Functional lung morphometry: another piece in the bpd prediction puzzle?

Despite considerable advancements in neonatal respiratory care, bronchopulmonary dysplasia (BPD) remains a burden for many survivors of premature birth.1 Rates of BPD remain high and

currently, clinicians have few therapies which effectively reduce BPD. Compounding this, many necessary treatments in the neonatal intensive care unit (NICU) can increase the risk of acute

lung injury, and thus BPD. Identifying specific interventions that are most likely to be beneficial, or harmful, involves understanding the risk profile of specific infants. To do so

requires clinically quantifiable measures which may assist in better characterising the target population. As our understanding of BPD and the profile of preterm infants managed in the NICU

has changed since the first description of BPD in 1969, so has the focus on relevant biomarkers which may predict a diagnosis of BPD early in life.2 In this issue of _Pediatric Research_,

Williams et al. report a novel approach to potentially predict BPD in preterm infants using functional respiratory system morphology that calculates an index of the adjusted alveolar surface

area of the lung (SA).3 The aim of their observational prospective study was to describe adjusted SA values in preterm infants at high risk of BPD and explore whether adjusted SA was

related to respiratory outcomes of prematurity known to be associated with BPD. Thirty extremely premature infants born <28 completed weeks’ gestation who were still receiving invasive

mechanical ventilation at 7 days were recruited for this study. They identified a lower adjusted SA between those infants who were discharged home on oxygen and those that were not (a

functional surrogate of BPD at discharge); median (range) 637 (232–838) cm3 versus 799 (444–903) cm3. There was no relationship between adjusted SA and grade of BPD or duration of mechanical

ventilation. There is a strong biological rationale to use SA to describe respiratory status in preterm infants. Preterm birth requires tidal ventilation of an immature lung before

alveolarisation has become the predominant developmental process, and often whilst in the saccular or canicular stages of lung development. Beyond these immediate consequences, mechanical

ventilation causes alveolar developmental arrest leading to a smaller alveolar surface area, simplified alveolar structure and airway enlargement (increase in deadspace). The physiological

manifestation of the altered capacity of alveolar-capillary gas exchange, and potential for supplementary oxygen, is thus related to lung morphology. It is important to focus on the

sophisticated process used to determine the adjusted SA index by Williams et al. First, the alveolar ventilation/perfusion ratio (VA/Q) of each infant was calculated from at least three

paired measurements of transcutaneous oxygen saturation (SpO2) and fraction of inspired oxygen (FiO2) whilst supine. The VA/Q was then considered within the expected oxyhaemoglobin

dissociation reference curve and adjusted for haemoglobin. From the VA/Q, the alveolar surface area of the lung (SA) was estimated using a predictive regression equation from a previous

study which validated functional morphometry with traditional stereological morphometry in a preterm baboon model. To further ensure the transferability of this regression equation to human

data, and reduce confounding variables for VA/Q, echocardiography was used to ensure left-to-right ductal flow and similar pulmonary perfusion and alveolar-arterial gradient between the

baboon model and human data. The resultant SA was finally adjusted by accommodating anatomical and physiological alveolar deadspace as well as alveolar tidal volume (VT) measured by

mainstream volumetric capnography. These adjustments were used to develop a more precise index of the functional SA taking part in gas exchange. In ideal measuring conditions, capnography

allows differentiation of the alveolar and deadspace volumes. The need to correct for estimated deadspace accounts for the unique lung architecture in preterm infants with evolving chronic

lung changes, which potentially include a substantial proportion of underdeveloped or damaged alveoli. The authors assessed the predictive capabilities of both SA and adjusted SA index to

measure clinically relevant indicators of BPD (grade, need for home oxygen and duration of mechanical ventilation). The novelty and strength of this study is the generation of a repeatable

estimation of total SA from a careful translation of a methodology previously validated against stereological morphometry in post-mortem preterm baboon lung tissue.4 The method of SA

estimation used by Williams et al. has the advantage of using physiological measurements readily obtained from commonly available NICU equipment without the need for interruption of clinical

care (such as inert gas washout). Furthermore, the computer-based calculation used has substantial potential for advancement, including speed, automation, and high throughput, which reduces

the risk of human error and variability to produce consistent results. This allows immediate information on disease state or treatments. The adjusted SA index could also be applied to other

respiratory diseases of infancy. The range of adjusted SA, deadspace and VA/Q values suggest that identifying a single narrow range of reliable, informative, and accurate absolute values is

unlikely. Rather, repeated measures and intra-subject comparison of the evolution of lung dysfunction informed by associated clinical events will be more useful. Current diagnostic criteria

for BPD reflect a simplistic snapshot in time. Predicting BPD risk is thus appealing, but the search for the best biomarkers for the prediction of BPD has been challenging.5 This is because

BPD results from complex interactions between the developmental lung state, treatments and complications, all of which influence the trajectory to BPD and may occur after an early tool has

estimated risk. Clinical, physiological, biochemical and, most recently, imaging with lung ultrasound (LUS) have been proposed as biomarkers, each with distinct advantages and disadvantages.

Biochemical markers (generally umbilical cord blood, plasma, urinary and tracheal aspirates) have shown promise and directly address the multi-modal inflammatory nature of BPD, but have the

disadvantage of invasiveness and off-site sample processing.5,6,7 Recently, the predictive performance of LUS has been promising in some, but not all, studies.8, 9 However, LUS is an

acquired skill which requires training. In contrast to these measures, adjusted SA is a method without these limitations, nor limited by age and vulnerable patient cohorts. Although the

adjusted SA in the second week after birth did not significantly correlate with the duration of supplemental oxygen therapy or grade of BPD, it did predict discharge with supplemental oxygen

with reasonable accuracy (AUC 0.815, sensitivity; 86%, specificity; 77%), both statistically and against other early BPD predictors. It should be noted that the study did not use adjusted

SA to predict BPD, as only a population of infants in whom the investigators determined would develop BPD were studied. It is unclear if this test would have the same predictive performance

in the general preterm population for the outcomes studied, and BPD generally. A surprising finding of the study was the high physiological and anatomical deadspace measures, median (range)

5.8 (3.9–9.7) and 5.1 (3.6–7.4) mL/kg, respectively, and an alveolar VT below that considered appropriate for gas exchange (1.90 (0.54–6.33) mL/kg). The authors propose that this may reflect

the under-appreciated and novel mechanisms of gas exchange (such as fresh gas spikes through deadspace). The true answer is probably more complex. Volumetric capnography assesses the

behaviour of CO2 over the duration of the expiratory cycle, with deadspace gas representing the initial CO2 changes and alveolar gas only being present at the end of expiration (CO2 wave

plateau). Although the authors used a low-volume mainstream capnograph, the low VT and fast respiratory rates characteristic of preterm respiration can result in over-representation of

deadspace.10 The study population had all received prolonged mechanical ventilation beyond the initial period of acute respiratory distress syndrome. It is likely that airway and alveolar

injury and changes had already occurred. Finally, pendelluft gas flow (movement of air within the lung) during tidal inflations may be common in adults with acute respiratory disease

syndrome receiving mechanical ventilation. Whether this also occurs in this population of high-risk preterm infants is a fascinating proposition. Minimally invasive estimation of SA appears

suitable for use in extremely preterm neonates, and may provide important information on gas exchange, lung function and disease pathophysiology not currently available in the NICU. This

opens exciting avenues for precision medicine to target specific hallmarks or stages of disease. Given the chronic and detrimental effects of BPD-associated damage on lung development and

function in later life, the potential of adjusted SA as an early prognosticator of later respiratory risk is appealing. However, standardisation of the method (for example against

ventilation support settings), inclusion of a lower-risk population including those on non-invasive ventilation, and temporal tracking of SA to monitor disease progression should be

conducted to demonstrate robustness and reproducibility. Even with these data, it is unlikely that accurate prediction of BPD or its clinical manifestations can be based on SA measurements

alone. The multi-modal nature of evolving chronic lung disease following preterm birth indicates that accurate diagnosis and prediction of BPD will require multiple validated tools

encompassing physiological measures, imaging modalities, markers of immunomodulatory, inflammatory, and oxidative stress, ventilatory treatments and clinical factors (such as degree of

prematurity and infection). The work of Williams et al suggests that adjusted SA may play an important part in this endeavour. REFERENCES * Doyle, L. W., Ranganathan, S. & Cheong, J. L.

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transport. _Arch. Dis. Child Fetal Neonatal Ed._ 90, F523–F526 (2005). Article  CAS  PubMed  PubMed Central  Google Scholar  Download references FUNDING D.G.T. is supported by a National

Health and Medical Research Council Leadership Level 1 Investigator Grant (Grant ID 1194911). D.G.T., Q.H.P., S.D. and A.S. are supported by the Victorian Government Operational

Infrastructure Support Program (Melbourne, Australia). Open Access funding enabled and organized by CAUL and its Member Institutions. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Neonatal

Research, Murdoch Children’s Research Institute, Parkville, VIC, Australia Qi Hui Poh, Sophia Dahm, David G. Tingay & Arun Sett * Department of Paediatrics, University of Melbourne,

Melbourne, VIC, Australia David G. Tingay * Newborn Services, Joan Kirner Women’s and Children’s, Sunshine Hospital, Western Health, St Albans, VIC, Australia Arun Sett * Department of

Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC, Australia Arun Sett Authors * Qi Hui Poh View author publications You can also search for this author inPubMed Google

Scholar * Sophia Dahm View author publications You can also search for this author inPubMed Google Scholar * David G. Tingay View author publications You can also search for this author

inPubMed Google Scholar * Arun Sett View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS All authors contributed equally to the review of the

original submission and structure of the editorial, with agreed paragraph lead authors shared equally. Q.H.P. and S.D. wrote the first draft under supervision from D.G.T. and A.S. All

authors contributed to redrafting the manuscript. CORRESPONDING AUTHOR Correspondence to David G. Tingay. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests.

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_et al._ Functional lung morphometry: another piece in the BPD prediction puzzle?. _Pediatr Res_ 94, 1593–1595 (2023). https://doi.org/10.1038/s41390-023-02701-3 Download citation *

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