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

Pulmonary alveolar proteinosis (PAP), a rare disease with an estimated prevalence of 3.7 to 6.2 cases per million persons [1, 2], is characterized by the accumulation of lipoprotein material in alveoli and terminal respiratory airways [3]. Current knowledge about PAP is based on case studies and individual case reports, and as such, the prevalence of PAP may vary due to differences in medical systems and facilities in different countries. According to the pathogenesis, PAP can be classified in three ways: congenital PAP, secondary PAP (sPAP) and autoimmune PAP (or acquired PAP, or idiopathic PAP) [4]. sPAP mainly develops as a result of hematological diseases, the use of immunosuppression drugs, dust inhalation and certain chronic infections with impaired alveolar macrophage function. Autoimmune PAP, which accounts for over 90% of PAP cases, is an autoimmune disease with autoantibodies targeting granulocyte macrophage colony stimulating factor (GM-CSF) [5].

According to previous reports, sPAP is different from autoimmune PAP in aspects besides the pathogenesis. For example, sPAP has different features on high-resolution computed tomography (HRCT) compared to autoimmune PAP [6] and sPAP has a much poorer prognosis compared with autoimmune PAP [7]. Knowledge of the clinical characteristics of sPAP are still limited as the majority of current literature is in the form of case reports, the largest series being a report by Ishii H which included 40 Japanese patients [7]. As we do not know whether the prevalence of sPAP in China has any differences compared to other countries, we retrospectively collected sPAP patients hospitalized from 2000 to 2016 in our hospital, listed their clinical features and symptoms, and we also reviewed all published cases in literature to learn more about the characteristics of sPAP around the world.

Since sPAP is a rare disease, less than 200 cases have been reported throughout the world, with most of them in form of case reports. H. Ishii [7] summarized the characteristics of 40 Japanese sPAP patients, which was the largest retrospective observational study about sPAP that we found. To the best of our knowledge, our study is the largest series of sPAP from a single center in China. We present some interesting findings. Firstly, TB is also a frequent underlying disease of sPAP in China, and fortunately, after effective anti-TB therapy, sPAP can be improved concurrently. Furthermore, hematologic disorders, especially MDS, are the predominant primary disease of sPAP, and these patients have a terrible prognosis with the majority dying within 2 years after diagnosis. Complications from other infections may accelerate the advancement of the disease.

In our center, 5.73% of PAP cases were determined to be sPAP, which is slightly lower than the percentage of sPAP (8.3% to 10%) in the Japanese case series [6, 7]. Both our study and existing literature illustrates that hematologic disorders are the most frequent underlying disease of sPAP. The study including 31 cases of sPAP with MDS found that sPAP is an important risk factor predicting adverse outcome of MDS with a 2-year survival of 46.2% [12]. In our cases, all of the 4 patients with MDS as the underlying disease died within 2 years. The pathomechanism of sPAP secondary to hematological diseases remains unknown. Mutations in GATA2 may be associated with sPAP [13, 14] since an autosomal dominant familial MDS and AML carried a heritable GATA2 mutation [15] and approximately one third of GATA2 mutation carriers also complicated sPAP [16]. It is speculated that a GATA2 deficiency leads to the alteration of alveolar cellular immunity because these patients had neither GM-CSF receptor mutations nor anti-GM-CSF autoantibodies. In the mice model, T-bet–over expressing T cells act to initiate the pathogenesis of sPAP [17]. Treatment of sPAP should focus on curing the underlying diseases. Bone marrow transplantation or cord blood transplantation can cure sPAP in these patients, but at the cost of an increased risk of infection and mortality [12, 18].

Some infectious diseases such as TB can cause sPAP, possibly due to microorganisms impairing the function of macrophages. The heavy burden of TB in China makes it a significant underlying disease in our cases. In this circumstance, treating the underlying infection(s) can ameliorate sPAP, as shown in our cases, 3 cases improved and 1 case remained stable after anti-TB therapy. However, autoimmune PAP might cause complications with infections including TB, Nocardia, and Aspergillus. An anti-GM-CSF autoantibody test is effective to distinguish these two situations since it is negative in the former while positive in the later. Besides antibiotics, GM-CSF replacement is ineffective to the former but of benefit to the latter.

In our study, only 33.3% of cases show interlobular septal thickening, which is regarded as a typical feature in the CT scan of autoimmune PAP patients [19]. Additionally, only 22.2% of them present GGO with patchy geographic pattern, which is more common in autoimmune PAP [6]. As a result, sPAP should be suspected in PAP patients whose CT scans only present GGO without interlobular septal thickening or in the absence of a geographic pattern. More detailed evaluation about infectious and hematologic diseases should be performed. Moreover, qualification of anti-GM-CSF-Ab is valuable for the differentiation of autoimmune or secondary PAP.

Several limitations must be stressed with regards to this study. First, since PAP is a rare disease, the value of this study is limited by its small sample size. Our study was also limited in scope in that the underlying disease in our sPAP cases only included hematological diseases and infections, without covering dust inhalation, autoimmune disease or tumors. Secondly, as a retrospective study, some patient characteristics and information are not comprehensive, such as arterial blood gas and lung function. Furthermore, because our hospital is the largest rare disease treatment center in China, patients admitted are usually more complex and serious cases, and as such, we cannot avoid selection bias. Meanwhile, occupational diseases were restrictively diagnosed and treated in designated hospitals in China, so PAP secondary to occupational exposure is difficult to diagnose in our hospital. It is also difficult to compare the result of a single Chinese center with those all over the world. Thus, we conducted a comprehensive review of all the available cases published in available literature to minimize selection bias. Finally, in the review, we did not account for other factors that may affect the variation of sPAP, such as the geographical features of the patients.

In summary, this study found that MDS and TB infection were the most frequent underlying causes of sPAP in this single center research in China and cases that secondary to MDS had a poor survival rate. However, after taking all the published cases into consideration, hematological disorders, especially MDS and CML, are the major primary disease in 68.9% of cases. sPAP was often middle age onset, but it had a fairly poor prognosis when the underlying diseases were hematologic disorders. The diagnosis of sPAP should be considered in PAP patients whose CT scan only presents GGO without interlobular septal thickening.