Pulmonary alveolar proteinosis (PAP) is a heterogeneous disease characterized by the accumulation of periodic acid-Schiff (PAS) stain-positive materials in the pulmonary alveolar space.1 PAP develops in association with other diseases such as hematological malignancies.2, 3 Here, we describe the first patient who showed the resolution of PAP after successful cord blood transplantation (CBT).
In 1995, a 36-year-old man presented with anemia and bleeding tendency. His complete blood count tests showed a white blood cell count of 2.8 × 109/l with neutrophils of 52%, hemoglobin concentration of 7.0 g/dl and platelet count of 23 × 109/l. Bone marrow (BM) examination showed hypercellularity without increase of myeloblasts. A diagnosis of myelodysplastic syndrome (MDS)-refractory anemia was made. In 2004, when he was 45 years old, he had become dependent on transfusion of red blood cells and platelets. In addition, myeloblasts in BM increased to 12%. He was considered as a candidate for hematopoietic stem cell transplantation (SCT). On pre-transplant examination in March 2005, chest computed tomographic (CT) scans revealed the diffuse small nodular opacities in the lungs (Figure 1a). He had no pulmonary symptoms. Arterial blood gas analysis showed PO2 of 83.5 mm Hg and PCO2 of 39.9 mm Hg. Pulmonary function tests showed forced vital capacity of 103.8% and forced expiratory volume in 1 s of 83.2%. Bronchoalveolar lavage fluid (BALF) showed a milky appearance, and contained macrophages of 91.6%, lymphocytes of 4.8%, and neutrophils of 3.6%. No infectious agents were detected. Transbronchial lung biopsy (TBLB) specimens revealed that the alveoli contained PAS-positive amorphous materials (Figure 2). Neutralizing autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) in the serum were not detected. These findings led to a diagnosis of PAP.
As he had no human leukocyte antigen (HLA)-matched BM donors, the patient underwent CBT from an unrelated male donor in June 2005. The cord blood (CB) donor had two antigen-mismatches in HLA-B and DR. The number of total nucleated cells in the CB unit before freezing was 2.36 × 107/kg. The conditioning regimen included 12 Gy total body irradiation, 120 mg/kg cyclophosphamide and 12 g/m2 cytarabine with the concomitant administration of recombinant human granulocyte colony-stimulating factor (G-CSF).4 Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. To facilitate neutrophil engraftment, 5 μg/kg/day G-CSF was administered intravenously from day +1 after CBT. On day +34, a neutrophil count consistently greater than 0.5 × 109/l was achieved. Complete donor chimerism of peripheral blood mononuclear cells was confirmed by using a polymerase chain reaction (PCR) method. Grade II acute GVHD involving the skin occurred, but was observed without steroid therapy. On day +40, preemptive therapy with ganciclovir was initiated for positive cytomegalovirus antigenemia. On day +49, he developed progressive exertional dyspnea. Chest CT scans on day +50 showed the increased nodular opacities of the left lung. BALF and TBLB specimens were again examined. A quantitative PCR analysis of the BALF specimen showed increased cytomegalovirus DNA of 600 copies/ml (normal, <200) and human herpesvirus-6 DNA of 50 000 copies/ml (normal, <200). Other infectious agents, including Candida, Aspergillus and Pneumocystis carinii, were not identified. TBLB specimens showed foamy macrophages together with fibrous tissues in the alveoli. PAS-positive amorphous materials were not observed in the specimens. Together with ganciclovir administration, steroid therapy with 2 mg/kg/day prednisolone was initiated on day +53, which soon led to remarkable improvement of hypoxia. Chest CT scans on day +64 showed that the nodular opacities of the left lung partially resolved. In addition, the diffuse small nodular opacities in the both lungs also tended to resolve. From day +67, the dose of prednisolone was gradually reduced. Chest CT scans 5 months after CBT showed almost complete resolution of the diffuse small nodular opacities in the lungs (Figure 1b). At the last follow-up evaluation at 11 months post-CBT, the patient was well and exhibited no signs and symptoms of PAP and MDS.
PAP is a heterogeneous disease classified into three clinically distinct forms: congenital, acquired and secondary.1 Secondary PAP develops in association with conditions involving functional impairment or reduced numbers of alveolar macrophages which can cause the decreased clearance of the surfactant proteins. Such conditions include hematological malignancies.2, 3 In addition, secondary PAP rarely occurs in patients after SCT. Cordonnier et al.2 reported two patients with chronic myelogenous leukemia (CML) and one patient with acute lymphoblastic leukemia who developed PAP during the neutropenic period after allogeneic bone marrow transplantation (BMT). We5 and Butnor et al.6 also reported two patients with acute myelogenous leukemia (AML) who developed PAP during the neutropenic period after CBT.
Previous reports have indicated that the prognosis of secondary PAP occurring during neutropenia is very poor because of high frequency of super-infections in the affected lungs. Impaired function of alveolar macrophages may be directly and indirectly associated with the high risk of infections.1 According to the study by Cordonnier et al.,2 two of three patients who developed PAP after BMT died of respiratory failure. In other studies by us5 and Butnor et al.,6 two patients who developed PAP after CBT also died of multi-organ failure, respectively. These results suggest that patients with PAP occurring after SCT have a high risk of organ failure as well as infections.
Secondary PAP in association with hematological malignancy can be improved after remission of an underlying disease.2 Dirksen et al.7 reported that allogeneic BMT for a patient with AML successfully led to remission of secondary PAP. In our patient, elimination of MDS clone by a myeloablative conditioning regimen and replacement of impaired alveolar macrophages with CB stem cell-derived normal alveolar macrophages might correct the pathology of PAP. However, the safety and efficacy of CBT for patients with PAP should be further investigated.
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Cordonnier C, Fleury-Feith J, Escudier E, Atassi K, Bernaudin JF . Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemia patients. Am J Respir Crit Care Med 1994; 149: 788–794.
Seymour JF, Begley CG, Dirksen U, Presneill JJ, Nicola NA, Moore PE et al. Attenuated hematopoietic response to granulocyte-macrophage colony-stimulating factor in patients with acquired pulmonary alveolar proteinosis. Blood 1998; 92: 2657–2667.
Takahashi S, Iseki T, Ooi J, Tomonari A, Takasugi K, Shimohakamada Y et al. Single-institute comparative analysis of unrelated bone marrow transplantation and cord blood transplantation for adult patients with hematologic malignancies. Blood 2004; 104: 3813–3820.
Tomonari A, Shirafuji N, Iseki T, Ooi J, Nagayama H, Masunaga A et al. Acquired pulmonary alveolar proteinosis after umbilical cord blood transplantation for acute myeloid leukemia. Am J Hematol 2002; 70: 154–157.
Butnor KJ, Sporn TA . Human parainfluenza virus giant cell pneu-monia following cord blood transplant associated with pulmonary alveolar proteinosis. Arch Pathol Lab Med 2003; 127: 235–238.
Dirksen U, Hattenhorst U, Schneider P, Schroten H, Gobel U, Bocking A et al. Defective expression of granulocyte-macrophage colony-stimulating factor/interleukin-3/interleukin-5 receptor common β chain in children with acute myeloid leukemia associated with respiratory failure. Blood 1998; 92: 1097–1103.
We thank Maki Monna-Oiwa for her secretarial assistance. We also thank the Kobayashi Foundation for financial support.
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