Improvement of native pulmonary alveolar proteinosis after contralateral single living-donor lobar lung transplantation: A case report.

PAP is a rare disease characterized by the accumulation of surfactant materials in the alveolar spaces due to the imbalance of surfactant homeostasis (production and clearance). We herein report a case of an 8-year-old girl who developed PAP after BMT from her mother for the treatment of DBA. The anemia was improved by BMT; however, respiratory dysfunction due to graft-versus-host disease gradually progressed. She eventually underwent right single LDLLT from her mother when she was 14 years old. A pathological examination of the excised lung confirmed the finding of diffuse bronchiolitis obliterans and unexpectedly revealed widespread alveolar proteinosis. Interestingly, the GGO of her native left lung on chest X-ray was improved after LDLLT. We present the very unique clinical course of this patient and discuss the mechanisms underlying the development of PAP after BMT and its improvement after LDLLT from the same donor.

Secondary pulmonary alveolar proteinosis: a single-center retrospective study (a case series and literature review).

BACKGROUND: Secondary pulmonary alveolar proteinosis (sPAP) is an extremely rare disease. The clinical features of sPAP patients remain to be summarizeds. METHODS: Patients pathologically diagnosed with PAP and with negative results for anti-granulocyte macrophage colony stimulating factor (GM-CSF) autoantibodies from Peking Union Medical College Hospital between January 2000 and July 2016 were retrospectively studied. The PubMed database was also searched for literature to collect published cases. RESULTS: In our center, nine patients were diagnosed as sPAP with a median age of 37 years. Hematological disorders, including myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), and pulmonary tuberculosis (TB) infection were the underlying diseases. Cases secondary to MDS had very poor prognosis as all of them survived less than 2 years after their diagnosis, while those secondary to TB had favorable prognosis. Only 33.3% of cases showed interlobular septal thickening in our sPAP group. Through literature review, 164 sPAP cases were collected. The age at diagnosis was 45.0 ± 14.8 years old and the gender radio was 1.20:1 (M:F). 61.9% of cases were diagnosed by bronchoscopy. MDS and CML were common underlying diseases in 34.1% and 15.2% of patients, respectively. Patients with sPAP secondary to hematological diseases had a short survival time and half of them died within 14.95 months after diagnosis. CONCLUSIONS: MDS and TB infection were the most frequent underlying causes of sPAP in this single-center research in China, with cases secondary to MDS having a poor survival rate. sPAP was more likely to be secondary to hematological disorders, especially MDS and CML and had a fairly poor prognosis in published cases. sPAP should be suspected in PAP patients whose CT scan presents only ground-glass opacities without interlobular septal thickening.

Secondary Pulmonary Alveolar Proteinosis Development during the Treatment for Anti-aminoacyl-tRNA Synthetase Antibody-positive Interstitial Lung Disease.

A 70-year-old woman with anti-aminoacyl-tRNA synthetase (ARS) antibody-positive interstitial lung disease (ARS-ILD) received daily medications and regular cyclophosphamide cycles for recurring exacerbations. Approximately four years after immunosuppression initiation, the patient was admitted for progressive dyspnea on exertion. Chest computed tomography (CT) findings were suggestive of acute exacerbation. Despite intensified immunosuppressive treatment, the radiographic findings worsened, and serum Krebs von den Lungen-6 (KL-6) levels increased. A bronchoalveolar lavage fluid (BALF) examination revealed amorphous globules and alveolar macrophages with eosinophilic granules. Owing to negative anti-GM-CSF antibody tests, a diagnosis of secondary pulmonary alveolar proteinosis (PAP) was established.

Autoimmune Pulmonary Alveolar Proteinosis Complicated by Myelodysplastic Syndrome: A Case Report.

Pulmonary alveolar proteinosis (PAP) is characterized by an abnormal surfactant accumulation in peripheral air spaces. Autoimmune PAP (APAP) results from macrophage dysfunction caused by anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, and the presence of antibodies more than the cutoff value is specific for APAP. In contrast, secondary PAP (SPAP) does not require anti-GM-CSF autoantibodies and is complicated by other diseases, including myelodysplastic syndrome (MDS). A 73-year-old man with anemia and thrombocytopenia was diagnosed with APAP and MDS simultaneously. The measurement of serum anti-GM-CSF autoantibodies is important for the correct diagnosis and management of PAP, even with an established diagnosis of underlying SPAP-suggestive disease.

Successful allogeneic hematopoietic stem cell transplantation for myelodysplastic neoplasms complicated with secondary pulmonary alveolar proteinosis and Behçet's disease harboring GATA2 mutation.

Myelodysplastic neoplasms (MDS) are defined by cytopenia and morphologic dysplasia originating from clonal hematopoiesis. They are also frequently complicated with diseases caused by immune dysfunction, such as Behçet's disease (BD) and secondary pulmonary alveolar proteinosis (sPAP). MDS with both BD and sPAP is extremely rare, and their prognosis is poor. In addition, haploinsufficiency of the hematopoietic transcription factor gene GATA2 is recognized as a cause of familial MDS and is frequently complicated by sPAP. Herein, we report a case of MDS combined with both BD and sPAP in association with GATA2 deficiency in a Japanese woman. Because she developed progressive leukopenia and macrocytic anemia during BD treatment at the age of 61, she underwent a bone-marrow examination and was diagnosed with MDS. She subsequently developed sPAP. At the age of 63, she underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Since allo-HSCT, she has maintained complete remission of MDS as well as the symptoms of BD and sPAP. Furthermore, we performed whole exome sequencing and identified the GATA2 Ala164Thr germline mutation. These findings suggest that patients with MDS, BD and sPAP should be considered for early allo-HSCT.

Secondary Pulmonary Alveolar Proteinosis Following Treatment with Azacitidine for Myelodysplastic Syndrome.

Secondary pulmonary alveolar proteinosis (sPAP) is a complication of myelodysplastic syndrome (MDS). A 60-year-old woman was diagnosed with MDS with excess blasts-1. Fifty-four months after the initial diagnosis, treatment with azacitidine was initiated. Seventy-three months after the diagnosis, a bone marrow examination revealed increased myeloblasts, at which time computed tomography showed diffuse ground-glass opacities and interlobular septal thickening in the bilateral lower lung fields. A lung biopsy revealed the presence of PAP; therefore, the clinical diagnosis of MDS/sPAP was confirmed. Careful attention should be paid to the development of sPAP in MDS patients with pulmonary lesions during azacitidine treatment.

Secondary pulmonary alveolar proteinosis treated by lung transplant: A case report.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a pulmonary disease characterized by disruption of surfactant homeostasis resulting in its accumulation in the alveoli. PAP is classically classified into three categories (Table 1): 1/primary (or autoimmune) with antibodies targeting the GM-CSF pathway, 2/secondary to another disease, typically a hematologic malignancy, and 3/genetic. CASE-REPORT: A 30 year-old woman received an allogenic hematopoietic stem cell transplantation (HSCT) after treatment for acute myeloid leukemia (AML). Within the first 6 months post HSCT, she developed an ocular, oral, digestive and hepatic graft-versus-host disease associated with a mixed ventilatory defect with a very severe obstructive syndrome and a severe CO diffusion impairment. High resolution computed tomography showed a classical "crazy paving" pattern. Aspect and differential cell count of BAL were normal. All microbiological samples remained culture negative. Histo-pathological analysis of transbronchial biopsies was unremarkable. Because of the severity of the respiratory insufficiency, open-lung biopsy (OBL) could not be performed. Despite multiple immunosuppressive therapies, lung function deteriorated rapidly; the patient also developed an excavated fungal lesion unresponsive to treatment. She underwent a bilateral lung transplant 48 months after HSCT. Histo-pathological analysis of explanted lungs showed obliterative bronchiolitis (OB), diffuse PAP and invasive cavitary pulmonary aspergillosis. CONCLUSIONS: This case illustrates the simultaneous occurrence of OB, PAP and a fungal infection in a 30-year old female patient who underwent HSCT for acute myeloid leukemia (AML). To our knowledge this is the only documented case of PAP associated with OB treated by lung transplantation.

Pulmonary alveolar proteinosis: time to shift?

Pulmonary alveolar proteinosis (PAP) is categorized into hereditary, secondary and autoimmune PAP (aPAP) types. The common pathogenesis is the ability of the alveolar macrophages to catabolize phagocytized surfactant is affected. Hereditary PAP is caused by mutations involving the GM-CSF signaling, particularly in genes for the GM-CSF receptor and sometimes by GATA2 mutations. Secondary PAP occurs in hematologic malignancies, other hematologic disorders, miscellaneous malignancies, fume and dust inhalation, drugs, autoimmune disorders and immunodeficiencies. aPAP is related to the production of GM-CSF autoantibodies. PAP is characterized morphologically by the inappropriate and progressive 'occupation' of the alveolar spaces by an excessive amount of unprocessed surfactant, limiting gas exchange and gradually exhausting the respiratory reserve. Myeloid cells' immunity deteriorates, increasing the risk of infections. Treatment of PAP is based on its etiology. In aPAP, recent therapeutic advances might shift the treatment option from the whole lung lavage procedure under general anesthesia to the inhalation of GM-CSF 'as needed'.

Secondary pulmonary alveolar proteinosis in hematologic malignancies.

Pulmonary alveolar proteinosis (PAP), characterized by deposition of intra-alveolar PAS positive protein and lipid rich material, is a rare cause of progressive respiratory failure first described by Rosen et al. in 1958. The intra-alveolar lipoproteinaceous material was subsequently proven to have been derived from pulmonary surfactant in 1980 by Singh et al. Levinson et al. also reported in 1958 the case of 19-year-old female with panmyelosis afflicted with a diffuse pulmonary disease characterized by filling of the alveoli with amorphous material described as "intra-alveolar coagulum". This is probably the first reported case of PAP in relation to hematologic malignancy. Much progress has been made on PAP first described by Rosen which is currently classified as idiopathic or primary or autoimmune PAP. Idiopathic PAP occurs as a result of auto-antibodies directed against granulocyte-macrophage colony stimulating factor (GM-CSF) impeding the surfactant clearing function of alveolar macrophages leading to progressive respiratory failure. Whole lung lavage and GM-CSF therapy has improved outcomes in patients with idiopathic PAP. Despite major advancement in the management of hematologic malignancy and its complications, little is known about the type of PAP first described by Levinson and now known as secondary PAP; a term also used when PAP occurs due to other causes such as occupational dusts. In this article we review and analyze the limited literature available in secondary PAP due to hematologic malignancies and present a case of PAP associated with chronic lymphocytic leukemia successfully treated with bendamustine and rituximab.

A case of secondary pulmonary alveolar proteinosis, but prior to myelodysplastic syndrome.

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder. We herein report the first case of PAP that happened 2 years before myelodysplatic syndrome (MDS). A 34-year-old Chinese presented with a developed recurrent cough and shortness of breath. Computed tomography scan disclosed ground-glass opacities with interlobular septal thickening. Histological examination showed eosinophilic dense homogenous material filling in the alveolar. This precipitate had a fine granular appearance. The eosinophilic material was periodic acid-Schiff reaction-positive. The patient was diagnosed with PAP. Two years later he was admitted to a hospital because of dizziness of 1-month duration. Hematological examination showed white blood cells was 2700, hemoglobin was 7.4 g/dL, and platelet count was 21,000 platelets/mm(3). Following bone marrow biopsy and histopathologic examination, he was diagnosed with MDS with refractory anemia and excess blasts. So for PAP patients, follow-up tests should be considered in order to find any possible underlying disease.