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Pulmonary Alveolar Proteinosis After Allogeneic Hematopoietic Stem-Cell Transplantation in Adults

A French Société Francophone de Greffe de Moelle et Thérapie Cellulaire Survey
      To the Editor:
      Pulmonary alveolar proteinosis (PAP) is related to a dysfunction in surfactant clearance by alveolar macrophages.
      • Trapnell B.C.
      • Nakata K.
      • Bonella F.
      • et al.
      Pulmonary alveolar proteinosis.
      It can be autoimmune (aPAP) due to anti-granulocyte-colony stimulating factor (GM-CSF) autoantibodies, hereditary, in relation with mutations in genes coding for subunits of the GM-CSF receptor or surfactant proteins, or secondary (sPAP) to hematologic diseases or environmental or drug exposure that alters alveolar macrophage functions.
      • Ishii H.
      • Seymour J.F.
      • Tazawa R.
      • et al.
      Secondary pulmonary alveolar proteinosis complicating myelodysplastic syndrome results in worsening of prognosis: a retrospective cohort study in Japan.
      We conducted a national survey with the help of French Society of Bone-Marrow Transplantation and Cellular Therapy that questioned the 43 French hematopoietic stem cell transplantation (HSCT) centers about adult-onset PAP after allogeneic hematopoietic stem-cell allograft. Five cases, diagnosed between January 2016 and June 2019, were retrieved from four distinct centers (Saint-Louis, Pitié-Salpétrière and Saint-Antoine hospital, Paris; University hospital of Poitiers). This retrospective study was approved by the research ethical committee of Foch Hospital (Institutional Review Board: No. 00012437). Medical charts and radiologic data were analyzed, and a centralized reviewing of BAL cytologic findings (including a periodic acid-Schiff [PAS] staining) was conducted in Foch hospital. The patients’ characteristics and PAP features are summarized in Table 1.
      Table 1Patient Clinical Characteristics
      CharacteristicPatient 1Patient 2Patient 3Patient 4Patient 5
      Age, y6466376930
      SexMaleFemaleFemaleFemaleMale
      Smoking statusActiveFormerNeverPassiveActive
      Hematologic diseaseAcute myeloid leukemiaMyelodysplasiaAcute myeloid leukemiaChronic lymphocytic leukemiaAcute myeloid leukemia
      Year of graft20162013201720132012
      Type of graftPeripheral stem cellsPeripheral stem cellsPeripheral stem cellsPeripheral stem cellsBone marrow
      DonorMismatched unrelated donorIdentical siblingMatched unrelated donorMatched unrelated donorMatched unrelated donor
      Conditioning regimen intensity

      type
      Myeloablative conditioning busulfan, fludarabineMyeloablative conditioning busulfan, fludarabine, antithymocyte globulinMyeloablative conditioning busulfan, fludarabineReduced-intensity conditioning busulfan, fludarabine, antithymocyte globulinMyeloablative conditioning busulfan, fludarabine
      Time between hematopoietic stem-cell transplantation and PAP, d30120045814602190
      Chronic graft vs host disease at time of PAP diagnosisNoneCutaneous sclerodermiformCutaneous liverCutaneous sclerodermiform liverCutaneous sclerodermiform
      Immunosuppressive regimen at time of PAP diagnosisCiclosporin mycophenolate mofetilCorticosteroids, ciclosporin, methotrexate, ruxolitinib, extracorporeal photochemotherapyRuxolitinib, extracorporeal photochemotherapyCorticosteroids, sirolimus (Rapamune), extracorporeal photochemotherapyCorticosteroids, sirolimus (Rapamune), ibrutinib, methotrexate, extracorporeal photochemotherapy
      Hematological status at time of PAP diagnosisAllograft rejection prolonged aplasiaRemission chimerism 100% donorRemission chimerism 100% donorRemission chimerism 100% donorRemission chimerism 100% donor
      Clinical presentationAcute fever, cough, dyspnea at rest, oxygen supplyProgressive slowly increasing dyspnea on exertion

      secondarily worsening with fever and acute respiratory failure
      AsymptomaticProgressive slowly increasing dyspnea on exertion that led to oxygen supply requirementProgressive mild dyspnea on exertion
      Main radiologic featuresDiffuse ground glass opacities, interlobular septal thickening, subpleural reticulations, predominant in lower lobesPatchy ground glass opacities, crazy paving, interlobular septa thickening, subpleural reticulations, predominant in upper lobesPatchy ground glass opacities, interlobular septa thickening, subpleural reticulations, predominant in lower lobesPatchy ground glass opacities, crazy paving, interlobular septa thickening, subpleural reticulations, predominant in upper lobesPatchy ground glass opacities, crazy paving, subpleural reticulations, alveolar condensation, predominant in upper lobes
      Pulmonary function test
       FVC, % theoryND111959971
       FEV1, % theory988411865
       Diffusing capacity of the lung for carbon monoxide, % theory45464754
      Promoting factor for PAPGraft rejectRuxolitinibRuxolitinibSirolimus (Rapamune)Sirolimus (Rapamune)
      Granulocyte macrophage–colony-stimulating factor auto antibodyNegativeNegativeNot doneNegativeNot done
      GATA2 mutationNegativeNegativeNot doneNot doneNot done
      ManagementCorticosteroids 1 mg/kg/d,

      second transplantation
      Ruxolitinib cessationCorticosteroids 0.5 mg/kg/d, ruxolitinib cessationSirolimus (Rapamune)cessationSirolimus (Rapamune)cessation
      Concomitant respiratory infectionCoronarovirus OC43Mycobacterium abscessusNoneNoneNone
      Duration of follow-up, mo28,

      Alive
      36,

      Alive
      9,

      Alive
      32,

      Alive
      17,

      Alive
      cGVHD = chronic graft vs host disease; CS = corticosteroids; GATA2 = GATA binding protein 2; GGO = ground glass opacities; HSCT = hematopoietic stem cell transplantation, MAC = myeloablative conditioning; MMUD = mismatched unrelated donor; MUD = matched unrelated donor; PAP = pulmonary alveolar proteinosis; RIC = reduced-intensity conditioning, TLCOc = diffusing capacity of the lung for carbon monoxide.
      Patient 1 was experiencing an engraftment failure when he presented acute respiratory symptoms and new interstitial images on thoracic CT scan. The BAL fluid was milky, enclosing altered macrophages, numerous debris, and PAS-stained extracellular material. He received a second haploidentical allograft concomitantly with high dose of corticosteroids. After a correct engraftment, the aplasia recovered, and the respiratory symptoms simultaneously greatly improved. Three months later, he had totally recovered with limited remaining subpleural reticulations and small bronchiectasis on CT scan.
      Patient 2 was receiving a combined treatment regimen that included ruxolitinib (20 mg/d) for a chronic graft vs host disease (cGVHD) when she experienced an insidious dyspnea, accompanied with a drop in her pulmonary functional test (PFT) results and new pulmonary images on CT scan.
      • Salvator H.
      • Berti E.
      • Catherinot E.
      • et al.
      Pulmonary alveolar proteinosis and Mycobacterium abscessus lung infection related to ruxolitinib after allogeneic stem cell transplantation.
      A first BAL fluid analysis was unremarkable, but the PAS staining was not assessable. The diagnosis of PAP was made on histologic analysis of video-assisted thoracoscopic lung biopsies that showed PAS-positive intra- eosinophilic proteinaceous granular material (Fig 1) and positive in culture for Mycobacterium abscessus. Due to a sudden decline in clinical status and blood cytopenia, antibiotics were started, and ruxolitinib was withdrawn. The clinical course was rapidly favorable, and the patient was weaned from oxygen. Four months later, her thoracic CT scan and PFTs were greatly improved.
      Figure thumbnail gr1
      Figure 1A-F, Histopathologic and cytopathologic findings on pulmonary biopsy and BAL fluid. A-B, Immunohistochemistry on lung biopsy specimen of patient 2 shows extracellular eosinophilic proteinaceous granular material (A, hematoxylin and eosin stain; original magnification, ×20; B, positive on periodic acid-Schiff stain; original magnification, ×20). C-D, BAL of patient 5 shows typical cytologic features of pulmonary alveolar proteinosis (C, extracellular grey deposit on May Grunwald Giemsa stain; original magnification, ×20; D, with positive staining with periodic acid-Schiff; original magnification, ×20). E-F, BAL of patient 3 at time of pulmonary alveolar proteinosis diagnosis, disclosing foamy and altered macrophages, cellular debris (E, May Grunwald Giemsa stain; original magnification, ×20; F, extracellular periodic acid-Schiff + material; periodic acid-Schiff stain; original magnification, ×20).
      Patient 3 was receiving ruxolitinib for a cGVHD for 8 months when a drop in her PFT values was observed and new radiologic anomalies appeared on thoracic CT scan, even though she was denying any respiratory symptoms. The BAL fluid was opalescent and disclosed 190,000 cells/mL with 78% altered macrophages, numerous debris, and PAS positive extracellular materiel (Fig 1). Ruxolitinib was replaced by mycophenolate mofetil with mild doses of prednisone. PFT values and thoracic CT scan showed improvement as soon as 2 months later.
      Patient 4 had received corticosteroids and sirolimus for 2 years for a cGVHD when he experienced a slowly increasing dyspnea. Thoracic CT scan anomalies were evocative of PAP features. The BAL fluid was milky, and cytologic analysis showed 90% macrophage, granular PAS positive cytoplasmic material and extracellular deposits. Sirolimus was withdrawn, and respiratory functional signs quickly improved. Ten months later, all the radiologic features that had suggested PAP had disappeared, and PFTs were within normal values.
      Patient 5 experienced a chronic severe cutaneous GVHD that required successive treatments including sirolimus and ibrutinib. He started complaining of mild dyspnea on exertion; a thoracic CT scan disclosed the apparition of new pulmonary anomalies. Despite ibrutinib withdrawal, his status dramatically had worsened 1 year later. The BAL fluid was milky, and cytologic analysis showed 90% of macrophages, PAS positive intracytoplasmic material, and extracellular deposits (Fig 1). Sirolimus was withdrawn, and the respiratory status normalized within 1 year.
      In the main, we report the largest cohort of sPAP occurring in adults in the aftermath of an allogeneic HSCT and the integrality of the cases declared in France between 2016 and 2019. These cases split into two distinct clinical situations: early acute PAP that occurred during the aplasia period (patient 1) and late onset progressive PAP related to a highly suggested drug-induced macrophage dysfunction (patients 2, 3, 4, and 5). Only a few reports have focused on sPAP in recipients of an allogeneic HSCT,
      • Ansari M.
      • Rougemont A.-L.
      • Le Deist F.
      • et al.
      Secondary pulmonary alveolar proteinosis after unrelated cord blood hematopoietic cell transplantation.
      • Cordonnier C.
      • Fleury-Feith J.
      • Escudier E.
      • Atassi K.
      • Bernaudin J.F.
      Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients.
      • Tomonari A.
      • Shirafuji N.
      • Iseki T.
      • et al.
      Acquired pulmonary alveolar proteinosis after umbilical cord blood transplantation for acute myeloid leukemia.
      • Pidala J.
      • Khalil F.
      • Fernandez H.
      Pulmonary alveolar proteinosis following allogeneic hematopoietic cell transplantation.
      mostly dealing with early sPAP in the context of profound leukopenia.
      PAP diagnosis after allogeneic HSCT can be challenging because of its lack of specificity in clinical and radiologic features. Lung biopsy is considered to be the gold standard, but the use of a less invasive procedure is to be preferred in highly immunocompromised patients. Because extracellular deposits that exhibit PAS staining are the hallmark of PAP, a wider use of PAS staining in BAL obtained from patients after HSCT might avoid the need for lung biopsy.
      Ruling out recurrence of the hematologic affection, the presence of anti-GM-CSF autoantibodies and GATA2 mutation is essential.
      • Griese M.
      • Zarbock R.
      • Costabel U.
      • et al.
      GATA2 deficiency in children and adults with severe pulmonary alveolar proteinosis and hematologic disorders.
      A systematic review of patient medications should be performed, and the temporal relationships between PAP onset and a specific medication should be investigated carefully. Numbers of drugs have been linked to the occurrence of PAP,
      • Salvator H.
      • Berti E.
      • Catherinot E.
      • et al.
      Pulmonary alveolar proteinosis and Mycobacterium abscessus lung infection related to ruxolitinib after allogeneic stem cell transplantation.
      ,
      • Pedroso S.L.
      • Martins L.S.
      • Sousa S.
      • et al.
      Pulmonary alveolar proteinosis: a rare pulmonary toxicity of sirolimus.
      ,
      • Sugiura H.
      • Nishimori H.
      • Nishii K.
      • et al.
      Secondary pulmonary alveolar proteinosis associated with primary myelofibrosis and ruxolitinib treatment: an autopsy case.
      whether they directly disrupt intracellular signaling pathways or induce genetic alterations that contribute to alveolar macrophages dysfunction. PAP occurrence was suspected to be induced by rapamycin in patients 4 and 5 and by ruxolitinib in patients 2 and 3. It makes sense because ruxolitinib inhibits Janus Kinase 1/2, which is essential for GM-CSF signaling in macrophages.
      The outcome of the PAP was favorable once the promoting factor was managed (second graft, withdrawal of the suspected drug). The role of corticosteroids in PAP resolution is uncertain, but rather unlikely (three of five patients totally recovered without the need for corticosteroids). Our observations are in line with the findings of Cordonnier et al
      • Cordonnier C.
      • Fleury-Feith J.
      • Escudier E.
      • Atassi K.
      • Bernaudin J.F.
      Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients.
      who described reversibility of PAP in five of 10 patients with secondary hematologic PAP after HSCT. The occurrence of a PAP should not limit further medical commitment and even might imply more aggressive treatment to achieve hematologic remission, up to HSCT indication.
      Secondary PAP is an uncommon event after HSCT that occurs in the aplasia period or is drug-induced. BAL analysis with PAS staining is the essential diagnostic procedure and should be performed systematically.

      Acknowledgments

      Author contributions: H. Salvator takes responsibility for the content of the manuscript; she designed the study, analyzed the data, and wrote the manuscript. L-J. Couderc designed the study and wrote the manuscript. C. Tcherakian , E. Catherinot, C. Givel, A. Chabrol, and C. Goyard revised the manuscript. S. Milin, S.M. Evrard, A. Fajac, V. Meignin, E. Longchampt, and J-F. Bernaudin performed cytologica analysis of bronchoalveolar fluid and histologic analysis of lung specimen. N. Maillard, S.N Guyen, L. Souchet, S. Sestili, A. Bergeron, L. Bondeelle, M.T. Rubio, M. Robin, and E. Brissot collected data. M-L. Chabi-Charvillat performed radiologic analysis. All authors read and approved the final manuscript.

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