Haruyuki Ishii, MD, PhD.
Department of Respiratory Medicine
Kyorin University Hospital.

Knowledge sharing:
State of the art of Pulmonary Alveolar Proteinosis in Japan

The data collection and research on Pulmonary Alveolar proteinosis (PAP) in Japan has steadily progressed since Dr. Nakata and colleagues discovered anti-granulocyte/macrophage colony-stimulating factor (GM-CSF) autoantibody in patients with PAP in 1999[1]. After this early achievement, our Japanese PAP research group was set up and led by Dr. Inoue, and through this network we have conducted various clinical and basic research projects in PAP. Our research has been funded several times by grants from Japanese Ministry of Health, Labour and Welfare, and Japanese Agency for Medical Research and Development.

Up to now, the number of PAP cases diagnosed by pathological findings and anti-GM-CSF autoantibody titer was 903 between 1999 to 2014. Ninety percent of all PAP cases were autoimmune PAP with positive serum anti-GM-CSF autoantibody. On the other hand, the number of secondary PAP, congenital PAP, and unclassified PAP cases were only a minority (Figure).

According to our Registry for autoimmune PAP[2], the mean number of new autoimmune PAP cases is 88 per year, with an incidence of 0.69 per million population. The  prevalence of autoimmune PAP is estimated at 6.11 per million population. The total number of autoimmune PAP correlates closely with the size of the regional population. Regarding patient management, we usually stratify autoimmune PAP by using a disease severity score (DSS) based on symptoms and PaO2 levels, which ranges from least (DSS-1) to most (DSS-5) severe.

Because autoimmune and congenital PAP were designated as rare intractable diseases in 2015 by the Japanese Ministry of Health (www.nanbyou.or.jp/entry/4774), patients with autoimmune PAP, including those with DSS < 3, are able to receive medical and financial support for treatment. Moreover, a PAP patient group was set up in 2010 in Japan and annual workshops for PAP patients have been held by the PAP patient group (pap-net.jp) together with our research group on a yearly basis.

With regard to secondary PAP, the number of patients with this PAP type is about six cases every year. Eighty percent of secondary PAP cases have some hematological disorders and the most frequent one is myelodysplastic syndrome (MDS)[3]. The prognosis of secondary PAP is very poor because its two-year survival rate after diagnosis of secondary PAP is only 46%. Although the pathogenesis of autoimmune PAP is related to the presence of anti-GM-CSF autoantibody, that of secondary PAP still remains unclear. Alveolar macrophages differentiated from abnormal hematopoietic stem cells have been reported in secondary PAP complicating MDS[4]. Moreover, the relationship between the onset of secondary PAP and GATA2-deficiency has been another focus of research in the pathogenesis of secondary PAP[5]. Stem cell transplantation has been proposed as treatment for secondary PAP complicating MDS, but the outcome is not very favourable because a number of risk factors such as infections and graft-versus-host disease can limit its benefit for the patients.

Unclassified PAP has been defined as PAP with negative anti-GM-CSF autoantibody and no underlying disease. Among our unclassified PAP cases, four had aberrations in the GM-CSF receptor genes (alpha or beta chains) and family history with intermarriage. Those cases were diagnosed as adult-onset hereditary PAP.

Concluding; in the Japanese PAP research group (www.pap-guide.jp/en/index.html) there are teams dedicated to autoimmune, secondary and congenital/hereditary PAP. Two new clinical trials of GM-CSF inhalation therapies are ongoing in Japan, one is Sponsor- and the other Investigator-driven, as part of the numerous ongoing research projects on this neglected disease.


  1. Kitamura T, Tanaka N, Watanabe J, Uchida K, Kanegasaki S, Yamada Y, Nakata K. Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte-macrophage colony stimulating factor. J Exp Med 1999; 190: 875-880
  2. Inoue Y, Trapnell BC, Tazawa R, et al. Characteristics of a large cohort of autoimmune pulmonary alveolar proteinosis Patients in Japan. Am J Respir Crit Care Med 2008; 177:752.
  3. Ishii H, Tazawa R, Kaneko C, Saraya T, Inoue Y, Hamano E, Kogure Y, Tomii K, Terada M, Takada T, Hojo M, Nishida A, Ichiwata T, Trapnell BC, Goto H, and Nakata K. Clinical Features of Secondary Pulmonary Alveolar Proteinosis: Pre-mortem Cases in Japan. Eur Respir J 2011; 37: 465-468
  4. Moriyama M, Yano T, Furukawa T, et al. Possible involvement of lung cells harboring an abnormal karyotype in the pathogenesis of pulmonary alveolar proteinosisassociated with myelodysplastic syndrome. Annals ATS 2015; 12 (8): 1251-53.
  5. Spinner MA, Sanchez LA, Hsu AP, et a. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, immunity. Blood 2014; 123 (6): 809-821.


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Dr. med. Francesco Bonella
Senior Clinical Researcher
Interstitial and Rare Lung Disease Unit
Ruhrlandklinik, Essen
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