Inhalation of Granulocyte-macrophage Colony-stimulating Factor (GM-CSF) for Autoimmune Pulmonary Alveolar Proteinosis (PAP)
Inhalation of Granulocyte-macrophage Colony-stimulating Factor (GM-CSF) for Autoimmune Pulmonary Alveolar Proteinosis (PAP)
The purpose of the study is to evaluate if inhaled granulocyte-macrophage colony stimulating
 factor delay the increase in alveolar-arterial oxygen difference, compared to no treatment,
 for adult patients with mild-to-moderate autoimmune pulmonary alveolar proteinosis in China
 over a two-year period.
Autoimmune pulmonary alveolar proteinosis (PAP, previously known as idiopathic PAP) is a rare
 interstitial lung disease elicited by the formation of autoantibodies which neutralize the
 activity of granulocyte-macrophage colony-stimulating factor (GM-CSF) which decreases
 macrophage clearance of surfactant.

 Currently, the standard treatment strategy for PAP is whole lung lavage (WLL)，which is
 invasive and has limitations. Inhaled GM-CSF therapy became a new option for PAP patients not
 only because of its effectiveness and safety, but it is convenient way for patients who are
 reluctant to do operation as well. We are planning to prospectively evaluate if inhaled
 granulocyte-macrophage colony stimulating factor would delay the increase in
 alveolar-arterial oxygen difference (A-aDO2, which is the most sensitive factor in evaluating
 APAP5), compared to placebo, for patients with mild-to-moderate autoimmune pulmonary alveolar
 over a two-year period.

 A total of 42 subjects with APAP who meet the inclusion criteria will be enrolled at Peking
 Union Medical College Hospital and Nanjing Drum Tower Hospital. After observe APAP patients
 for 3 months to rule out patients who resolved spontaneously, the participants will undergo
 randomization (by random number table)and stratified into two different groups by their DSS.
 Then they will be treated by GM-CSF (using nebulizer, 150ug bid) every other week or no
 treatment for 6 months, and will be followed on an outpatient basis at 2 weeks, and 1, 3, 6,
 9, 12, 15, 18, 21 and 24 months after initiation of therapy.
Accessible population:

 Adult patients with mild-to-moderate autoimmune pulmonary alveolar and without spontaneous
 remission will be enrolled at Peking Union Medical College Hospital and Nanjing Drum Tower
 Hospital.

 Inclusion Criteria:

 -  Adult autoimmune PAP subjects will be included: 1) a positive PAS stain from BALF or
 lung biopsy; 2) high level of serum anti-GM-CSF antibody (>2.39ug/ml, the cut-off
 point in our hospital); 3) age above 18 years old; 4) exclude hereditary and secondary
 PAP.

 -  Able to give written informed consent and comply with the requirements of the study.

 -  Patients are not eligible for the whole lung lavage (WLL), decided by clinicians.

 -  Eligibility for GM-CSF inhalation: 1) Disease severity score (DSS) is 1-3; 2) No
 treatment with GM-CSF therapy or WLLin the 3 months prior to enrollment. Definition of
 DSS2: 1, no symptom and PaO2>=70mmHg；2, PaO2>=70mmHg with symptoms；3, PaO2>=60 and
 <70mmHg; 4, PaO2>=50 and <60mmHg; 5, PaO2<50mmHg.

 Exclusion Criteria:

 -  Patients will be observed for 3 months and all APAP patients who resolved
 spontaneously will be excluded from our study.

 -  PAP resulting from another condition (e.g. occupational exposure to silica, underlying
 HIV, respiratory infections, myeloproliferative disorder or leukaemia);

 -  A normal or low-titre serum anti-GM-CSF antibody (≤2.39ug/ml);

 -  History of severe allergic or anaphylactic reactions to humanized or murine monoclonal
 antibodies；

 -  Chronic lung disease associated with already existing respiratory failure (such as
 pulmonary emphysema or fibrosis);

 -  Other serious medical conditions which, in the opinion of the investigator, would make
 the patient unsuitable for the study.

 -  Pregnancy.