Clinical trial NCT03007134: Multicenter International Cross-Sectional Evaluation of Pulmonary Alveolar Proteinosis Trial
Official title: Multicenter International Cross-Sectional Evaluation of Pulmonary Alveolar Proteinosis Trial
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Pulmonary Alveolar Proteinosis
Lead sponsor: Children's Hospital Medical Center, Cincinnati
Sponsor class: OTHER
Collaborators: name: Rare Diseases Clinical Research Network
name: National Center for Research Resources (NCRR)
First posted: 2017-01-02
Enrollment: 73
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Autoimmune PAP

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Standardize the anti-GM-CSF autoantibody ELISA
timeFrame: 1 year
Secondary outcomes:
measure: Geographic distribution of anti-GM-CSF autoantibody levels
timeFrame: 1 years
measure: Breadth of the autoimmune antibody phenotype of individuals with autoimmune PAP
timeFrame: 3 years
measure: Age of onset PAP symptoms
timeFrame: 2 years
measure: Age at the time of definitive PAP diagnosis
timeFrame: 2 years
measure: Length of time from onset of symptoms and definitive diagnosis of autoimmune PAP
timeFrame: 2 years
measure: Gender distribution among PAP patients
timeFrame: 2 years
measure: Tobacco use among PAP patients
timeFrame: 2 years
measure: Major medical history comparison among PAP patients
timeFrame: 2 years
measure: Disease severity variability among autoimmune PAP patients from various geographic locations
timeFrame: 2 years
measure: Number of secondary infections that occur in patients with primary PAP
timeFrame: 2 years
measure: Type of secondary infections that occur in patients with primary PAP
timeFrame: 2 years
Other outcomes:
Locations:
city: Greenville
country: United States
facility: Brody School of Medicine
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Essen
country: Germany
facility: Ruhrlandklinik Essen
city: Pavia
country: Italy
facility: Clinica Malattie Apparato Respiratorio Università di Pavia
city: Niigata
country: Japan
facility: University of Niigata Medical and Dental School
city: Osaka
country: Japan
facility: NHO Kinki-Chuo Chest Center
Study officials:
affiliation: Children's Hospital Medical Center, Cincinnati
name: Bruce Trapnell
role: STUDY_CHAIR
References: