PAP is a rare syndrome of surfactant accumulation and resulting hypoxemic respiratory
failure that occurs in a number of diseases classified pathogenically into three groups:
primary PAP (caused by disruption of GM-CSF signaling - autoimmune PAP, hereditary PAP),
secondary PAP (caused by reduction in alveolar macrophage numbers and/or functions), and
surfactant dysfunction-related PAP (caused by mutations in genes required for normal
surfactant production). In current clinical practice, PAP is diagnosed based on a lung
biopsy; an approach that is not able to identify the PAP-causing disease in anyone.
Current therapy involves the physical removal of surfactant by a procedure in which the
lungs are repeatedly filled with saline and emptied - whole lung lavage, which is
invasive, inefficient, and not widely available, especially for children. Importantly,
research advances have elucidated the pathogenesis of diseases causing PAP in most
patients and have identified new diagnostic and therapeutic approaches. Simple
blood-based research tests can now identify the PAP-causing disease in about 95% of
patients. Further, several promising potential disease-specific therapies are currently
in development. The long-term goals of the Rare Lung Diseases Consortium include
improving the diagnosis and therapy of people with PAP.
Part A: A major goal of this protocol is to establish a National PAP Registry. Our
central hypothesis is that a nationwide campaign to enroll and communicate with a large
cohort of PAP patients will have important benefits including 1) accelerating the
translation of research diagnostics into clinical practice, 2) increasing knowledge among
patient and healthcare communities about PAP, and 3) engagement of PAP patients and
doctors in planning and conducting PAP research. The specific objectives of this study
are to: 1) determine the ability of the DBSC GMAb Test to correctly identify autoimmune
PAP among people with PAP of any type, 2) estimate the prevalence of autoimmune PAP, 3)
increase communication and knowledge about PAP-causing diseases, PAP research advances,
and future research studies among PAP patients, healthcare providers, the medical
community, the PAP Foundation, the Translational Pulmonary Science Center (TPSC) and the
general public, 4) evaluate the ability of DBSC-based test to correctly identify genetic
factors that increase the risk of developing PAP; and 5) to evaluate the ability of the
DBSC GMAb Test to correctly identify autoimmune PAP among people with PAP of any type, or
another lung diseases, and healthy controls. The target population is any person
diagnosed with PAP. The study design will involve recruitment, screening, and enrollment
of Participants via short telephone-based study visits, completion of questionnaires, and
collection of capillary blood from the fingertip by Participants in their home using a
DBSC, which are then sent by US mail to the TPSC for evaluation. The experimental
approach will compare GMAb levels from DBSCs from Participants diagnosed with PAP and
determine the fraction of autoimmune PAP patients among individuals with PAP. DBSC-based
genetic testing will be compared to current blood-based methods for identification of
known genetic risk factors for developing PAP. Lastly, DBSC GMAb values will be compared
to GMAb values from healthy and lung disease controls to determine the ability of the
DBSC GMAb test to identify patients with autoimmune PAP. Anticipated results will
establish a National PAP registry, validate tests for diagnosis of diseases causing PAP
in more than 90% of patients, increase awareness and understanding of PAP among patients
and healthcare providers, and provide for a patient voice in PAP research. These results
will impact the field by: 1) transforming how PAP is diagnosed, 2) increasing access to
diagnostic testing - of special importance to those in remote locations, and 3) engaging
PAP patient and healthcare communities in planning and implementing PAP research
including a prospective natural history study and clinical trials evaluating several
potential, disease-specific therapies.
Part B: A major goal of Part B of this protocol is to perform a retrospective,
longitudinal, chart-based natural history study of aPAP, to develop a disease severity
score that reflects how aPAP patients feel and function, including objective measures of
lung function and pathology, and to develop and test novel tools to measure the severity
of aPAP lung disease. Our central hypothesis is that defining the natural history of aPAP
using an outcome measure that incorporates how patients feel, function, and breathe as a
function of the severity of their disease and developing tools to measure clinical
outcomes will accelerate pharmacotherapeutic development for aPAP. The specific
objectives of Part B of this study are to: 1) perform a retrospective, longitudinal,
chart-based natural history study of aPAP, 2) host focus groups to obtain patient input
regarding health survey content, 3) establish a disease severity score that reflects how
aPAP patients feel and function and that includes objective measures of lung function and
pathology, and 4) evaluate the ability of a mobile phone-based exercise test to monitor
disease severity in aPAP patients. The target population are patients diagnosed with
aPAP. The study design will involve review of retrospective, longitudinal review of
medical records from aPAP patients and engagement of the patient community to establish a
disease severity score that reflects how aPAP patients feel and function and to test a
home-based method to remotely evaluate the exercise capacity of aPAP patients. The
experimental approach will be to collect and review retrospective, longitudinal medical
records of aPAP patients. Additionally, participants will release routine clinic data to
the study team and complete questionnaires that measure symptoms, function, and quality
of life at the time of routine clinic visits to facilitate development of an aPAP disease
severity score (aPAP-DSS). The aPAP-DSS will be a composite of patient-reported and
objective function data measuring patient's breathlessness - using a dyspnea index
(Dyspnea-I), oxygen delivery - using a lung function index (LungFxn-I), therapeutic
oxygen requirement - using a supplemental oxygen index (sO2-I), and health status and
function - using a quality of life index (QoL-I). We will compare the multivariate
aPAP-DSS with A-aDO2 - the gold standard for measuring lung dysfunction in aPAP, with
radiological lung density - a direct measure of amount of pathological surfactant
accumulation that causes the clinical manifestations of aPAP, and the St. George's
Respiratory Questionnaire - a health outcomes tool. Lastly, aPAP patients will also be
able to participate in the pilot testing of a mobile phone-based app to measure the
exercise capacity. Specifically, we will evaluate the ability of the 5-minute
standardized exercise protocol (STEP) test (5MST) to outperform the 6-minute walk test
(6MWT) as a measure of impaired exercise capacity in aPAP patients and the accuracy and
acceptability of the app-based remote 6MWT and 5MST compared to standardized clinic-based
exercise testing. Anticipated results will be collection and organization of data on the
natural history of aPAP and identification of gaps that can be addressed in a future
prospective natural history study. We will also evaluate novel tools to measure aPAP
disease severity and exercise capacity via a remote, home-based application. These
results will impact the field by 1) improving our understanding of the clinical course of
aPAP, 2) providing a simple tool to measure disease severity in terms of how aPAP
patients feel and function using information readily available in the standard medical
record, and 3) develop and test a novel patient-reported outcome assessment tool to
measure how aPAP patient's function.