A randomized phase II clinical trial of stereotactic body radiation therapy (SBRT) and systemic pembrolizumab with or without intratumoral avelumab/ipilimumab plus CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells in solid tumors.

BACKGROUND: Radiotherapy (RT) synergizes with immune checkpoint blockade (ICB). CD1c(BDCA-1)+/CD141(BDCA-3)+ myeloid dendritic cells (myDC) in the tumor microenvironment are indispensable at initiating effector T-cell responses and response to ICB. METHODS: In this phase II clinical trial, anti-PD-1 ICB pretreated oligometastatic patients (tumor agnostic) underwent a leukapheresis followed by isolation of CD1c(BDCA-1)+/CD141(BDCA-3)+ myDC. Following hypofractionated stereotactic body RT (3 × 8 Gy), patients were randomized (3:1). Respectively, in arm A (immediate treatment), intratumoral (IT) ipilimumab (10 mg) and avelumab (40 mg) combined with intravenous (IV) pembrolizumab (200 mg) were administered followed by IT injection of myDC; subsequently, IV pembrolizumab and IT ipilimumab/avelumab were continued (q3W). In arm B (contemporary control arm), patients received IV pembrolizumab, with possibility to cross-over at progression. Primary endpoint was 1-year progression-free survival rate (PFS). Secondary endpoints were safety, feasibility, objective response rate, PFS, and overall survival (OS). RESULTS: Thirteen patients (10 in arm A, eight non-small cell lung cancer, and five melanoma) were enrolled. Two patients crossed over. One-year PFS rate was 10% in arm A and 0% in arm B. Two patients in arm A obtained a partial response, and one patient obtained a stable disease as best response. In arm B, one patient obtained a SD. Median PFS and OS were 21.8 weeks (arm A) versus 24.9 (arm B), and 62.7 versus 57.9 weeks, respectively. An iatrogenic pneumothorax was the only grade 3 treatment-related adverse event. CONCLUSION: SBRT and pembrolizumab with or without IT avelumab/ipilimumab and IT myDC in oligometastatic patients are safe and feasible with a clinically meaningful tumor response rate. However, the study failed to reach its primary endpoint. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT04571632 (09 AUG 2020). EUDRACT: 2019-003668-32. Date of registration: 17 DEC 2019, amendment 1: 6 MAR 2021, amendment 2: 4 FEB 2022.

Therapeutical strategies in cavitary legionnaires' disease, two cases from the field and a systematic review.

BACKGROUND: Legionnaires' Disease (LD) rarely evolves into pulmonary abscesses. The current systematic review has been designed to explore therapeutical strategies in pulmonary cavitary LD. METHODS: A research strategy was developed and applied to the databases Embase, Pubmed, and Web of Science from the 1st of January 2000 to the 1st of November 2022. Original articles, case series, case reports, and guidelines written in English, French, German, Italian, and Dutch were considered. Furthermore, medical records of patients treated at the University Hospital UZ Brussel for LD cavitary pneumonia, between the 1st of January 2016 to the 1st of January 2022, were reviewed. RESULTS: Two patients were found by the UZ Brussel's medical records investigation. Through the literature review, 23 reports describing 29 patients, and seven guidelines were identified. The overall evidence level was low. RESULT OF SYNTHESIS (CASE REPORTS): The median age was 48 years and 65% were male. A polymicrobial infection was detected in 11 patients (44%) with other aerobic bacteria being the most commonly found. At diagnosis, 52% of patients received combination therapy, and fluoroquinolones were the preferred antimicrobial class. Anaerobic coverage was neglected in 33% of patients. RESULT OF SYNTHESIS (GUIDELINES): Three guidelines favor monotherapy with fluoroquinolones or macrolides, while one suggested an antimicrobial combination in case of severe LD. Four guidelines recommended anaerobic coverage in case of lung abscesses. CONCLUSION: To date, the evidence supporting cavitary LD treatment is low. Monotherapy lowers toxicity and might be as effective as combination therapy. Finally, anaerobes should not be neglected.

Fat misbehaving in the abdominal cavity: a pictorial essay.

Intra-abdominal fat is abundantly present in both the peritoneum and retroperitoneum. Fat necrosis or inflammation are common findings in abdominal imaging. The most common pathologies that we encounter are epiploic appendagitis, omental infarction, mesenteric panniculitis, and encapsulated fat necrosis. Less common entities that can occur are pancreatic saponification, heterotopic mesenteric ossification, and pseudolipoma of the capsule of Glisson. These entities can mimic more urgent pathologies such as appendicitis, diverticulitis, or malignancies.

The quantitative link of lung clearance index to bronchial segments affected by bronchiectasis.

In adult patients with cystic fibrosis (CF), the lung clearance index (LCI) derived from the multiple breath washout relates to both acinar and conductive ventilation heterogeneity. The latter component predicts an association between LCI and the number of bronchial segments affected by bronchiectasis. Here, we experimentally demonstrated this association in patients with CF, and also examined an ancillary group of patients with non-CF bronchiectasis. We conclude that lung disease severity in terms of number of bronchial segments results in an associated LCI increase, likely constituting a portion of LCI that cannot be reversed by treatment in patients with CF lung disease.

Pulmonary disease in cystic fibrosis: assessment with chest CT at chest radiography dose levels.

PURPOSE: To investigate a computed tomographic (CT) protocol with iterative reconstruction at conventional radiography dose levels for the assessment of structural lung abnormalities in patients with cystic fibrosis ( CF cystic fibrosis ). MATERIALS AND METHODS: In this institutional review board-approved study, 38 patients with CF cystic fibrosis (age range, 6-58 years; 21 patients <18 years and 17 patients >18 years) underwent investigative CT (at minimal exposure settings combined with iterative reconstruction) as a replacement of yearly follow-up posteroanterior chest radiography. Verbal informed consent was obtained from all patients or their parents. CT images were randomized and rated independently by two radiologists with use of the Bhalla scoring system. In addition, mosaic perfusion was evaluated. As reference, the previous available conventional chest CT scan was used. Differences in Bhalla scores were assessed with the χ(2) test and intraclass correlation coefficients ( ICC intraclass correlation coefficient s). Radiation doses for CT and radiography were assessed for adults (>18 years) and children (<18 years) separately by using technical dose descriptors and estimated effective dose. Differences in dose were assessed with the Mann-Whitney U test. RESULTS: The median effective dose for the investigative protocol was 0.04 mSv (95% confidence interval [ CI confidence interval ]: 0.034 mSv, 0.10 mSv) for children and 0.05 mSv (95% CI confidence interval : 0.04 mSv, 0.08 mSv) for adults. These doses were much lower than those with conventional CT (median: 0.52 mSv [95% CI confidence interval : 0.31 mSv, 3.90 mSv] for children and 1.12 mSv [95% CI confidence interval : 0.57 mSv, 3.15 mSv] for adults) and of the same order of magnitude as those for conventional radiography (median: 0.012 mSv [95% CI confidence interval : 0.006 mSv, 0.022 mSv] for children and 0.012 mSv [95% CI confidence interval : 0.005 mSv, 0.031 mSv] for adults). All images were rated at least as diagnostically acceptable. Very good agreement was found in overall Bhalla score ( ICC intraclass correlation coefficient , 0.96) with regard to the severity of bronchiectasis ( ICC intraclass correlation coefficient , 0.87) and sacculations and abscesses ( ICC intraclass correlation coefficient , 0.84). Interobserver agreement was excellent ( ICC intraclass correlation coefficient , 0.86-1). CONCLUSION: For patients with CF cystic fibrosis , a dedicated chest CT protocol can replace the two yearly follow-up chest radiographic examinations without major dose penalty and with similar diagnostic quality compared with conventional CT.

Predictive value of pattern classification 24 hours after radiofrequency ablation of liver metastases on CT and positron emission tomography/CT.

PURPOSE: To assess a classification scheme for predicting local tumor progression (LTP) after radiofrequency (RF) ablation of liver metastases, using predefined patterns on contrast-enhanced computed tomography (CT) and positron emission tomography (PET) combined with CT (PET/CT) acquired 24 hours after RF ablation. MATERIALS AND METHODS: There were 45 metastases in 20 patients treated. After 24 hours, imaging of the ablation zones was performed with contrast-enhanced PET/CT. Three independent radiologists prospectively assessed contrast-enhanced CT and combined PET/CT images to identify three patterns: pattern I, no tissue enhancement or fluorodeoxyglucose uptake between the ablation zone and the liver parenchyma; pattern II, a rimlike pattern; and pattern III, a peripheral nodule. PET/CT images obtained after 8-10 weeks were evaluated for LTP. The patterns were analyzed for their sensitivity, specificity, positive predictive value, and negative predictive value for predicting LTP. RESULTS: Pattern I was most frequently observed (81% for contrast-enhanced CT and 61% for PET/CT) as well as for ablation zones that showed LTP (52% and 37%, respectively). Conversely, pattern II was observed for tumors that were completely ablated (6% and 29%, respectively). Patterns II and III together had the highest sensitivity for predicting LTP (48% and 63%, respectively); pattern III had the highest specificity (94% and 95%, respectively). For nodular patterns, test characteristics were better for PET/CT compared with contrast-enhanced CT, but the difference was not significant. Nodular patterns > 1 cm achieved high positive predictive value (both 100%). CONCLUSIONS: Inflammation and hyperemia can hinder interpretation on imaging 24 hours after RF ablation, especially on PET/CT. Nodular patterns around the ablation zone on early contrast-enhanced CT and PET/CT have a high predictive value for LTP and should be taken into account for disease management.

Miliary Tuberculosis with Diffuse Pulmonary and Extrapulmonary Involvement.

Teaching Point: In patients coming from countries with a high prevalence of tuberculosis and presenting with chronic infectious disease, tuberculosis with pulmonary and/or extrapulmonary involvement should be included in the differential diagnosis.

Features of post-obstructive pneumonia in advanced lung cancer patients, a large retrospective cohort.

BACKGROUND: Post-obstructive pneumonia refers to an infection of the lung parenchyma distal to a bronchial obstruction. Previous experience-based studies reported a high prevalence of this infection among patients with a medical history of advanced lung neoplasia, up to 40-55%. OBJECTIVES: The current study was designed to investigate the features of post-obstructive pneumonia in lung cancer, including its predictors and the discriminants for 30-day mortality. METHOD: Data from medical records at the tertiary University centre, UZ Brussel, were collected retrospectively between January 2016 and January 2021. Patients affected by lung cancer stages III and IV were included. A multidisciplinary team, composed of a pulmonologist, an infectious disease specialist and a chest radiologist, identified patients affected by post-obstructive pneumonia. RESULTS: A total of 408 patients were included, of which 46 (11%) were diagnosed with post-obstructive pneumonia. Multivariable logistic regression for predictors of disease onset found significant differences for squamous cell carcinoma (OR:2.46 p-value: .014) and hilar location of the tumour (OR:2.72 p-value: .021). However, no significant differences were identified with regards to age or comorbidities. Furthermore, 30-day mortality among post-obstructive pneumonia patients was 30%. Multivariable logistic regression for prediction of 30-day mortality found significant differences in CURB-65 score (OR:73.20 p-value: .001) and smoking status (OR:0.009 p-value: .015). CONCLUSIONS: Within this cohort, the prevalence of post-obstructive pneumonia in advanced lung cancer patients was lower than previously reported. Squamous cell carcinoma and a hilar tumour location were two variables associated with disease development, independent of age and comorbidities. Furthermore, a higher CURB-65 score at post-obstructive pneumonia diagnosis was correlated with mortality.

The Value of 18F-FDG PET/CT in Predicting the Response to PD-1 Blocking Immunotherapy in Advanced NSCLC Patients with High-Level PD-L1 Expression.

BACKGROUND: The objective of this study was to evaluate if 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT)-derived parameters are useful in predicting response and survival after programmed cell death protein 1 (PD-1) blocking immunotherapy in patients with advanced NSCLC characterized by a high programmed death-ligand 1 (PD-L1) expression (≥50%) on immunohistochemistry. PATIENTS AND METHODS: In 30 patients with advanced stage IV non-small-cell lung cancer (NSCLC) and high PD-L1 expression, 18F-FDG PET/CT parameters before start of treatment with PD-1 blocking immunotherapy were evaluated retrospectively. In 24 out of the 30 patients, 18F-FDG PET/CT was available 8 to 9 weeks after start of the treatment. Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and metabolic responses assessed on 18F-FDG PET/CT were compared. RESULTS: Median follow-up was 20 months (range, 4.2-37.6). Median PD-L1 expression was 80%. The objective response rate with RECIST 1.1 was 53.3%. Median progression-free survival (PFS) was 12.4 months (95% confidence interval [CI], 1.0-37.8), and median overall survival (OS) was 14.9 months (95% CI, 2.4-38.2). Baseline 18F-FDG PET/CT parameters did not differ between responders and non-responders (all P > .05). The maximum standardized uptake value (SUVmax) was the only 18F-FDG PET/CT parameter associated with PFS (P = .04), with a trend for OS (P = .06). At first evaluation, response according to total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) were associated with PFS and OS (both P < .0001). This was not the case for RECIST 1.1 (P = .29 for PFS and P = .38 for OS). CONCLUSION: Clinical response and survival were independent from metabolic tumor volume at baseline. Reduction of metabolic tumor volume after 8 to 9 weeks of treatment was a better predictor for prolonged survival than RECIST 1.1.

Clinical status and lung function 10 weeks after severe SARS-CoV-2 infection.

INTRODUCTION: Since studies about clinical status after COVID-19 are scarce, we conducted a cross sectional study with assessment of residual symptoms, lung function and chest CT. MATERIALS AND METHODS: During an outpatient follow-up visit, chest CT, pulmonary function and COVID-19 related symptoms were assessed approximately 10 weeks after diagnosis. Demographics, baseline (time of diagnosis) CT score and blood results were collected from patient files. Association between lung function and clinical characteristics (baseline), blood markers (baseline), chest CT (baseline and follow-up) and symptom score (followup) was analysed. Mann-Whitney U tests and Chi squared tests were used for statistical comparison between subgroups with and without restriction. RESULTS AND DISCUSSION: Two hundred-twenty subjects were evaluated at a median follow-up of 74±12 (SD) days. Median symptom and median CT score at follow-up were 1(IQR=0- 2) and 2(IQR=0-6) respectively. Forty-six percent of patients had normal lung function, while TLC and TLCO below the lower limit of normal were observed in 38% and 22% of subjects respectively. This restrictive pulmonary impairment was associated with length of hospital stay (8 vs 6 days; p=0.003), admission to the intensive care unit (27% vs 13%;p=0.009), and invasive mechanical ventilation (10% vs 0.7%;p=0.001), but not with symptom score or CT score at baseline and follow-up. CONCLUSIONS: Fifty-four percent of COVID-19 survivors had abnormal lung function 10 weeks after diagnosis. Restriction was the most prevalent pulmonary function, with the more critically ill patients being more prone to this condition. Yet, restriction could not be linked with abnormal imaging results or residual symptoms.

Diagnostic accuracy of screening tests for patients suspected of COVID-19, a retrospective cohort study.

BACKGROUND: The diagnostic gold standard for Coronavirus-2019 disease (CoViD-19) is reverse transcriptase-polymerase chain reaction (RT-PCR). However, its sensitivity might be suboptimal. The current study aims to investigate predictive factors for false-negative nasopharyngeal RT-PCR in CoViD-19 patients. Additionally, the specificity and sensitivity of RT-PCR on the nasopharyngeal swab, serology and chest computerized-tomography (CCT) as a screening tool for the diagnosis of CoViD-19 were investigated. METHODS: Medical records of patients admitted at the university hospital UZ Brussel during the CoViD-19 epidemic were reviewed. A group of CoViD-19 patients with false-negative RT-PCR was identified through scrupulous examination of medical records. Serological testing was performed through chemiluminescent microparticle assay. RESULTS: Eighteen CoViD-19 patients with 'false negative' RT-PCR were identified and compared to 51 'true positives'. Logistic regression for prediction of 'false negative' RT-PCR found significantly higher serology results at hospitalization and more intensive care unit admission in the group with false-negative testing. In a cohort of 228 patients, the sensitivity of RT-PCR for the diagnosis of CoViD-19 was 85%. The sensitivity of serology was 86% and its specificity 92%. Chest computerized-tomography (CCT) showed a sensitivity of 93%, its specificity was 62%. By combining RT-PCR and serology results any 'false negative' could be excluded. CONCLUSIONS: In this cohort, the sensitivity and specificity of RT-PCR and serology for the diagnosis of CoViD-19 were high and comparable. CCT had the highest sensitivity and confirmed its efficacy as a screening tool. CoViD-19 patients, who have a more severe presentation, might have negative RT-PCR and positive serology results.

Evolution of lung function and chest CT 6 months after COVID-19 pneumonia: Real-life data from a Belgian University Hospital.

INTRODUCTION: Most post COVID-19 follow-up studies are limited to a follow-up of 3 months. Whether a favorable evolution in lung function and/or radiological abnormalities is to be expected beyond 3 months is uncertain. MATERIALS AND METHODS: We conducted a real-life follow-up study assessing the evolution in lung function, chest CT and ventilation distribution between 10 weeks and 6 months after diagnosis of COVID-19 pneumonia. RESULTS: Seventy-nine patients were assessed at 6 months of whom 63 had chest CT at both follow-up visits and 46 had multiple breath washout testing to obtain lung clearance index (LCI). The study group was divided into a restrictive (n = 39) and a non-restrictive subgroup (n = 40) based on TLC z-score. Restriction was associated with a history of intubation, neuromuscular blockade use and critical illness polyneuropathy. Restriction significantly improved over time, but was not resolved by 6 months (median TLC z-score of -2.2 [IQR: -2.7; -1.5] at 6 months versus -2.7 [IQR: -3.1; -2.1] at 10 weeks). LCI did not evolve between both follow-up visits. Symptoms and chest CT score improved irrespective of restriction. CONCLUSION: We observed a disconnect between the improvement of COVID-19 related symptoms, chest CT lesions, and corresponding lung function. While CT imaging is almost normalized at 6 months, a further reduction of pulmonary restriction may be hoped for beyond 6 months in those patients showing restriction at their first follow-up visit.

Antibiotic Prescriptions Targeting Bacterial Respiratory Infections in Admitted Patients with COVID-19: A Prospective Observational Study.

INTRODUCTION: Although bacterial co- and superinfections are rarely present in patients with COVID-19, overall antibiotic prescribing in admitted patients is high. In order to counter antibiotic overprescribing, antibiotic stewardship teams need reliable data concerning antibiotic prescribing in admitted patients with COVID-19. METHODS: In this prospective observational cohort study, we performed a quantitative and qualitative evaluation of antibiotic prescriptions in patients admitted to the COVID-19 ward of a 721-bed Belgian university hospital between 1 May and 2 November 2020. Data on demographics, clinical and microbiological parameters and antibiotic consumption were collected. Defined daily doses (DDD) were calculated for antibiotics prescribed in the context of a (presumed) bacterial respiratory tract infection and converted into two indicators: DDD/admission and DDD/100 hospital bed days. A team of infectious disease specialists performed an appropriateness evaluation for every prescription. A driver analysis was performed to identify factors increasing the odds of an antibiotic prescription in patients with a confirmed COVID-19 diagnosis. RESULTS: Of 403 eligible participants with a suspected COVID-19 infection, 281 were included. In 13.8% of the 203 admissions with a COVID-19 confirmed diagnosis, antibiotics were initiated for a (presumed) bacterial respiratory tract co-/superinfection (0.86 DDD/admission; 8.92 DDD/100 bed days; 39.4% were scored as 'appropriate'). Five drivers of antibiotic prescribing were identified: history of cerebrovascular disease, high neutrophil/lymphocyte ratio in male patients, age, elevated ferritin levels and the collection of respiratory samples for bacteriological analysis. CONCLUSION: In the studied population, the antibiotic consumption for a (presumed) bacterial respiratory tract co-/superinfection was low. In particular, the small total number of DDDs in patients with confirmed COVID-19 diagnosis suggests thoughtful antibiotic use. However, antibiotic stewardship programmes remain crucial to counter unnecessary and inappropriate antibiotic use in hospitalized patients with COVID-19. TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov (NCT04544072).

Ventilation heterogeneity in smokers: role of unequal lung expansion and peripheral lung structure.

Smoking-induced ventilation heterogeneity measured at the mouth via established washout indices [lung clearance index (LCI) and alveolar mixing efficiency (AME)] potentially results from unequal expansion, which can be quantified by computer tomography (CT), and structural changes down to the lung periphery, characterized by CT parametric response mapping indices [percentage of lung affected by functional small airway disease (PRMfSAD) and emphysema (PRMEmph)]. By combining CT imaging and nitrogen (N2) washout tests in smokers, we specifically examined the roles of unequal lung expansion and peripheral structure. We first extracted three-dimensional maps of local lung expansion from registered inspiratory/expiratory CT images in 50 smokers (GOLD 0-IV) to compute for each smoker the theoretical N2 washout concentration curve solely attributable to unequal local expansion. By a head-on comparison with washout N2 concentrations measured at the mouth in the same smokers supine, we observed that 1) LCI increased from 4.8 ± 0.2 (SD) to 6.6 ± 0.8 (SD) due to unequal lung expansion alone and further increased to 9.0 ± 1.5 (SD) independent of local expansion and 2) AME decreased (from 100% by definition) to 95 ± 2 (SD)% due to unequal expansion alone and further decreased to 75 ± 7(SD)% independent of local expansion. In a multiple regression between the washout indices and CT-derived PRMfSAD and PRMEmph, LCI was related to PRMfSAD (r = +0.58; P < 0.001), whereas AME was related to both PRMfSAD (rpartial = -0.44; P = 0.002) and PRMEmph (rpartial = -0.31; P = 0.033), in line with AME being dominated by alterations in peripheral structure. We conclude that smokers showing an increased LCI without corresponding AME decrease are predominantly affected by unequal lung expansion, whereas an AME decrease with a commensurate LCI increase indicates a smoking-induced alteration of peripheral structure.NEW & NOTEWORTHY A head-on comparison between imaging and multiple breath washout in supine smokers shows that computer tomography-measured unequal local lung expansion accounts for 50% or less of smoking-induced increase in ventilation heterogeneity. The contributions from unequal lung expansion and peripheral structure to the two main washout indices also explain their respective association with parametric response mapping indices.

Comparative Interpretation of CT and Standard Radiography of the Pleura.

Many diseases affect the pleural space in both adults and children, including common diseases such as pneumonia, cancer and heart failure. Pleural effusion is the most common manifestation of pleural disease, and it is often a secondary effect of another disease process. Imaging plays a crucial role in the management of pleural disease. Chest radiography often remains the first examination in the assessment of these patients. Depending on the clinical context, the optimal imaging technique for further evaluation might be computed tomography (CT), ultrasound (US), or magnetic resonance (MR).

Inhaled Aerosol Distribution in Human Airways: A Scintigraphy-Guided Study in a 3D Printed Model.

BACKGROUND: While it is generally accepted that inertial impaction will lead to particle loss as aerosol is being carried into the pulmonary airways, most predictive aerosol deposition models adopt the hypothesis that the inhaled particles that remain airborne will distribute according to the gas flow distribution between airways downstream. METHODS: Using a 3D printed cast of human airways, we quantified particle deposition and distribution and visualized their inhaled trajectory in the human lung. The human airway cast was exposed to 6 µm monodisperse, radiolabeled aerosol particles at distinct inhaled flow rates and imaged by scintigraphy in two perpendicular planes. In addition, we also imaged the distribution of aerosol beyond the airways into the five lung lobes. The experimental aerosol deposition patterns could be mimicked by computational fluid dynamic (CFD) simulation in the same 3D airway geometry. RESULTS: It was shown that for particles with a diameter of 6 µm inhaled at flows up to 60 L/min, the aerosol distribution over both lungs and the individual five lung lobes roughly followed the corresponding distributions of gas flow. While aerosol deposition was greater in the main bronchi of the left versus right lung, distribution of deposited and suspended particles toward the right lung exceeded that of the left lung. The CFD simulations also predict that for both 3 and 6 µm particles, aerosol distribution between lung units subtending from airways in generation 5 did not match gas distribution between these units and that this effect was driven by inertial impaction. CONCLUSIONS: We showed combined imaging experiments and CFD simulations to systematically study aerosol deposition patterns in human airways down to generation 5, where particle deposition could be spatially linked to the airway geometry. As particles are negotiating an increasing number of airways in subsequent branching generations, CFD predicts marked deviations of aerosol distribution with respect to ventilation distribution, even in the normal human lung.