More air for later - determinants of the lung function plateau, piama 23-25 years investigation

COPD is one of the leading causes of morbidity and mortality worldwide.
Although COPD generally manifests at older age, events early in life may
significantly contribute to impaired lung function. It has been estimated that
half of COPD cases can be attributed to low lung growth leading to a low
maximum level of lung function attained in early adulthood (*the plateau*).
This underlines the importance of investigating the determinants of the
plateau.

Primary Objective:
We will investigate the following primary research questions:
1. What are exposomic factors that predict the maximum attained level of lung
function?
2. What are genetic predictors of the maximum attained level of lung function?
3. Which airway epithelial DNA methylation signatures are linked to the maximum
attained level of lung function?

Secondary Objective(s):
Which multi-omics prediction signatures that can be derived from genomics,
epigenomics, transcriptomics, and internal (i.e. chemical exposome measures and
respiratory microbiome) and external exposome can classify subjects with a low
maximum attained level of lung function?

We will invite all participants of the PIAMA (Prevention and Incidence of
Asthma and Mite Allergy) birth cohort around age 25 years, and measure pre- and
post-bronchodilator FEV1, FVC, and FEF25-75, perform multiple breath washout
tests (MBW) to determine the lung clearance index (LCI), draw blood for
exposomic analyses and measurements of total and allergen specific IgE as well
as some cardio metabolic markers, perform nasal brushing for epigenetic and
transcriptomic analyses and naso- and oropharyngeal swabs for respiratory
microbiota analyses.
We will relate the plateau to external (e.g. air pollution, green space,
physical activity) and internal (e.g. chemical) exposome measures of PIAMA
participants collected throughout the life-course from before birth up to 23-25
years. Combined with our (epi)-genetics and microbiota data, we aim to
determine a multi-omics signature of low lung function in early adulthood,
which can be used to detect subjects at risk of subsequent COPD.

We will address the current Covid19 epidemic in our program: Complaints like
fever, cough, sore throat, difficulty breathing, runny nose and sneezing in 24
hours before the appointment has to result in cancelation of the visit. Also a
positive self-test results in postponing of the appointment for at least 6
weeks. During the COVID-19 epidemic, we will take extra safety measures for
participants and research assistants to avoid cross-infections during the
clinical examinations, e.g. no overlap in visits, 1.5 m distance between people
when possible, extra surface and materials cleaning in research area, hand
disinfection, airing of the research room, gloves, glasses and mask for the
research assistant. The research assistant performs a selftest on the day of
examinations, and will cancel all visits in case of a positive test.
The reversibility test involves administration of a short-acting ß2-
sympathicomimetic bronchodilator (e.g. salbutamol) during the lung function
tests. To reduce risks to minimal, we will consider as contra-indications any
presence of thyreotoxicosis, heart failure, heart attacks or surgery in the
past 3 months, hypertension, or use of heart glycosides. Salbutamol is a
standard asthma drug, used by some PIAMA participants as part of their asthma
treatment. As lung function measurements are affected by pregnancy, we will
postpone the investigations when the participant is in the second half of
pregnancy.
In the past, nasal brushing caused slight inconvenience, and therefore we used
topical lidocaine spray for analgesia. We have now developed a soft brush that
can be applied with minimal discomfort to the participant. No lidocaine spray
is necessary anymore. This soft brush was applied in over 200 6-year-old
children participating in the MAKI trial
(https://www.umcutrecht.nl/en/Research/Strategic-themes/Child-Health-science-for
-life/Respiratory-infections/Respiratory-syncytial-virus/Clinical-trials-and-stu
dies/Maki-trial), without noticeable problems, such as tearing, and nose
bleeding.
All tests will be performed by trained and experienced personnel, and if any
discomfort can be expected, it will most likely be from venipuncture. The
inconvenience expected, however, is very likely to be minimal and transient. In
past PIAMA clinical evaluations, participants voluntarily performed practically
all tests without any complaints or discomfort. Risk and burden in
participating are therefore minimal. However, if previous experiences in some
of the tests were uncomfortable for a participant, the tests involved can be
skipped upon the participant*s request.
Obviously, performing this clinical evaluation in PIAMA participants is
essential considering the great amount of data we already have on these
subjects. However, the PIAMA population is a group of young adults from the
general population and findings in this group will be translatable to the
current Dutch population in this age range.