Elucidating the early determinants of chronic lung disease: development of tools to enhance measurement and interpretation of lung function
Submitting InstitutionUniversity College London
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Paediatrics and Reproductive Medicine
Summary of the impact
We have made substantial contributions to the diagnosis of lung disease
by providing tools to assess and interpret lung function accurately across
the entire lifespan. These contributions include: effects of lung disease
being more clearly distinguished from those of normal growth, development
and aging; increased understanding of the early determinants of adult
respiratory disease and improved diagnosis of chronic obstructive lung
disease. Commercially available equipment for assessing lung
function in infants and preschool children has been developed based on our
work and our recently developed multi-ethnic, all-age lung growth
charts have been endorsed internationally and are now in widespread
Respiratory diseases cause around 50% of acute illness in children. Over
20 years, the Portex Respiratory Unit at the UCL Institute of Child Health
(ICH) has developed methods and equipment, enabling studies of lung growth
and development during early life. We have created sophisticated all-age,
multi-ethnic `lung growth charts' (reference equations) which have allowed
effects of disease to be identified more clearly. These tools have been
incorporated into commercially available equipment. Prior to the 1990s,
assessment of infant lung function was limited to a few specialised
physiology laboratories. Professor Janet Stocks co-founded the European
Respiratory Society/American Thoracic Society (ERS/ATS) Task Force on
infant lung function testing to facilitate more widespread and
standardised applications. During the 1990s, an increasing number of
infant lung function tests were developed and validated by this group,
resulting in the first textbook in the area  which is now used
in infant laboratories world-wide. Stocks has subsequently updated this
textbook via a series of published reports and chapters to establish
standards both for users and manufacturers [2, 3].
Having successfully established standardised methods for assessing lung
function in sleeping infants [1-3], there remained the challenge
of undertaking measurements in awake preschool children, in whom
respiratory problems are common, but complex to diagnose. Children below 5
years were hitherto considered `untestable', but the ICH team achieved a
high success rate in 3-5 year-olds, and participated in international
efforts to standardise their application . Hence, for the first
time, continuous assessments of lung function became feasible from birth
to old age. Development of the multiple breath washout technique
(collaboration with P. Gustafsson, Sweden), has revolutionised the way in
which early lung disease can be detected in young children with Cystic
Fibrosis (CF) [3, 4]. Measurements during the preschool years are
predictive of lung function at school age, providing a window for earlier
therapeutic interventions .
These developments allowed increasing application in clinical management
and facilitated research into the early determinants of lung disease: e.g.
effects of low birth weight and maternal smoking in pregnancy on
subsequent lung health, and evolution of lung disease following extremely
preterm birth (MRC EPICure study) and in those diagnosed with CF. In 1998,
JS established the London CF collaboration (LCFC) , which has
demonstrated that children diagnosed through newborn screening have
significantly better growth and lung function when compared with their
clinically diagnosed counterparts, and that undertaking routine chest CTs
is not diagnostically helpful during the first year of life.
Use of lung function tests to guide clinical management of lung disease
requires appropriate reference equations with which to detect
abnormalities. These were, however, poorly developed for infants and
preschool children and for those not of white European ancestry.
Commencing in 1995 with publication of prediction equations for lung
volumes from birth to adulthood, the ICH team led numerous initiatives to
rectify this situation (in collaboration with Professor Philip Quanjer,
Netherlands), culminating in the recent publication of `All-age'
multi-ethnic equations for spirometry [5, 6]. These have improved
our interpretation of lung disease in children with CF and sickle cell
disease, especially during the transition to adult care, and also in
elderly patients with COPD.
References to the research
 Stocks J, Sly P, Tepper RS, Morgan WJ (eds). Infant Respiratory
Function Testing: a practical guide. New York: Wiley-Liss, John Wiley
& Sons, Inc. Publication, 1996. ISBN:0471076821. Available on request.
 Stocks J, Lum S. Pulmonary function tests in infants and preschool
children. In: Wilmott RW, Boat TF, Bush A, Chernick V, Deterding R, Ratjen
F, eds. Kendig's disorders of the respiratory tract in children.
Philadelphia, USA: Elsevier; 2012: 169-210. ISBN:978143719840. Available
 Aurora P, Stanojevic S, Wade A, et al. Lung Clearance Index at 4
years predicts subsequent lung function in children with Cystic Fibrosis.
Am J Respir Crit Care Med 2011; 183: 752-8.
 Quanjer PH, Stanojevic S, Cole TJ et al. Multi-ethnic reference
values for spirometry for the 3-95 year age range: the global lung
function 2012 equations. Eur Resp J 2012:40; 1324-43. http://dx.doi.org/10.1183/09031936.00080312
For all-age multi-ethnic equations, see also www.lungfunction.org.
Since 1993, the research programme has been supported by peer-reviewed
grants totalling £6.8m, (JS PI: £4.7m), including £1.3m from the Wellcome
Trust, £881,700 from the MRC, £700,626 from the CF Trust and £253,559 from
Details of the impact
Over the past 15 years, the respiratory physiology team at ICH has played
a major role, both nationally and internationally, in the development,
validation and standardisation of methods of assessing respiratory
function in infants and preschool children. As a result, standardised
equipment, software and guidelines for infant and paediatric lung function
tests are in widespread use around the world.
Impacts on development of equipment
In 2000 [ref 2], we published recommendations on equipment for assessing
infant lung function. Accordingly, such equipment has been developed in
line with our recommendations, and is now commercially available and in
use world-wide. For example, we worked with CareFusion on their BabyBody
device — they report on this collaboration as follows: "The current 5th
generation, Jaeger MasterScreen BabyBody, resulted from collaborative
efforts of the Jaeger R&D and the Portex Respiratory Unit teams.
This collaboration ensured that the MasterScreen BabyBody was
cross-validated against existing, previously validated instruments, so
that compliance could be achieved with the ATS/ERS guidelines
[ref 2] which represent the current standards of paediatric health
professionals in this field". This device has been sold around the
world [a]. Similarly, since publication of our research showing
that the lung clearance index is a far more sensitive measure of early
lung disease than standard spirometry [refs 3 & 4], commercially
available multiple gas washout devices such as the ndd EasyOne ProLAB have
been developed, to enhance widespread international clinical usage [b].
All-age reference equations for lung function
During the past five years, we have published all-age reference equations
to improve accurate diagnosis of lung disease [refs 5 & 6], which have
rapidly led to changes in practice (see below) and commercial equipment
around the world. We made the GLI-2012 equations available through the
resource website (www.lungfunction.org)
which had 7,488 unique visitors in the first six months of 2013, with over
500 hits each from the USA, Canada, Japan, Germany and the Netherlands.
The GLI-2012 equations have been endorsed by all major international
respiratory societies including the European Respiratory Society, the
American Thoracic Society, the Australian and New Zealand Society of
Respiratory Science; the Asian Pacific Society for Respirology; the
Thoracic Society of Australia and New Zealand; and the American College of
Chest Physicians [c]. They have also been adopted by both national
and international professional clinical and public health organisations
such as the UK CF registry, the Health Survey for England [d] and
the US NIHR Sickle Cell Anaemia Sleep and Asthma Cohort (SAC) study [e].
These equations have also changed the way lung function is reported in
commercial equipment, due to our identification of appropriate
age-specific lower limits of normal for spirometric outcomes, rather than
dependence on fixed thresholds. Morgan Scientific, a leading manufacturer
of pulmonary function instrumentation and software, reports that: "As
soon as we heard about the GLI initiative we eagerly accommodated the
equations, I believe we were the first manufacturer to do so. As our
customer base is heavily centred in ...pediatric hospitals in the USA,
there has been keen interest in adopting the GLI set" [f].
Other manufacturers who have confirmed their use of our equations include:
CareFusion, Medical Graphics corporation, Cosmed, Ganshorn, Medikro,
Medisoft, Medset, MIR, Morgan, ndd Medical and nSpire [g].
One benefit of our all-age equations is that they overcome the serious
potential errors which can occur when a child is switched from paediatric
to adult equations at 18 years of age. Previously, this could result in a
sudden apparent drop in lung function by as much as 25%, simply due to the
equations selected (Kirkby et al, Eur Resp J 2011:39;1256-7). Our all-age
equations remove this sudden change, and as a result, are being adopted in
an increasing number of establishments to ensure a smooth transition
between paediatric and adult care. In 2011, Janet Stocks was awarded a
Lifetime Achievement Award by the European Respiratory Society in
recognition that her work has "helped give paediatric medicine the
tools to better understand and treat the respiratory illnesses of
childhood" [h]. She has also recently been awarded the
British Paediatric Respiratory Society 2013 lifetime achievement award in
recognition of her `commitment in advancing the care of children with
respiratory disease in the UK' [i].
Change in clinical practice
Our work has been widely cited in Standard Operating Procedures for
measuring lung function, demonstrating the impact our work has had on
clinical practice [j].
Great Ormond Street Hospital report that: "the substantial clinical
impact that the work by Professor Janet Stocks and her team has made
...[has occurred] not only at Great Ormond Street Children's Hospital,
but also in other respiratory units ...nationally and internationally...
During the past 5 years we have introduced routine lung function tests
for all clinically diagnosed infants with CF throughout infancy and the
preschool years to help guide management — whereas in the past objective
tests of lung function only commenced from 5-6 y upwards. This has led
to the description of early changes in CF hitherto unidentified and an
upscaling of our management protocols... [With the] published findings
of Prof Stocks' group on early structural and functional changes...
patient directed escalation of therapy to halt early changes during
these crucial early years is introduced — with protocols that have been
adopted by other centres in the greater London region. We are now
interpreting all clinical lung function results using the GLI 2012
equations, which has overcome problems previously faced when
interpreting results from children from Black and ethnic minorities and
when transitioning between paediatric and adult care. This seminal work
finally makes sense of the longitudinal tracking of lung function in
children through childhood, adolescence and into adulthood....we are
also now routinely using MBW as a sensitive marker of early lung disease
in clinical practice.... Of considerable clinical significance is
Professor Stocks' detailed review of outcome measures for assessing lung
function... in newborn screened CF infants. This important work led to
our clinical decision to limit CT scanning (with its inherent radiation
burden) to just those children who are showing unexplained clinical
decline and remove it from our routine surveillance programme with cost
benefits to the NHS and reduction in harm to patients [k].
In addition, Yale University report that: Our work would not have
been possible without the landmark publications by the research team at
the University College London (UCL).... It is because of the outstanding
work of the UCL team that I am better positioned to evaluate and manage
respiratory symptoms in aging populations, both as a pulmonologist and
Fully funded research fellows from around the world regularly apply to
undertake training in the specialised paediatric respiratory laboratories
at ICH, such that we now have collaborative satellite sites established in
Southampton, Munster, Lisbon, Barcelona, Montreal, Toronto and Australia
(Melbourne, Victoria; Perth, WA and Newcastle, NSW.
Sources to corroborate the impact
[a] Letter of testimony from CareFusion. Copy available on request
including map of international distribution.
[b] Letter of testimony from ndd. Copy available on request
Endorsement by major international respiratory societies. Full list on
p.1,339 of reference 6. Copy of correspondence confirmation endorsement
from the American College of Chest Physicians, Asia Pacific Society of
Respiratory and Australian & New Zealand Society of Respiratory
Science available on request.
[e] Confirmation provided by co-ordinator of this study at the Washington
University School of Medicine. Copy available on request.
[f] Email from Morgan Scientific. Copy available on request.
[g] Results of our survey available here: http://www.lungfunction.org/manufacturers.html.
Full correspondence available on request.
[h] ERS Citation available at: http://www.ersnet.org/ers-funding/awards/item/4441-2011-ers-awardees.html
[i] Copy of BPRS Award letter available on request.
[j] Standard operating protocols
i) Primary Care Commissioning "Guide to quality Assured Diagnostic
ii) Nursing times article "How to Interpret Spirometry" 2011,
[k] Testimony from Consultant in respiratory paediatrics, Great Ormond
Street Hospital. Copy available on request.
[l] Testimony from Yale University Medical School. Copy available on