as Pneumocystis jirovecii, viral infections, or Nocardia, and both hematologic malignancies and post-hematopoietic cell transplantation (HCT) for hematologic malignancies.9–15 Dyspnea and cough predominate in the clinical presentation, whereas some cases may be discovered radiographically in the absence of symptoms. Radiographic imaging commonly demonstrates diffuse bilateral alveolar opacities, with a predilection for the central middle and lower lung, and high-resolution computed tomography scan (CT) demonstrates diffuse ground-glass opacity; typical radiographic findings seen in autoimmune PAP may not be seen in secondary PAP.16 Samples from bronchoalveolar lavage (BAL) demonstrate opaque or milky appearance, and cytologic findings include alveolar macrophages containing PAS-positive material. Definitive diagnosis is made by pathologic examination of lung biopsy, confirming the presence of PAS-positive material in the terminal bronchioles and alveoli. Serum or BAL anti-GM-CSF titer has been reported to have high diagnostic accuracy for autoimmune PAP. There have been few reports of secondary PAP being associated with hematologic malignancies and even less specifically after HCT. We report, herein, a case of secondary PAP following allogeneic HCT for CML. A 40-year-old woman was originally diagnosed with CML in chronic phase in July 2007. Her initial presentation was notable for constitutional symptoms, splenomegaly and the following hematologic parameters: total WBC count of 250 000, hemoglobin 11.7 g/dL and platelet count of 225 000. BM biopsy demonstrated a hypercellular marrow, 10% myeloid blasts, 5% basophils and the cytogenetic

finding of t(9:22). Initial leukoreduction was achieved with hydroxyurea, and she was treated thereafter with imatinib 600 mg daily. With disease progression to accelerated phase, therapy was changed to dasatinib 70 mg twice daily. Anagrelide was also utilized to control progressive thrombocytosis. Clonal evolution was demonstrated with the development of trisomy8 on BM cytogenetics. Given disease progression, she was referred for allogeneic HCT. Other past medical history was notable for an B12 pack  year smoking history. Pre-HCT pulmonary function tests demonstrated the following: forced vital capacity 105%, forced expiratory volume in 1 second 112% and diffusion capacity carbon monoxide 64% of predicted values, respectively. High-resolution chest CT did not demonstrate any pulmonary parenchymal abnormalities. In April 2008, she received conditioning therapy with fludarabine 40 mg/m2 for four consecutive daily doses (days 6 through 3), each followed by i.v. BU. The initial dose of BU was 145 mg/m2, and dose adjustment was performed based on pharmacokinetic studies to achieve a target AUC of 5300 mmol/min for each of the 4 days. She received an infusion of allogeneic peripheral blood-mobilized stem cells from a 10/10 HLA-matched unrelated donor, with a total CD34 þ cell dose of 10  106. Immune suppression consisted of tacrolimus targeted to therapeutic levels of 10–15 ng/mL, and MTX delivered on days 1, 3, 6 and 11 after HCT. Immediate post-HCT complications included grade 2 mucositis and nausea. Additional postHCT complications included the following: biopsy-proven acute GVHD of the gastrointestinal tract in July 2008 requiring therapy with 1 mg/kg of glucocorticoids, followed by a tapering course, mycophenolate mofetil and sirolimus; multiple complications from steroid therapy including proximal myopathy, weakness, osteopenia and hypertension; and bilateral pulmonary emboli treated with systemic anticoagulation, later replaced by an inferior vena cava filter because of the bleeding risk associated with weakness and multiple falls. Through the duration of follow-up, her CML remained in sustained complete molecular remission. In October 2009, she presented with unexplained progressive exertional dyspnea and non-productive cough. She had no fever and no upper respiratory symptoms. Clinical examination was notable for decreased breath sounds bilaterally, tachypnea and an oxygen saturation of 96% without supplementation. Echocardiogram confirmed normal systolic function with an ejection fraction of 60% and no other abnormalities. High-resolution chest CT demonstrated extensive ground-glass opacity throughout the chest, with scattered small nodular densities.

Letter to the Editor


Bronchoscopy with BAL was performed, with lavage samples notable for their opaque, milky character. BAL fluid cytology demonstrated reactive bronchial cells and proteinaceous debris, but did not detect PAS-positive material-engorged macrophages. Anti-GM-CSF titer was not performed. Broad-spectrum antibiotics were initiated on presentation. No BAL cultures (bacterial, viral, fungal, pneumocystis and nocardia) showed an infection. She was discharged with supplemental oxygen after her acute dyspnea improved, but returned in November 2009 with a further clinical decline notable for worsened dyspnea, cough and hypoxia (arterial blood gas on 10 L supplemental oxygen: pH 7.46, pO2 55, pCO2 48 and O2 saturation 88%). High-resolution chest CT again demonstrated extensive bilateral ground-glass attenuation, with interval progression from the previous study. Over the 14-day hospital admission, her oxygenation worsened, requiring bilevel positive airway pressure support; with FiO2 of 50–60%, PaO2 on serial arterial blood gases ranged from 104 to 150 mm Hg. Immune suppression, including systemic mycophenolate mofetil and sirolimus, was continued. Prednisone was increased from 17.5 mg daily on admission to a maximum of 30 mg daily. No other additional immune suppressive agents were added in this setting. Ultimately, she underwent flexible fiberoptic bronchoscopy with right thoracoscopy and lung biopsy; wedge resection of the right middle, upper and lower lobes was performed. Gross examination revealed spongy, tan-red surface and parenchyma. Microscopic examination confirmed viable lung tissue with extensive involvement with PAS-positive alveolar proteinaceous material from the right middle, upper and lower lobe wedge resection samples (Figures 1 and 2). There was no evidence of recurrent malignancy, infection or alternate etiology. In ongoing follow-up after discharge, she demonstrated clinical improvement with amelioration of her dyspnea, ongoing functional recovery and gradual weaning of supplemental oxygen. By the time of discharge, oxygen saturation was 94–97% on 2 L nasal canula. Additionally, repeated highresolution chest CT performed B3 weeks later demonstrated improved aeration of the lungs, but persistent ground-glass opacities. Given this trajectory of recovery, whole lung lavage was deferred. Experimental therapies such as GM-CSF, plasmapheresis or rituximab were not considered. By her last clinic visit, she had an oxygen saturation of 97% on room air. Despite her overall pattern of clinical recovery on follow-up, she expired suddenly at home, with no confirmation of cause of death at B22 months after HCT. PAP is a rare diffuse pulmonary disease characterized by the accumulation of alveolar proteinaceous material associated with characteristic clinical and radiographic findings. Secondary PAP associated with hematologic malignancies and HCT represents a minority of the overall burden of this disease, but it is an important diagnostic and therapeutic concern to hematologists and transplant physicians. Previous reports have identified secondary PAP associated with hematologic malignancies including myelodysplastic syndrome,9 pediatric leukemia11 and CML.13 Others have reported secondary PAP following

Figure 1 Hematoxylin and eosin-stained section of lung shows alveoli containing amorphous, eosinophilic precipitate in lumina consisting of type II pneumocytes, lamellar bodies and necrotic alveolar macrophages.

Figure 2 The precipitate derived from surfactant phospholipids and protein components stains positive for PAS.

autologous transplantation,14 cord blood transplantation15 and cord blood transplantation and in association with parainfluenza virus 3.10 We report a case of secondary PAP following allogeneic HCT for CML. From this case, several questions emerge. First, there is uncertainty in the underlying biology of post-HCT PAP. It has been speculated that macrophage dysfunction or deficient numbers of macrophages during periods of pronounced granulocytopenia after conditioning therapy may permit the accumulation of phospholipid surfactant and surfactant apoproteins. Alternatively, abstracting from allied data in autoimmune PAP where antiGM-CSF Abs appear to have a central role, one could also surmise that donor–host alloimmunity could similarly manifest, leading to PAP. Interestingly, post-HCT PAP developed in this case in the absence of any clinically apparent GVHD and under the global immune suppression Bone Marrow Transplantation

Letter to the Editor


mediated by glucocorticoids, mycophenolate mofetil and sirolimus. As an anti-GM-CSF Ab titer was not examined in serum or BAL fluid in this case, we cannot elaborate further. Interestingly, there have been cases in which transplantation—including autologous HCT for acute myelogenous leukemia12 and cord blood allogeneic HCT for myelodysplastic syndrome17—has been reported to successfully treat PAP associated with hematologic malignancies. Prolonged remission from PAP has been reported in these cases after HCT, but further conclusions are limited, particularly as PAP can have a self-limited course irrespective of therapy. These cases may have resolved in the absence of HCT. This case is instructive, as it identifies an important consideration for hematologists and transplant physicians in the differential diagnosis of diffuse alveolar processes when the more common considerations after HCT, such as infectious etiologies, idiopathic pneumonia syndrome and diffuse alveolar hemorrhage, have been ruled out. This case also suggests particular challenges in the diagnostic evaluation of PAP post-HCT: Bronchoscopy and BAL may be instructive; however, PAS-positive material-laden macrophages were not seen in this case. BAL and serum anti-GM-CSF titer also have excellent reported diagnostic accuracy in literature examining idiopathic PAP, but not secondary PAP.18,19 Ultimately, diagnosis may require lung biopsy, which imposes potentially significant risk to HCT recipients. Consideration should be given to transbronchial biopsy, as this may be diagnostic.20 Thus, decisions in the diagnostic approach to this condition require careful consideration of associated risks and potential benefits. Another major area of uncertainty is the optimal therapeutic approach for secondary PAP after transplantation. Even in cases of congenital or autoimmune PAP, the natural history is heterogeneous. As some may experience self-limited disease, decisions about timing of intervention are difficult; however, spontaneous resolution in alveolar proteinosis is relatively rare.21 Expert opinion suggests initiating therapy for those with severe clinical and physiologic abnormalities. There is also relatively limited quality evidence in support of major therapeutic options, such as whole lung lavage,22 and even less evidence in support of experimental interventions, such as GM-CSF, plasmapheresis or rituximab.23–25 These limitations are even more pronounced in the consideration of therapy for post-HCT secondary PAP. Several difficult questions remain, including the following: Is it appropriate to adapt proposed treatment thresholds and therapeutic modalities from allied PAP literature to the setting of post-HCT PAP? Is whole lung lavage feasible and safe post-HCT? Is there a role for other experimental therapies in post-HCT PAP? Excluding other competing mortality threats post-HCT, can one adopt prognostic estimates from allied PAP literature in the setting of post-HCT PAP? Answers to all of these questions are constrained by the rarity of this condition.

Conflict of interest The authors declare no conflict of interest. Bone Marrow Transplantation

J Pidala1,3, F Khalil2,3 and H Fernandez1,3 Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA; 2 Department of Pathology, Moffitt Cancer Center, Tampa, FL, USA and 3 Department of Oncological Sciences, University of South Florida, Tampa, FL, USA E-mail: [email protected]fitt.org


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