Increased intrapulmonary shunt and alveolar dead space post-COVID-19.

Increased intrapulmonary shunt (QS/Qt) and alveolar dead space (VD/VT) are present in early recovery from 2019 Novel Coronavirus (COVID-19). We hypothesized patients recovering from severe critical acute illness (NIH category 3-5) would have greater and longer lasting increased QS/Qt and VD/VT than patients with mild-moderate acute illness (NIH 1-2). Fifty-nine unvaccinated patients (33 males, aged 52 [38-61] yr, body mass index [BMI] 28.8 [25.3-33.6] kg/m2; median [IQR], 44 previous mild-moderate COVID-19, and 15 severe-critical disease) were studied 15-403 days postacute severe acute respiratory syndrome coronavirus infection. Breathing ambient air, steady-state mean alveolar Pco2, and Po2 were recorded simultaneously with arterial Po2/Pco2 yielding aAPco2, AaPo2, and from these, QS/Qt%, VD/VT%, and relative alveolar ventilation (40 mmHg/[Formula: see text], VArel) were calculated. Median [Formula: see text] was 39.4 [35.6-41.1] mmHg, [Formula: see text] 92.3 [87.1-98.2] mmHg; [Formula: see text] 32.8 [28.6-35.3] mmHg, [Formula: see text] 112.9 [109.4-117.0] mmHg, AaPo2 18.8 [12.6-26.8] mmHg, aAPco2 5.9 [4.3-8.0] mmHg, QS/Qt 4.3 [2.1-5.9] %, and VD/VT16.6 [12.6-24.4]%. Only 14% of patients had normal QS/Qt and VD/VT; 1% increased QS/Qt but normal VD/VT; 49% normal QS/Qt and elevated VD/VT; 36% both abnormal QS/Qt and VD/VT. Previous severe critical COVID-19 predicted increased QS/Qt (2.69 [0.82-4.57]% per category severity [95% CI], P < 0.01), but not VD/VT. Increasing age weakly predicted increased VD/VT (1.6 [0.1-3.2]% per decade, P < 0.04). Time since infection, BMI, and comorbidities were not predictors (all P > 0.11). VArel was increased in most patients. In our population, recovery from COVID-19 was associated with increased QS/Qt in 37% of patients, increased VD/VT in 86%, and increased alveolar ventilation up to ∼13 mo postinfection. NIH severity predicted QS/Qt but not elevated VD/VT. Increased VD/VT suggests pulmonary microvascular pathology persists post-COVID-19 in most patients.NEW & NOTEWORTHY Using novel methodology quantifying intrapulmonary shunt and alveolar dead space in COVID-19 patients up to 403 days after acute illness, 37% had increased intrapulmonary shunt and 86% had elevated alveolar dead space likely due to independent pathology. Elevated shunt was partially related to severe acute illness, and increased alveolar dead space was weakly related to increasing age. Ventilation was increased in the majority of patients regardless of previous disease severity. These results demonstrate persisting gas exchange abnormalities after recovery.

Intrapulmonary shunt and alveolar dead space in a cohort of patients with acute COVID-19 pneumonitis and early recovery.

BACKGROUND: Pathological evidence suggests that coronavirus disease 2019 (COVID-19) pulmonary infection involves both alveolar damage (causing shunt) and diffuse microvascular thrombus formation (causing alveolar dead space). We propose that measuring respiratory gas exchange enables detection and quantification of these abnormalities. We aimed to measure shunt and alveolar dead space in moderate COVID-19 during acute illness and recovery. METHODS: We studied 30 patients (22 males; mean±sd age 49.9±13.5 years) 3-15 days from symptom onset and again during recovery, 55±10 days later (n=17). Arterial blood (breathing ambient air) was collected while exhaled oxygen and carbon dioxide concentrations were measured, yielding alveolar-arterial differences for each gas (P A-aO2 and P a-ACO2 , respectively) from which shunt and alveolar dead space were computed. RESULTS: For acute COVID-19 patients, group mean (range) for P A-aO2 was 41.4 (-3.5-69.3) mmHg and for P a-ACO2 was 6.0 (-2.3-13.4) mmHg. Both shunt (% cardiac output) at 10.4% (0-22.0%) and alveolar dead space (% tidal volume) at 14.9% (0-32.3%) were elevated (normal: <5% and <10%, respectively), but not correlated (p=0.27). At recovery, shunt was 2.4% (0-6.1%) and alveolar dead space was 8.5% (0-22.4%) (both p<0.05 versus acute). Shunt was marginally elevated for two patients; however, five patients (30%) had elevated alveolar dead space. CONCLUSIONS: We speculate impaired pulmonary gas exchange in early COVID-19 pneumonitis arises from two concurrent, independent and variable processes (alveolar filling and pulmonary vascular obstruction). For most patients these resolve within weeks; however, high alveolar dead space in ∼30% of recovered patients suggests persistent pulmonary vascular pathology.

Pulmonary function testing during SARS-CoV-2: An ANZSRS/TSANZ position statement.

The Thoracic Society of Australia and New Zealand (TSANZ) and the Australian and New Zealand Society of Respiratory Science (ANZSRS) commissioned a joint position paper on pulmonary function testing during coronavirus disease 2019 (COVID-19) in July 2021. A working group was formed via an expression of interest to members of both organizations and commenced work in September 2021. A rapid review of the literature was undertaken, with a 'best evidence synthesis' approach taken to answer the research questions formed. This allowed the working group to accept findings of prior relevant reviews or societal document where appropriate. The advice provided is for providers of pulmonary function tests across all settings. The advice is intended to supplement local infection prevention and state, territory or national directives. The working group's key messages reflect a precautionary approach to protect the safety of both healthcare workers (HCWs) and patients in a rapidly changing environment. The decision on strategies employed may vary depending on local transmission and practice environment. The advice is likely to require review as evidence grows and the COVID-19 pandemic evolves. While this position statement was contextualized specifically to the COVID-19 pandemic, the working group strongly advocates that any changes to clinical/laboratory practice, made in the interest of optimizing the safety and well-being of HCWs and patients involved in pulmonary function testing, are carefully considered in light of their potential for ongoing use to reduce transmission of other droplet and/or aerosol borne diseases.

Effect of combination inhaled therapy on ventilation distribution measured by SPECT/CT imaging in uncontrolled asthma.

Asthma is characterized by heterogeneous ventilation as measured by three-dimensional ventilation imaging. Combination inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) treatment response is variable in asthma, and effects on regional ventilation are unknown. Our aims were to determine whether regional ventilation defects decrease after ICS/LABA treatment and whether small airways dysfunction predicts response in uncontrolled asthma. Twenty-two symptomatic participants with asthma underwent single-photon emission computed tomography (SPECT)/CT imaging with Technegas, before and after 8-wk fluticasone/formoterol (1,000/40 µg/day) treatment. Lung regions that were nonventilated, low ventilated, or well ventilated were calculated using an adaptive threshold method and were expressed as a percentage of total lung volume. Multiple-breath nitrogen washout (MBNW) was used to measure diffusion-dependent and convection-dependent small airways function (Sacin and Scond, respectively). Forced oscillation technique (FOT) was used to measure respiratory system resistance and reactance. At baseline and posttreatment, Scond z-score was related to percentage of nonventilated lung, whereas Sacin z-score was related to percentage of low-ventilated lung. Although symptoms, spirometry, FOT, and MBNW improved following treatment, there was no mean change in ventilation measured by SPECT. There was, however, a wide range of changes in SPECT ventilation such that greater percentage of nonventilated lung, older age, and higher Scond predicted a reduction in nonventilated lung after treatment. SPECT ventilation defects are overall unresponsive to ICS/LABA, but the response is variable, with improvement occurring when small airways dysfunction and ventilation defects are more severe. Persistent ventilation defects that correlate with Scond suggest that mechanisms such as non-ICS responsive inflammation or remodeling underlie these defects.NEW & NOTEWORTHY This study provides insights into the mechanisms of high-dose ICS treatment in uncontrolled asthma. Ventilation defects as measured by SPECT/CT imaging respond heterogeneously to increased ICS/LABA treatment, with improvement occurring when ventilation defects and impairment of convection-dependent small airways function are more severe. Persistent correlations between ventilation defects and measures of small airways function suggest the potential presence of ICS nonresponsive inflammation and/or remodeling.

Controlled versus free breathing for multiple breath nitrogen washout in healthy adults.

Multiple breath nitrogen washout (MBNW) quantifies ventilation heterogeneity. Two distinct protocols are currently used for MBNW testing: "controlled breathing", with targeted tidal volume (V T) and respiratory rate (RR); and "free breathing", with no constraints on breathing pattern. Indices derived from the two protocols (functional residual capacity (FRC), lung clearance index (LCI), S cond, S acin) have not been directly compared in adults. We aimed to determine whether MBNW indices are comparable between protocols, to identify factors underlying any between-protocol differences and to determine the between-session variabilities of each protocol. We performed MBNW testing by both protocols in 27 healthy adult volunteers, applying the currently proposed correction for V T to S cond and S acin derived from free breathing. To establish between-session variability, we repeated testing in 15 volunteers within 3 months. While FRC was comparable between controlled versus free breathing (3.17 (0.98) versus 3.18 (0.94) L, p=0.88), indices of ventilation heterogeneity derived from the two protocols were not, with poor correlation for S cond (r=0.18, p=0.36) and significant bias for S acin (0.057 (0.021) L-1 versus 0.085 (0.038) L-1, p=0.0004). Between-protocol differences in S acin were related to differences in the breathing pattern, i.e. V T (p=0.004) and RR (p=0.01), rather than FRC. FRC and LCI showed good between-session repeatability, but S cond and S acin from free breathing showed poor repeatability with wide limits of agreement. These findings have implications for the ongoing clinical implementation of MBNW, as they demonstrate that S cond and S acin from free breathing, despite V T correction, are not equivalent to the controlled breathing protocol. The poor between-session repeatability of S cond during free breathing may limit its clinical utility.

Ventilation heterogeneity and oscillometry predict asthma control improvement following step-up inhaled therapy in uncontrolled asthma.

BACKGROUND AND OBJECTIVE: Abnormal peripheral airway function is an important feature of asthma and relates to asthma symptoms and poor asthma control. We aimed to determine whether peripheral airway function, as measured by forced oscillatory impedance and multiple-breath nitrogen washout (MBNW), relates to symptom improvement in asthmatic participants with uncontrolled asthma, after stepping up to high-dose ICS/LABA treatment. METHODS: A total of 19 subjects (14 females, mean age: 29.9 ± 13.6 years) with uncontrolled asthma, as defined by an ACQ5 > 1.5, taking 500 µg/day fluticasone equivalent or less, underwent spirometry, plethysmography, fractional exhaled FeNO, forced oscillatory resistance (Rrs5Hz ) and reactance (Xrs5Hz ), and indices of MBNW ventilation heterogeneity (lung clearance index (LCI), diffusion-convection-dependent (Sacin) and convection-dependent (Scond)). Measurements were made before and after 8 weeks of treatment with fluticasone/formoterol combination inhaler 250/10 µg, 2 puffs twice daily. RESULTS: Treatment improved ACQ5 (P = 0.0002), FEV1 (P = 0.02), FVC (P = 0.04), FeNO (P = 0.0008), Xrs5Hz (P = 0.01), LCI (P = 0.0002), Sacin (P = 0.006) and Scond (P = 0.01). At baseline, ACQ5 correlated with Xrs5Hz (rs = 0.52, P = 0.03) and Rrs5Hz (rs = 0.55, P = 0.02). The improvement in ACQ5 was predicted by more abnormal baseline LCI (P = 0.03), Scond (P = 0.02) and Rrs5Hz (P = 0.006). Baseline Scond was the best predictor of a clinically meaningful improvement in asthma control (ΔACQ > 0.5, ROC-AUC = 0.91, P = 0.007). CONCLUSION: Step-up to high-dose combination treatment in uncontrolled asthma is associated with improved peripheral airway function as measured by Xrs5Hz and MBNW. Baseline MBNW and FOT parameters correlated with the improvement in symptoms and may predict a positive response to up-titration in uncontrolled asthmatic patients.

Dismantling the pathophysiology of asthma using imaging.

Asthma remains an important disease worldwide, causing high burden to patients and healthcare systems and presenting a need for better management and ultimately prevention and cure. Asthma is a very heterogeneous condition, with many different pathophysiological processes. Better measurement of those pathophysiological processes are needed to better phenotype disease, and to go beyond the current, highly limited measurements that are currently used: spirometry and symptoms. Sophisticated three-dimensional lung imaging using computed tomography and ventilation imaging (single photon emission computed tomography and positron emission tomography) and magnetic resonance imaging and methods of lung imaging applicable to asthma research are now highly developed. The body of current evidence suggests that abnormalities in structure and ventilatory function measured by imaging are clinically relevant, given their associations with disease severity, exacerbation risk and airflow obstruction. Therefore, lung imaging is ready for more widespread use in clinical trials and to become part of routine clinical assessment of asthma.

V/Q SPECT-Normal Values for Lobar Function and Comparison With CT Volumes.

Ventilation and perfusion lung imaging with SPECT/CT permits accurate delineation of the individual lobes of the lungs using the CT images for use in ascribing the relative functional contribution to overall lung function of the lobes of both ventilation and perfusion. Moreover, an advantage of using Technegas as the ventilation agent and radiolabelled macro-aggregated albumin microspheres as the perfusion agent is that the deposition pattern is fixed upon administration and thus different patient postures can be studied and the effect of gravity and position determined, even though the scans must be acquired with the subject supine using conventional gamma camera SPECT/CT systems. In this paper we report on normal ranges for functional contribution of the individual lobes of the lung to overall function studied in the supine and erect positions in a small cohort of normal subjects. Differences are seen between the anatomical volumes as determined by segmentation of the CT scans and the ventilation and perfusion contributions in the different positions. As pulmonary function testing in the respiratory laboratory is usually performed in the upright position we perform all of our clinical imaging lung function studies in this position (for radiotracer administration) also. The methodology for measuring lobar function is minimally invasive, readily available, and would be hard to imagine being acquired as readily with any other technique.

Contribution of peripheral airway function to changes in FEV1/FVC and RV/TLC with aging.

Multiple breath nitrogen washout (MBNW) indices provide insight into ventilation heterogeneity globally [lung clearance index (LCI)] and within acinar (Sacin) and conducting (Scond) airways. Normal aging leads to an accelerated deterioration of Sacin in older adults, but little is known about the contribution of peripheral airway function to changes in pulmonary function indices reflecting expiratory airflow [forced expiratory volume in one second (FEV1)/forced vital capacity (FVC)] and gas trapping [residual volume (RV)/total lung capacity (TLC)] with aging. We aimed to examine associations between MBNW and FEV1/FVC as well as RV/TLC in healthy adults, and to determine if these relationships differ in older (≥50 yr) versus younger subjects (<50 yr). Seventy-nine healthy adult volunteers aged 23-89 yr with no cardiac or respiratory disease and a smoking history of <5 pack-years underwent spirometry, plethysmography, and MBNW. After adjustment for sex, height, and body mass index, the following relationships were present across the entire cohort: Sacin was inversely related to FEV1/FVC (R2 = 0.22, P < 0.001); Sacin and Scond were positively related to RV/TLC (R2 = 0.53, P < 0.001); on separate analyses, the relationship between Sacin and FEV1/FVC was strongest in the older group (R2 = 0.20, P = 0.003) but markedly weaker in the younger group (R2 = 0.09, P = 0.04); and Sacin and Scond were related to RV/TLC in older (R2 = 0.20, P = 0.003) but not younger subgroups. No relationships were observed between LCI and FEV1/FVC or RV/TLC. Changes in FEV1/FVC and RV/TLC are at least in part due to changes in peripheral airway function with aging. Further studies of the relationships between MBNW and standard pulmonary function indices may prove useful for their combined application and interpretation in obstructive airways disease. NEW & NOTEWORTHY This study explores associations between multiple breath nitrogen washout (MBNW) and standard pulmonary function indices reflecting expiratory airflow [forced expiratory volume in one second (FEV1)/forced vital capacity (FVC)] and gas trapping [residual volume (RV)/total lung capacity (TLC)] in healthy adults across a wide range of ages. We have demonstrated statistically significant relationships between MBNW and FEV1/FVC as well as RV/TLC. These findings provide novel evidence of the contribution of peripheral airway function to changes in standard pulmonary function indices with aging.

Peripheral ventilation heterogeneity determines the extent of bronchoconstriction in asthma.

In asthma, bronchoconstriction causes topographically heterogeneous airway narrowing, as measured by three-dimensional ventilation imaging. Computation modeling suggests that peripheral airway dysfunction is a potential determinant of acute airway narrowing measured by imaging. We hypothesized that the development of low-ventilation regions measured topographically by three-dimensional imaging after bronchoconstriction is predicted by peripheral airway function. Fourteen asthmatic subjects underwent ventilation single-photon-emission computed tomography/computed tomography scan imaging before and after methacholine challenge. One-liter breaths of Technegas were inhaled from functional residual capacity in upright posture before supine scanning. The lung regions with the lowest ventilation (Ventlow) were calculated using a thresholding method and expressed as a percentage of total ventilation (Venttotal). Multiple-breath nitrogen washout was used to measure diffusion-dependent and convection-dependent ventilation heterogeneity (Sacin and Scond, respectively) and lung clearance index (LCI), before and after challenge. Forced expiratory volume in 1 s (FEV1) was 87.6 ± 15.8% predicted, and seven subjects had airway hyperresponsiveness. Ventlow at baseline was unrelated to spirometry or multiple-breath nitrogen washout indices. Methacholine challenge decreased FEV1 by 23 ± 5% of baseline while Ventlow increased from 21.5 ± 2.3%Venttotal to 26.3 ± 6.7%Venttotal (P = 0.03). The change in Ventlow was predicted by baseline Sacin (rs = 0.60, P = 0.03) and by LCI (rs = 0.70, P = 0.006) but not by Scond (rs = 0.30, P = 0.30). The development of low-ventilation lung units in three-dimensional ventilation imaging is predicted by ventilation heterogeneity in diffusion-dependent airways. This relationship suggests that acinar ventilation heterogeneity in asthma may be of mechanistic importance in terms of bronchoconstriction and airway narrowing.NEW & NOTEWORTHY Using ventilation SPECT/CT imaging in asthmatics, we show induced bronchoconstriction leads to the development of areas of low ventilation. Furthermore, the relative volume of the low-ventilation regions was predicted by ventilation heterogeneity in diffusion-dependent acinar airways. This suggests that the pattern of regional airway narrowing in asthma is determined by acinar airway function.

Day-to-day variability of oscillatory impedance and spirometry in asthma and COPD.

Variability in airway function may be a marker of disease activity in COPD and asthma. The aim was to determine the effects of repeatability and airway obstruction on day-to-day variability in respiratory system resistance (Rrs) and reactance (Xrs) measured by forced oscillation technique (FOT). Three groups of 10 subjects; normals, stable asthmatic and stable COPD subjects underwent daily FOT recordings for 7 days. Mean total and inspiratory Rrs and Xrs, and expiratory flow limitation (EFL) Index (inspiratory - expiratory Xrs), were calculated. The ICC's were high for all parameters in all groups. Repeatability, in terms of absolute units, correlated with airway obstruction and was therefore lowest in COPD. Day-to-day variability was due mostly to repeatability, with a small contribution from the mean value for some parameters. FOT measures are highly repeatable in health, stable asthma and COPD in relation to the wide range of measures between subjects. For home monitoring in asthma and COPD, either the coefficient of variation or individualized SDs could be used to define day-to-day variability.

Airway closure on imaging relates to airway hyperresponsiveness and peripheral airway disease in asthma.

The regional pattern and extent of airway closure measured by three-dimensional ventilation imaging may relate to airway hyperresponsiveness (AHR) and peripheral airways disease in asthmatic subjects. We hypothesized that asthmatic airways are predisposed to closure during bronchoconstriction in the presence of ventilation heterogeneity and AHR. Fourteen asthmatic subjects (6 women) underwent combined ventilation single photon emission computed tomography/computed tomography scans before and after methacholine challenge. Regional airway closure was determined by complete loss of ventilation following methacholine challenge. Peripheral airway disease was measured by multiple-breath nitrogen washout from which S(cond) (index of peripheral conductive airway abnormality) was derived. Relationships between airway closure and lung function were examined by multiple-linear regression. Forced expiratory volume in 1 s was 87.5 ± 15.8% predicted, and seven subjects had AHR. Methacholine challenge decreased forced expiratory volume in 1 s by 23 ± 5% and increased nonventilated volume from 16 ± 4 to 29 ± 13% of computed tomography lung volume. The increase in airway closure measured by nonventilated volume correlated independently with both S(cond) (partial R(2) = 0.22) and with AHR (partial R(2) = 0.38). The extent of airway closure induced by methacholine inhalation in asthmatic subjects is greater with increasing peripheral airways disease, as measured by ventilation heterogeneity, and with worse AHR.

The relationship between airflow obstruction, emphysema extent, and small airways function in COPD.

BACKGROUND: The severities of COPD (FEV(1) % predicted) and airflow obstruction (FEV(1)/FVC) are considered to be due to both emphysema and small airways disease. To our knowledge, this has not been previously confirmed by combined measurements of emphysema and of small airway function. We hypothesized that small airways disease and emphysema extent contribute independently to the severity of both COPD and airflow obstruction. METHODS: Twenty-six subjects with COPD underwent measurements with forced oscillation technique (FOT) at 6 Hz and single-breath nitrogen washout. Respiratory system resistance, respiratory system reactance (Xrs), and expiratory flow limitation (EFL) index (measured as mean inspiratory Xrs − expiratory Xrs) were derived from FOT. Closing volume/vital capacity (CV/VC) was derived from the washout. Emphysema extent was measured as low attenuation areas < -910 Hounsfield units, expressed as a percentage of CT scan lung volume from multislice CT scans taken at total lung capacity. RESULTS: Subjects were aged (mean ± SD) 69.6 ± 8.0 years. Postbronchodilator FEV(1) was 64.8 ± 19.8% predicted, and diffusing capacity of lung for carbon monoxide was 50.7 ± 15.8% predicted. Emphysema extent was 22.6% ± 15.0% CT scan volume. CV/VC was 16.9% ± 7.9%; Xrs, -3.72 ± 3.03 cm H(2)O/L/s; and EFL index, 3.88 ± 3.93 cm H(2)O/L/s. In multiple regression analyses, FEV(1)/FVC was predicted by both emphysema and CV/VC (model r(2) = 0.54, P < .0001) whereas FEV(1) % predicted was predicted by emphysema and EFL index (model r(2) = 0.38, P = .0014). CONCLUSIONS: The severities of COPD and airflow obstruction are independently predicted by both small airways disease and emphysema extent.