1 Introduction

Pulmonary alveolar proteinosis (PAP) is a rare disease, first reported by Rosen et al. in 1958 [1]. PAP is characterized by the abnormal accumulation of alveolar surfactant protein in alveolar spaces. PAP can be classified into 3 categories: congenital, idiopathic or primary, and secondary. These 3 subtypes comprise 2, 80, and 10% of PAP, respectively. PAP predominantly affects male sex with a male/female ratio of 2.65. The median age when a diagnosis of PAP is made is 39 [2]. A mutation in a gene encoding surfactant protein B or C, or a mutation in the βc chain of the receptor for the granulocyte macrophage colony-stimulating factor (GM-CSF) cause congenital PAP (cPAP). Idiopathic PAP (iPAP) is the most common form, believed to be an autoimmune disorder mediated by an antibody against GM-CSF. Indeed, in the blood of patients with iPAP, anti-GM-CSF antibody is detected at high levels. Smokers comprise a majority (72%) of patients with iPAP [3–6].

Secondary PAP (sPAP) develops in association with hematologic malignancies such as lymphomas and leukemias, viral or fungal infections, and with pulmonary damage caused by the inhalation of silica or titanium. The anti-GM-CSF antibody is not detectable in patients with sPAP or cPAP. The cause of sPAP is unclear; however, some malignancy-related factors that irritate pulmonary tissues and functional defects of alveolar macrophages have been suggested as causative factors [7, 8].

Clinical symptoms of PAP include exertional dyspnea, productive cough, and fever. The diagnosis of PAP is made based on the findings of chest X-ray, CT, bronchoalveolar lavage (BAL), and transbronchial lung biopsy (TBLB). Of these, pulmonary CT shows a characteristic feature, that is, a crazy-paving appearance, and the fluid obtained by BAL has a milky appearance and contains a large amount of surfactant protein. The histological picture of a TBLB specimen shows periodic acid-Schiff (PAS)-positive amorphous substances in the alveoli. In addition, serum levels of LDH, sialylated carbohydrate antigen KL-6 (KL-6) and surfactant protein D (SP-D), SP-A, and carcinoembryonic antigen are high in patients with PAP. The blood concentration of KL-6 is closely correlated with disease activity [2, 8–10].

We encountered a patient with myelodysplastic syndrome (MDS-RAEB by FAB classification) complicated by severe sPAP, and herein report successful allogenic bone marrow transplantation (BMT) for both disorders.

2 Case report

A 48-year-old male was diagnosed with myelodysplastic syndrome (MDS)-refractory anemia (MDS-RA by FAB Classification), because of the presence of thrombocytopenia, circulating myeloblasts, and an abnormal karyotype (47, XY, +8) of bone marrow cells, in January 2006. An allogeneic bone marrow transplantation (BMT) was planned because he required frequent platelet transfusions. He did not have an HLA-matched sibling donor, and so he registered with the Japan Marrow Donor Program (JMPD). A total body check before allogeneic BMT was performed in February 2007. On this occasion, there were no abnormal findings on chest X-ray, and we decided to perform BMT in May 2007. Just before BMT, he developed dyspnea and fever. Physically, fine crackles were audible in the bilateral back. Arterial blood gas analysis in room air revealed hypoxemia and hypocapnea. Chest X-ray showed opaque consolidation in the bilateral lower chest. Chest CT scanning showed diffuse ground-glass opacity with interlobular septal thickening, which is termed a crazy-paving pattern (Fig. 1). Spirometry revealed a lower normal ventilatory capacity with a tendency toward restriction (%VC = 91.2%, FEV1.0% = 83.99%). A pulmonary diffusing capacity test with carbon monoxide showed a low gas transfer capacity (%DLCO = 31.1). The effluent obtained by BAL demonstrated a milky appearance. The protein extracted from the BAL fluid was positive on PAS staining. Culture of the fluid for bacteria and fungus yielded negative results. Both Grocott–Gomori methenamine-silver staining and Pneumocystis carinii DNA analysis (PCR) were negative. TBLB was not performed because of the presence thrombocytopenia and a bleeding tendency. Serum levels of SP-D, SP-A, and KL-6 were markedly elevated to 200 ng/mL (normally below 110), 62.7 ng/mL (normaly below 43.8), and 3,115 U/mL (normally 0–499), respectively. Anti-GM-CSF antibody was not detected in the serum. Based on these findings, a diagnosis of PAP secondary to MDS was made.

Fig. 1
figure 1

X-ray image and thin-section, high-resolution CT scanning of the chest. a X-ray image when the patient developed sPAP (May 2007). b Scan when he developed sPAP, showing ground-glass opacity (crazy-paving pattern) (June 2007). c After whole lung lavage (WLL) (June 2007). d Scan 18 months after BMT (January 2009). Although pleural effusions in the bilateral lower lobes are seen, crazy-paving pattern has disappeared

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On day 14 after admission, his serum KL-6 concentration increased to 9,541 U/mL, and the arterial partial oxygen pressure decreased to 42.4 mmHg at ambient air. Therefore, whole lung lavage (WLL) was performed in combination with fresh plasma transfusions to correct the clotting deficiency. WLL was successfully performed with the satisfactory recovery of outflow fluid (15 L for the left lung, 22 L for the right) (Fig. 2). After WLL, his ventilation improved, although fever presumably due to pulmonary infection persisted. At this time, the MDS advanced to MDS-RAEB with white cell counts around 5 × 109/L and 10~38% myeloblasts.

Fig. 2
figure 2

Outfluids from whole lung lavage (WLL). a An Outfluid soon after the start of WLL. The fluid is highly opaque. b Outfluid at the end of WLL. The fluids are almost translucent

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Two months after WLL, his ventilation worsened again with a marked elevation of the serum KL-6 concentration to 3,665 U/mL; therefore, he was treated with a second WLL (15 L for the left lung, 21 L for the right) with a satisfactory recovery of the ventilatory capacity. The concentration of the KL-6 in the BAL fluid was 302,050 U/mL.

To improve both MDS and PAP, we performed allogeneic BMT in September 2007. The donor was an HLA full-matched unrelated donor. Reduced intensity condictioning (RIC) was employed, consisting of 45 mg of fludarabine for 5 consecutive days, 100 mg of L-PAM (melphalan) for 2 days, and 2 Gy of total body irradiation. GVHD prophylaxis was performed with tacrolimus and methylprednisolone (60 mg/day, intravenously). In September 2007, 2.14 × 109 donor marrow cells (of these, CD34-positive cells comprised 3.4 × 108/kg) were infused. From day 5 after BMT, 300 μg of G-CSF was administrated daily. Because he was continuously febrile, broad-spectrum antibiotics, amphotericin B, ganciclovir, and concentrated human IgG were administrated before and after BMT. Granulocytic engraftment was achieved on day 16 after BMT. The complete donor chimerism of bone marrow cells was confirmed by a PCR method on day 27. Grade I acute GVHD involving the skin developed, and was successfully treated with 25 mg of methylprednisolone. The clinical course before and after BMT is shown in Fig. 3.

Fig. 3
figure 3

Clinical course before and after BMT. WLL whole lung lavage; BMT bone marrow transplantation; CMV cytomegalovirus; bacteremia : bacteremia with Corynebacterium sp.; bacteremia : with Corynebacterium sp.; bacteremia : with Bacillus cereus

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On day 22, his dyspnea progressed, and a chest CT scan showed increased nodular opacities of the bilateral lungs. Therefore, a third WLL was performed on day 26 after BMT using an invasive ventilation procedure, with improvement of the arterial oxygen partial pressure and his general condition. On days 60–90 after BMT, serum SP-D, SP-A, and KL-6 levels were significantly decreased, and the crazy-paving pattern on chest CT had almost disappeared. As post-BMT complications, he had many infectious events including bacteremia with Bacillus cereus, Corynebacterium sp., Staphylococcus epidermidis, and fungemia with Trichosporon (Fig. 3); however, antibiotics or antifungal agents to respective microorganism were effective. He became free of red cell and platelet transfusions on days 106 and 108, respectively. He generally became afebrile from March 2008 with lower CRP levels (Fig. 3) and was discharged in September 2008. In outpatient department, he continued to follow a relatively favorable course and exhibited no signs or symptoms of PAP and MDS, although he sometimes had febrile episodes that were improved by oral antibiotics and antifungal agents. In April 2009, he developed septicemia with Enterococcus faecium and died in next month. On this occasion, chest CT scanning did not show the crazy-paving pattern.

3 Discussion

The modality of PAP treatment depends on the type of disorder. Lung transplantation is the only potentially curative treatment for cPAP, but, otherwise, supportive treatments such as oxygen inhalation are employed. For iPAP, WLL, plasmapheresis, or the inhalation of GM-CSF is performed, being effective for 40–60% of patients [2, 9–11]. On the other hand, the elimination of underlying disorders or causative agents may be optimal for sPAP. Therefore, hematopoietic stem cell transplantation (HSCT) has been attempted for some sPAP patients with hematologic malignancies. Although a number of patients with hematologic malignancies, who developed sPAP after HSCT has been reported [7, 12, 13], the number of transplanted patients who simultaneously had hematologic malignancies and sPAP is very few as shown in Table 1 [14–17]. As one of the causes of sPAP in MDS, functional impairment or reduced number of alveolar macrophages has been supposed [17]. Therefore, the rationale for employing HSCT to treat such patients with MDS complicated by sPAP lies in the elimination of MDS clone by the conditioning procedure and replacement of impaired alveolar macrophages with stem cell-derived normal macrophages. As the modality of HSCT for patients with sPAP-associated hematologic malignancies, RIC as employed in the present patient, may be desirable because of minimal pulmonary damage after RIC and subsequent lower risk of pulmonary infection after HSCT. Sufficient GVHD prophylaxis using tacrolimus or cyclosporine A and short-term methotrexate may be required to avoid further pulmonary damage caused by GVHD because pulmonary function of these patients had already been impaired by sPAP involvement.

Table 1 Patients with hematologic malignancies complicated by pulmonary alveolar proteinosis, who received HSCT reported in the literature
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The prognosis of transplanted patients, however, has generally been poor. Of 2 patients with sPAP-associated acute leukemia, who received allogeneic HSCT, only 1 patient survived for more than 12 months [14]. Of interest, one patient with AML-M5 with sPAP survived for more than 25 months after autologous peripheral HSCT [15]. An allo-transplanted patient with chronic myeloid leukemia complicated with sPAP reportedly died soon after allogeneic HSCT [16]. Regarding MDS complicated by sPAP, only 1 patient received cord blood HSCT and survived for more than 11 months [17]. Major causes of death in these allo-transplanted patients included invasive pulmonary aspergillosis and sepsis [14, 16], indicating that HSCT for patients with sPAP-associated hematologic malignancies is relatively risky because of susceptibility to infection and pulmonary dysfunction prior to HSCT.

In the present patient, the management of PAP employing repeated WLL may have contributed to the successful BMT. Prior to this treatment, we were afraid of the dissemination of infectious microorganism throughout the lungs, because the patient was febrile and exhibited high CRP levels. Despite this, the patient did not develop pneumonia or fever, and CRP levels declined after the procedure. In addition to dual WLL before BMT, we performed third WLL after BMT because of the worsening PAP. Because of a highly immunodeficient period, we again worried about severe pulmonary infection; however, the patient’s course was uneventful, and he showed an improvement of the respiratory function. Administration of broad-spectrum antibiotics, amphotericin B, ganciclovir, and concentrated human IgG, as described above, may have contributed to the prevention of life-threatening infection.

To our knowledge, WLL during HSCT for sPAP-associated hematologic malignancies conducted 3 times has not been reported. WLL, therefore, in our experience, can be safely performed for such patients, and should be taken into consideration as a conditioning procedure for HSCT. In addition, Chan et al. supposed indications of WLL for patients with PAP (at least one of the following); (1) resting PaO2 <65 mmHg (at sea level), (2) alveolar-arterial O2 gradient ≧40 mmHg, (3) measured shunt fraction >10–12%, (4) severe dyspnea and hypoxemia at rest or on exercise [18]. We performed WLL in each occasion in the present patient according to above criteria of 1, 2, and 4.