Multicenter International Cross-Sectional Evaluation of Pulmonary Alveolar Proteinosis Trial

The purpose of this study is to (1) compare a technically improved assay with an existing assay used to measure serum anti-GM-CSF antibodies in stored serum samples previously obtained from patients diagnosed with either primary, secondary, congenital or idiopathic pulmonary alveolar proteinosis (PAP), other chronic diseases or disease-free, healthy individuals; (2) determine the prevalence and levels of anti-GM-CSF autoantibodies and (3) define the breadth of the autoimmune antibody responses in primary PAP patients from the United States, Japan, Australia, and Europe using previously collected serum samples; and (4) using a chart review approach, compare the clinical, radiologic and laboratory features of primary PAP patients to determine if differences exist among patients in these globally geographically distributed regions.

Study Overview

• Status: Completed
• Conditions: Pulmonary Alveolar Proteinosis
• Intervention / Treatment: Other: Retrospective Chart Review

Detailed Description

The Rare Lung Disease Consortium (RLDC), a group of geographically-dispersed clinical research sites, has been established to conduct collaborative clinical research regarding rare lung diseases. The collaborative work includes diagnostic, therapeutic and other studies in patients with pulmonary alveolar proteinosis (PAP), lymphangioleiomyomatosis (LAM), alpha-1 antitrypsin deficiency (AATD), or hereditary interstitial lung diseases. These patients can have delayed or incorrect diagnoses, and sub-optimal clinical management. The present protocol is focused to individuals with PAP.

PAP occurs as primary, secondary, congenital and idiopathic forms. RLDC investigators have previously shown that primary PAP is strongly associated with high levels of circulating, neutralizing anti-GM-CSF autoantibodies. Absence of GM-CSF bioactivity is thought to impair alveolar macrophage and blood neutrophil functions including reduced surfactant catabolism (alveolar macrophages - thought to result in surfactant accumulation in primary PAP) and immune dysfunction (neutrophil dysfunction, and possibly macrophage dysfunction - thought to increase the risk of infection in primary PAP). Secondary PAP is caused by an underlying condition believed to impair alveolar macrophage surfactant catabolism. Secondary PAP is related to other conditions, including myelogenous leukemias, infections and environmental exposures. Congenital PAP is caused by mutations in the genes encoding surfactant protein (SP)-B, SP-C or the ABCA3 transporter. Idiopathic PAP is that which results from unknown mechanisms. Anti-GM-CSF autoantibodies appear to be absent in secondary, congenital and idiopathic PAP.

This cross sectional study protocol is designed to evaluate the autoimmune aspect of PAP in patients that are currently being followed by clinical investigators in the Rare Lung Disease Consortium (RLDC). The study involves a retrospective chart review and serological analysis of preexisting, stored serum samples from individuals diagnosed with PAP. Thus, this study will not involve any direct interactions or contact with PAP patients or any other study participants. It will yield diagnostic information regarding the use of anti-granulocyte macrophage-colony stimulating factor (GM-CSF) autoantibody testing in patients with PAP. It will also yield information about the extent of the autoimmune response in primary PAP. In addition, the study will compare/contrast the clinical phenotypes of individuals with anti-GM-CSF autoantibody-positive PAP in various regions of the world. A stringent evaluation of the autoimmune aspects of PAP including rigorous anti-GM-CSF antibody testing will provide a better understanding of PAP and is expected to confirm the usefulness of serum anti-GM-CSF antibody testing in the clinical diagnosis of PAP. The study will evaluate the rate of serious or opportunistic infections and other clinical and demographic data from patients in various regions of the world to determine if significant differences exist, which will provide important knowledge regarding infectious and other complications associated with PAP.

• Study Type: Observational
• Enrollment (Actual): 73

Contacts and Locations

Study Locations

• Germany
  • Essen, Germany
    • Ruhrlandklinik Essen
• Italy
  • Pavia, Italy
    • Clinica Malattie Apparato Respiratorio Università di Pavia
• Japan
  • Niigata, Japan
    • University of Niigata Medical and Dental School
  • Osaka, Japan
    • NHO Kinki-Chuo Chest Center
• United States
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • Brody School of Medicine
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Autoimmune PAP

Description

Inclusion Criteria:

Data and Serum must be from individuals of any age with confirmed diagnosis of PAP based on the following criteria:

• Radiographic features consistent with PAP
• Pathological or cytological findings consistent with PAP determined by either open lung biopsy, transbronchial biopsy or bronchoalveolar lavage cell/fluid cytology.
• Elevated anti-GM-CSF autoantibody concentration, when available

Ability of the international PI's and their research coordinators to ship samples in compliance with this study.

Exclusion Criteria:

• No established diagnosis of PAP
• Incomplete chart records in which >25% of the requested data is unable to be confirmed.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Standardize the anti-GM-CSF autoantibody ELISA	To compare a novel assay to an existing assay used to measure anti-GM-CSF autoantibodies in banked serum samples previously collected from individuals diagnosed with primary, secondary, congenital or idiopathic PAP, other chronic disorders, or disease-free, healthy individuals.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Geographic distribution of anti-GM-CSF autoantibody levels	GM-CSF autoantibody concentration in patients with autoimmune PAP	1 years
Breadth of the autoimmune antibody phenotype of individuals with autoimmune PAP	Autoimmune antibody phenotype of individuals with autoimmune PAP	3 years
Age of onset PAP symptoms	Range of age at onset of symptoms of PAP among PAP patients from different global geographic regions	2 years
Age at the time of definitive PAP diagnosis	Range of age at the time of definitive pathologic diagnosis of PAP among PAP patients from different global geographic regions	2 years
Length of time from onset of symptoms and definitive diagnosis of autoimmune PAP	Length of time between the onset of symptoms and a definitive pathologic diagnosis of PAP among PAP patients from different global geographic regions	2 years
Gender distribution among PAP patients	Gender distribution among PAP patients from different global geographic regions	2 years
Tobacco use among PAP patients	Variability of tobacco use among PAP patients from different global geographic regions	2 years
Major medical history comparison among PAP patients	Variability of associated major medical diagnoses among PAP patients from different global geographic regions	2 years
Disease severity variability among autoimmune PAP patients from various geographic locations	Severity of the disease at onset among PAP patients from different global geographic regions	2 years
Number of secondary infections that occur in patients with primary PAP	Number of participants documented to have had a secondary infection(s)	2 years
Type of secondary infections that occur in patients with primary PAP	List the specific organisms documented to have infected PAP patients	2 years

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborators: National Center for Research Resources (NCRR); Rare Diseases Clinical Research Network
• Investigators: Study Chair: Bruce Trapnell, Children's Hospital Medical Center, Cincinnati

Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (Actual): July 1, 2010
• Study Completion (Actual): July 1, 2011

Study Registration Dates

• First Submitted: November 28, 2016
• First Submitted That Met QC Criteria: December 29, 2016
• First Posted (Estimate): January 2, 2017

Study Record Updates

• Last Update Posted (Estimate): January 2, 2017
• Last Update Submitted That Met QC Criteria: December 29, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Pulmonary Alveolar Proteinosis
• Other Study ID Numbers: 2008-1204; RR019498 (Other Grant/Funding Number: NIH Office of Rare Disease Research)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No