The research, led by Florian Wyler and colleagues at Bern University Hospital and the University of Bern in Switzerland, tackles a problem that has long frustrated clinicians and researchers alike. The main outputs of a washout test are the lung clearance index, or LCI, which measures how many lung turnovers are needed to clear the resident nitrogen, and the functional residual capacity, or FRC, the volume of air remaining in the lungs at the end of a normal breath out. Irregular breathing behaviors can bias both numbers, but the current gold standard for judging whether a measurement is trustworthy is expert quality control: a trained physician, nurse, or scientist visually inspects the signals and decides whether to accept or reject the test. That judgment is slow, requires rare expertise, and, crucially, is subjective.

The subjectivity is not a minor nuisance. Washout measurements typically last several minutes and are routinely performed in awake children from preschool age onward, so measurements full of minor, ambiguous irregularities are the norm rather than the exception. Two experienced raters can disagree about whether a given test should be kept, especially when the irregularities fall into a grey zone between clearly acceptable and clearly unusable. Existing guidelines also rely on fixed empirical thresholds, such as allowable variation in end-expiratory lung volume, without any direct way of estimating what those deviations actually do to the LCI or FRC. The Bern team set out to replace that guesswork with a quantitative, reproducible estimate of impact.

The core of the new approach is a mathematical model of how nitrogen is diluted during the washout. For any given breath, the model relates an input of breathing behavior to an expected output of nitrogen dilution, taking into account the current end-expiratory lung volume, physiological and machine dead spaces, and the fact that washout efficiency declines as the test proceeds, because well-ventilated lung regions empty first while poorly ventilated regions hold on to their nitrogen longer. The model’s parameters are estimated individually from each measurement, using the carbon dioxide and flow signals to locate dead space and fitting a linear efficiency curve over the course of the washout.

With this model in place, the algorithm runs paired simulations for each measurement. One simulation uses the observed breathing behavior, including whatever irregularities occurred; the other uses an idealized version in which the behavior in question, say a drifting end-expiratory lung volume, is replaced by a stable target. If the two simulations produce nearly identical LCI and FRC values, the irregularity was harmless. If they diverge, the size of the divergence, expressed as a percentage, becomes a behavior-specific quality control outcome. The team built seven such tests, covering changes in end-expiratory lung volume, tidal volume variability and size, leaks or trapped gas, the method used to determine end-tidal nitrogen concentration, signal synchronization, and breath detection. A measurement was deemed acceptable if no single test exceeded an estimated impact of 15 percent.

To validate the tool, the researchers re-analyzed an extraordinary dataset: 2,471 nitrogen washout measurements from 84 children with cystic fibrosis, collected between 2012 and 2019 across 754 visits, each visit including at least three completed measurements. The algorithm ran successfully on every single measurement without any manual intervention, taking roughly four seconds per test on an ordinary office computer. That speed matters, because expert quality control is one of the practical barriers to wider adoption of washout testing in clinical routine. The overall acceptance rate was 76 percent of visits, and the mean per-visit variance of LCI dropped from 0.72 turnovers when all measurements were included to 0.39 turnovers when only algorithm-accepted measurements were counted.

The most striking finding is how much of the natural variability in washout results can be attributed to quality control factors. The combined impact estimate from all tests explained around 45 percent of the within-visit variability of LCI in the children with cystic fibrosis, and the median Pearson correlation between estimated impact and observed within-visit LCI variation was 0.83. The largest single effect on LCI came from leaks or trapped gas, which exceeded the acceptability threshold in 31 percent of measurements, followed by changes in end-expiratory lung volume at 23 percent and variations in breath size around the end of the test at 19 percent. Leaks and trapped gas are particularly common in cystic fibrosis because the disease produces extended washout tails, in which the end-tidal nitrogen concentration hovers near the end-of-test threshold and occasionally ticks upward as poorly ventilated pockets of gas are slowly released.

The team also compared the automated judgments with human experts using a second dataset of 100 measurements from six-year-old children, half with cystic fibrosis and half healthy, drawn from the Bern and Swiss infant lung development cohorts. Agreement between the algorithm and expert raters was moderate, with Cohen’s kappa ranging from 0.32 against the rating made on the day of the test to 0.46 against a retrospective rating. Notably, that level of agreement was comparable to the agreement between two experienced human raters themselves, which stood at 0.65. Some disagreements were instructive: current guidelines instruct raters to reject any measurement with a leak, no matter how small, whereas the automated system tolerates minor leaks as long as their estimated impact on outcomes remains negligible. Conversely, experts sometimes struggled to judge visually whether a transient shift in end-expiratory lung volume mattered, while the model could quantify it directly.

The implications extend beyond cystic fibrosis clinics. Because the algorithm judges every irregularity on the same scale, its estimated impact on the primary outcomes, it replaces a patchwork of device-specific and behavior-specific thresholds with a single interpretable metric. The threshold itself can be tuned to the purpose of the test: a strict 15 percent cutoff for research repeatability, or a looser criterion when a clinical LCI is already far above the upper limit of normal and a modest bias would not change the diagnosis. The tool can also be applied retrospectively when measurements are re-analyzed with updated algorithms, and it inherently distinguishes between signal anomalies caused by genuine leaks and those fully explained by the patient’s underlying breathing pattern, a distinction that is especially valuable in patients who cannot achieve high-quality tidal breathing.

Limitations remain. The algorithm was developed for nitrogen washout data from the Ecomedics Exhalyzer D and relies on carbon dioxide, tracer gas, and flow signals; some tests are specific to that device setup, though the authors note that only minor adaptations would be needed for sulfur hexafluoride measurements or other devices. The current implementation runs after the measurement is complete, so a live version that warns operators mid-test to restart a compromised measurement would require further development. Still, the study demonstrates a feasible, fast, and reproducible method for assigning impact estimates to breathing irregularities, and it explains a substantial share of the measurement noise that has long plagued washout testing. For a technique whose value depends on detecting subtle changes in ventilation inhomogeneity over years of follow-up, an objective quality control standard could make the difference between a noisy research tool and a dependable clinical instrument.

Subject of Research: Automated model-based quality control for multiple-breath washout lung function testing in children

Article Title: Quality control in multiple-breath washout measurements: an automated, model-based approach quantifies effects on primary outcomes

Article References: Wyler, F., Borer, S., Curdy, M., Bovermann, X., Frauchiger, B. S., & Latzin, P. (2026). Quality control in multiple-breath washout measurements: an automated, model-based approach quantifies effects on primary outcomes. Frontiers in Medical Engineering, 4, Article 1774073. https://doi.org/10.3389/fmede.2026.1774073

Image Credits: AI Generated

DOI: 10.3389/fmede.2026.1774073

Keywords: multiple-breath washout, lung clearance index, quality control, cystic fibrosis, functional residual capacity, pediatric lung function, nitrogen washout, ventilation inhomogeneity, automated algorithm, respiratory medicine, clinical engineering, Bern University Hospital

To understand why timing matters so much in cystic fibrosis, it helps to review the biology of the disease. Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator, or CFTR, a protein that functions as a chloride and bicarbonate channel on the surface of epithelial cells lining the airways, pancreas, sweat glands, and other organs. When CFTR is absent or dysfunctional, salt and water transport across these epithelia is disrupted, dehydrating the airway surface liquid that normally allows cilia to sweep inhaled pathogens and debris out of the lungs. The result is thick, sticky mucus, chronic infection, relentless inflammation, and, over years, structural lung damage. In the pancreas, the same mechanism blocks digestive enzyme delivery, producing exocrine pancreatic insufficiency in the majority of patients, which impairs growth and nutrition from infancy onward.

The F508del mutation, a deletion of the amino acid phenylalanine at position 508 of the CFTR protein, is carried on at least one allele by roughly ninety percent of people with cystic fibrosis worldwide, and many patients, like those in the new study, are homozygous for it. F508del-CFTR is a doubly defective protein: it folds poorly and is largely retained and degraded inside the cell before it ever reaches the cell membrane, and the small fraction that does reach the surface has an abbreviated residence time and impaired channel gating. This dual defect motivated the development of combination therapy. Lumacaftor acts as a corrector, improving the folding and trafficking of F508del-CFTR so that more protein reaches the cell surface, while ivacaftor acts as a potentiator, increasing the open probability of the channels that do arrive. Together, the two drugs restore a meaningful fraction of CFTR function in patients homozygous for F508del.

CFTR modulators were first tested and approved in adolescents and adults, and the extension of this therapeutic class to younger children has proceeded through carefully staged clinical trials. Phase 3 open-label studies established the safety, pharmacokinetics, and pharmacodynamics of lumacaftor/ivacaftor in children aged two to five years and, subsequently, in children aged one to less than two years, all homozygous for F508del-CFTR. A phase 2 placebo-controlled trial in children two through five years of age further examined whether the drug combination could alter the trajectory of early disease. These trials were essential regulatory stepping stones, but they involved relatively small numbers of children followed under the controlled conditions of a clinical trial. What has been missing is evidence from routine clinical practice, where adherence, dosing, comorbidities, and monitoring differ from the trial setting. The Italian multicenter study addressed precisely this gap by evaluating real-life effectiveness and safety of lumacaftor/ivacaftor in preschool children.

The findings, as summarized in the commentary, provide important real-world evidence that early CFTR modulation improves biomarkers of CFTR function, pulmonary outcomes, and early lung physiology while maintaining an acceptable safety profile. The most direct biomarker of CFTR activity is the sweat chloride concentration. Because defective chloride transport in sweat glands is the biochemical hallmark of cystic fibrosis, elevated sweat chloride is the diagnostic gold standard, and reductions in sweat chloride following modulator therapy serve as a pharmacodynamic readout of restored channel function. Proof-of-concept work with ivacaftor established sweat chloride as a responsive biomarker, and subsequent studies have documented that modulator-induced reductions vary considerably between individuals, a heterogeneity that clinicians must keep in mind when interpreting individual responses. The Italian study’s demonstration that sweat chloride improves in treated preschoolers confirms that the drugs are engaging their biological target even in very young children.

Perhaps more consequential than the biomarker data are the pulmonary findings. Lung disease in cystic fibrosis begins far earlier than symptoms suggest, and by the preschool years many children already have measurable abnormalities even though standard spirometry remains normal. This is because forced expiratory volume in one second, the workhorse measure of lung function in older patients, is insensitive to the early peripheral airway disease that characterizes the beginning of the cystic fibrosis lung phenotype. The lung clearance index, derived from multiple-breath washout testing, measures the ventilation inhomogeneity that arises when small airways become obstructed, and it can be performed reliably in sleeping preschool children. Normative multiple-breath washout data corrected for sensor error have made standardized interpretation possible, and longitudinal studies have shown that an elevated lung clearance index at four years of age predicts subsequent lung function, and that determinants of progression measured by this index can be identified early in life. In other words, the lung clearance index captures the earliest, still potentially reversible phase of cystic fibrosis lung disease.

Against this background, the observation that early lumacaftor/ivacaftor therapy improves early lung physiology takes on real significance. The phase 2 placebo-controlled trial of lumacaftor/ivacaftor in children two through five years of age had previously suggested effects on disease progression, and the new real-world data extend that signal into routine care. If modulator therapy started in the preschool years can hold the lung clearance index in the normal range, or prevent the rise that typically heralds progressive small airway obstruction, clinicians may be able to defer or prevent the cascade of infection, inflammation, and structural remodeling that has historically defined the disease course. Chest computed tomography scores, which quantify structural lung damage, have also been shown to improve with the newer triple-combination modulator elexacaftor/tezacaftor/ivacaftor in people aged twelve years and older in the RECOVER trial, reinforcing the principle that CFTR restoration can favorably influence both physiology and structure.

The therapeutic landscape has, of course, moved beyond lumacaftor/ivacaftor. The triple combination of elexacaftor, tezacaftor, and ivacaftor, which pairs two correctors with a potentiator, has demonstrated substantially greater clinical benefit than earlier dual combinations and has been tested in an open-label phase 3 trial in children aged two to five years with at least one F508del allele. Many centers now favor triple therapy where it is available and appropriate. Nevertheless, the Italian study of lumacaftor/ivacaftor remains valuable for several reasons. It documents the effectiveness of dual modulator therapy under real-world conditions in a population in which trial data were limited, it adds to the safety database for young children exposed to these drugs during a critical window of lung development, and it demonstrates the feasibility of conducting multicenter prospective effectiveness studies in this age group. Lumacaftor/ivacaftor also continues to be used in parts of the world where access to newer, more expensive modulators is constrained, making real-world evidence about its performance directly relevant to global practice.

Safety considerations are central to any discussion of treating preschool children with chronic medications. Young children are not simply small adults: they metabolize drugs differently, they cannot reliably report symptoms, and their organs are still developing. The phase 3 studies of lumacaftor/ivacaftor in children aged two to five and one to less than two years established age-appropriate dosing based on pharmacokinetic modeling and documented a tolerability profile consistent with that seen in older patients, with the important caveat that liver function monitoring is required because transaminase elevations have been observed with lumacaftor-containing regimens. The commentary emphasizes that the multicenter Italian study maintained an acceptable safety profile in routine practice, which is reassuring for clinicians who must weigh the long-term benefits of early intervention against the burdens of daily therapy, drug interactions, and laboratory surveillance in toddlers and preschoolers.

The larger message of this body of work is a conceptual one about the natural history of cystic fibrosis and the window in which it can be modified. For decades, treatment was largely reactive, responding to infections and decline as they occurred, and the median survival improved slowly through airway clearance, inhaled antibiotics, pancreatic enzyme replacement, and nutritional support. CFTR modulators changed the equation by addressing the primary molecular defect, and the accumulating evidence from infants and preschoolers suggests that the earlier the molecular defect is corrected, the better the chance of preserving near-normal organ function. Newborn screening now identifies most affected children within weeks of birth, and pancreatic insufficiency in early childhood can be managed with enzyme replacement and nutritional strategies in the era of personalized medicine. What remains is to determine, through studies like the Italian multicenter investigation and the trials that preceded it, exactly how early modulator therapy should begin, which biomarkers best guide treatment decisions in individual children, and whether the improvements seen in sweat chloride and lung clearance index translate into the ultimate outcomes that matter: preserved lung structure, freedom from chronic infection, and a life expectancy and quality of life approaching those of children without the disease. The real-world data from preschool children homozygous for F508del, together with the expert commentary they prompted, support the broader concept that intervention during early childhood offers a genuine opportunity to modify disease progression before irreversible organ damage develops, and they provide clinicians and families with evidence that starting treatment early is not merely biologically plausible but demonstrably beneficial.

Subject of Research: Real-world effectiveness and safety of early CFTR modulator therapy in preschool children with cystic fibrosis

Article Title: Early CFTR modulation and clinical outcomes in preschool cystic fibrosis

Article References: Lawandos, L., & Sodhi, C. P. (2026). Early CFTR modulation and clinical outcomes in preschool cystic fibrosis. Pediatric Research. https://doi.org/10.1038/s41390-026-05441-2

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05441-2

Keywords: cystic fibrosis, CFTR modulators, lumacaftor/ivacaftor, F508del, preschool children, lung clearance index, sweat chloride, pediatric research, early intervention, real-world evidence, lung disease progression, Early

Spirometry, the familiar test in which a patient blows forcefully into a mouthpiece, measures how much air can be exhaled and how quickly. It is cheap, widely available and reproducible, which explains its dominance in both clinics and research studies. Yet it fundamentally measures airflow through large and medium airways. The injury pattern left by extreme preterm birth, often described as chronic lung disease of prematurity or bronchopulmonary dysplasia in its severe forms, is primarily one of disrupted alveolar and vascular development. The distal lung, where gas exchange actually happens, and the pulmonary circulation, which must carry the entire cardiac output through a finely branched vascular tree, are the structures most affected. Spirometry can remain deceptively normal in people whose gas transfer capacity and pulmonary vasculature are substantially impaired.

The evidence for this blind spot is accumulating rapidly. A study by Harris and colleagues, published in Pediatric Research, examined school-aged children born preterm and found that reduced diffusion of carbon monoxide across the lung, a marker of impaired gas exchange surface, was associated with elevated pulmonary artery pressures. This finding is significant because it links two silent abnormalities: a lung that cannot transfer oxygen efficiently and a heart that must pump against higher resistance in the pulmonary circulation. Neither abnormality would necessarily be flagged by a routine spirometry test, and both may progress quietly for decades before producing symptoms.

Longitudinal data reinforce the concern. Research published in the European Respiratory Journal followed individuals born extremely preterm into adulthood and documented persistent deficits in lung diffusion capacity that did not normalize with growth. A systematic review and meta-analysis by Gibbons and colleagues in the European Respiratory Review synthesized findings across lung volumes, gas transfer and oscillometry, a technique that measures airway resistance during quiet tidal breathing rather than forced expiration. Together, these studies sketch a consistent picture: preterm birth leaves a durable imprint on the distal lung and its mechanics that forced expiratory volumes capture only partially, if at all.

The clinical implications extend beyond the lungs. Survivors of extreme preterm birth appear to face elevated long-term risks of pulmonary vascular disease and cardiovascular complications, a concern articulated in a lifespan-oriented framework by Simpson and colleagues in The Lancet Respiratory Medicine. The developing lung and its vasculature are built in tandem during the canalicular and saccular stages of gestation, precisely the window that extreme preterm birth interrupts. When alveolarization is curtailed, the vascular tree that should accompany each new alveolus is curtailed with it. The result is a lung with fewer, larger airspaces and a reduced, remodeled vascular bed, a combination that increases the workload on the right ventricle and may set the stage for pulmonary hypertension and early cardiovascular decline in adult life.

What would a comprehensive assessment look like in practice? The commentary by Beaven and Finlay points toward a battery of complementary tests, each interrogating a different component of the cardiopulmonary system. Lung clearance index, derived from multiple-breath washout, quantifies ventilation inhomogeneity in the small airways and peripheral lung units, and has proven sensitive to early lung disease in other pediatric populations. Body plethysmography measures total lung volumes, revealing the restricted or hyperinflated patterns that spirometry alone can miss. The single-breath or rebreathing diffusing capacity for carbon monoxide directly probes the gas exchange surface. Oscillometry adds information about peripheral airway resistance without requiring maximal effort, an important advantage in young children who cannot reliably perform forced maneuvers.

Cardiovascular assessment deserves equal billing. Echocardiography can estimate pulmonary artery pressures and right ventricular function, while newer techniques such as cardiac magnetic resonance imaging offer precise quantification of right ventricular mass and ejection fraction. Exercise testing integrates the entire system, revealing whether oxygen delivery keeps pace with metabolic demand, and cardiopulmonary exercise testing can unmask limitations that are invisible at rest. Reduced exercise capacity has been documented in preterm-born cohorts, and the physiological basis, whether ventilatory limitation, gas exchange impairment, vascular limitation or deconditioning, can only be disentangled by measuring multiple variables simultaneously during exertion.

The concept of treatable traits offers a compelling rationale for this expanded toolkit. As Zanetto and colleagues argued recently in the American Journal of Respiratory and Critical Care Medicine, clinicians caring for preterm-born individuals with chronic lung disease of prematurity should identify and target specific, modifiable characteristics across the lifespan rather than relying on a single diagnostic label. A patient with preserved spirometry but reduced diffusion capacity and elevated pulmonary artery pressures needs a very different management plan from one with airflow obstruction and air trapping. Without comprehensive phenotyping, the first patient may be falsely reassured and the second may receive therapies that do not address their dominant abnormality. Treatable traits might include airway reactivity, ventilation inhomogeneity, impaired gas transfer, pulmonary vascular dysfunction, muscle weakness and physical deconditioning, each with its own therapeutic levers.

There are practical hurdles to overcome before comprehensive assessment becomes standard care. Many of the recommended tests require specialized equipment, trained personnel and cooperative patients, which limits their availability in ordinary clinical settings and in the low-resource environments where much of the world’s preterm births occur. Reference ranges for children and young adults born preterm are incomplete for several modalities, complicating interpretation. Radiation exposure argues against routine computed tomography, and the research community continues to seek safe, non-invasive imaging surrogates of alveolar and vascular structure. Standardizing protocols across centers and across the age spectrum, from infancy through adulthood, remains an unfinished project, and longitudinal cohorts that follow preterm-born individuals with repeated multi-modal assessments are still relatively rare.

Nevertheless, the direction of travel is clear. The generation born after the widespread adoption of surfactant therapy and gentle ventilation is now reaching adulthood in large numbers, and their long-term cardiopulmonary trajectory is becoming a matter of public health, not just neonatology. Detecting silent gas exchange impairment and early pulmonary vascular change during the school years, when interventions such as exercise programs, vaccination, smoking prevention and targeted follow-up can still alter the course, is far preferable to discovering these problems when symptomatic disease emerges in mid-life. The commentary by Beaven and Finlay makes the case that spirometry, whatever its virtues, cannot carry this burden alone. A comprehensive cardiopulmonary assessment, combining measures of lung volume, ventilation distribution, gas transfer, airway mechanics, pulmonary hemodynamics and exercise capacity, offers the best chance of understanding, monitoring and ultimately improving the lifelong health of the fastest-growing population of adult survivors of neonatal intensive care.

Subject of Research: Cardiopulmonary assessment of lung and cardiovascular outcomes in survivors of extreme preterm birth

Article Title: Beyond spirometry: towards comprehensive cardiopulmonary assessment after extreme preterm birth

Article References: Beaven, M. L., & Finlay, P. (2026). Beyond spirometry: towards comprehensive cardiopulmonary assessment after extreme preterm birth. Pediatric Research. https://doi.org/10.1038/s41390-026-05399-1

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05399-1

Keywords: extreme preterm birth, bronchopulmonary dysplasia, spirometry, lung diffusion capacity, pulmonary hypertension, chronic lung disease of prematurity, lung clearance index, oscillometry, cardiopulmonary exercise testing, treatable traits, pediatric lung function, right ventricular function