Radiolabelled leucocytes in human pulmonary disease.

Introduction: Radionuclides for leucocyte kinetic studies have progressed from non-gamma emitting cell-labelling radionuclides through gamma emitting nuclides that allow imaging of leucocyte kinetics, to the next goal of positron emission tomography (PET). Sources of data: Mostly the authors' own studies, following on from studies of the early pioneers. Areas of controversy: From early imaging studies, it appeared that the majority of the marginated granulocyte pool was located in the lungs. However, later work disputed this by demonstrating the exquisite sensitivity of granulocytes to ex vivo isolation and labelling, and that excessive lung activity is artefactual. Areas of agreement: Following refinement of labelling techniques, it was shown that the majority of marginated granulocytes are located in the spleen and bone marrow. The majority of leucocytes have a pulmonary vascular transit time only a few seconds longer than erythrocytes. The minority showing slow transit, ~5% in healthy persons, is increased in systemic inflammatory disorders that cause neutrophil priming and loss of deformability. Using a range of imaging techniques, including gamma camera imaging, whole-body counting and single photon-emission computerized tomography, labelled granulocytes were subsequently used to image pulmonary trafficking in lobar pneumonia, bronchiectasis, chronic obstructive pulmonary disease and adult respiratory distress syndrome. Growing points: More recently, eosinophils have been separated in pure form using magnetic bead technology for the study of eosinophil trafficking in asthma. Areas timely for developing research: These include advancement of eosinophil imaging, development of monocyte labelling, development of cell labelling with PET tracers and the tracking of lymphocytes.

Use of 111-Indium-labeled autologous eosinophils to establish the in vivo kinetics of human eosinophils in healthy subjects.

Eosinophils are the major cellular effectors of allergic inflammation and represent an important therapeutic target. Although the genesis and activation of eosinophils have been extensively explored, little is known about their intravascular kinetics or physiological fate. This study was designed to determine the intravascular life span of eosinophils, their partitioning between circulating and marginated pools, and sites of disposal in healthy persons. Using autologous, minimally manipulated 111-Indium-labeled leukocytes with blood sampling, we measured the eosinophil intravascular residence time as 25.2 hours (compared with 10.3 hours for neutrophils) and demonstrated a substantial marginated eosinophil pool. γ camera imaging studies using purified eosinophils demonstrated initial retention in the lungs, with early redistribution to the liver and spleen, and evidence of recirculation from a hepatic pool. This work provides the first in vivo measurements of eosinophil kinetics in healthy volunteers and shows that 111-Indium-labeled eosinophils can be used to monitor the fate of eosinophils noninvasively.

Obstructive sleep apnoea and perioperative medicine: a growing concern.

Obstructive sleep apnoea represents a sizable public health and economic burden. Owing to rising obesity rates, the prevalence of obstructive sleep apnoea is increasing, and it is a condition that is significantly underdiagnosed. Exacerbated by the COVID-19 pandemic, the backlog of elective surgeries is also sizable and growing. A combination of these factors means that many patients due to have surgery will have obstructive sleep apnoea, either diagnosed or otherwise. Patients with obstructive sleep apnoea have a significantly increased risk of operative complications, but the evidence base for optimum perioperative management of these patients is limited. This article reviews sleep apnoea, its prevalence and its impact on operative management and perioperative outcomes for patients. The evidence base for screening and treating undiagnosed obstructive sleep apnoea is also comprehensively assessed. Finally, a pathway to manage patients with possible undiagnosed obstructive sleep apnoea is proposed, and areas for further research identified.

Measuring whole-body neutrophil redistribution using a dedicated whole-body counter and ultra-low doses of 111Indium.

BACKGROUND: There is increasing interest in the 'homing' of neutrophils to bone marrow. The aim of this study was to measure the whole-body redistribution of (111) In using a whole-body counter following the administration of ultra-small activities of (111) In-labelled neutrophils. METHODS: The detectors of a dedicated whole-body counter were fitted with lead collimators. Whole-body (111) In distribution was recorded at 45 min, 24 h, and 2, 4, 7 and 10 days after administration of (111) In-labelled neutrophils (0·29-0·74 MBq) in eight healthy non-smokers, five healthy smokers, eight patients with inactive bronchiectasis, three with asthma and nine with chronic obstructive pulmonary disease (COPD). RESULTS: Intravascular 45-min (111) In-labelled neutrophil recovery was not significantly different between groups, ranging from 33 (SD 8%) in healthy smokers to 45 (14%) in healthy non-smokers (P > 0·05). Peaks were identified on the whole body count profile corresponding to the chest, upper abdomen (liver/spleen) and pelvis (bone marrow). (111) In distribution changed between 45 min and 24 h and then remained stable thereafter. Peak chest counts increased ∼ 1·5-fold between 45 min and 24 h, whereas upper abdominal peak counts decreased by ∼ 25% with no significant inter-group differences. The increment in pelvic counts (∼ 2·7-fold) was similar between groups, except COPD patients, in whom it was 2·04 (0·35; P < 0·02 vs. healthy participants). CONCLUSIONS: Assuming neutrophils are distributed only between blood, liver, spleen and bone marrow, the data suggest that marrow pools 25% and destroys 67% of circulating neutrophils, rising in COPD to 40% and 80%, respectively, possibly as a result of the effects on marrow of chronic hypoxaemia.

Quantification of neutrophil migration into the lungs of patients with chronic obstructive pulmonary disease.

OBJECTIVE: To quantify neutrophil migration into the lungs of patients with chronic pulmonary obstructive disease (COPD). METHODS: Neutrophil loss via airways was assessed by dedicated whole-body counting 45 min, 24 h and 2, 4, 7 and 10 days after injection of very small activities of (111)In-labelled neutrophils in 12 healthy nonsmokers, 5 healthy smokers, 16 patients with COPD (of whom 7 were ex-smokers) and 10 patients with bronchiectasis. Lung accumulation of (99m)Tc-labelled neutrophils was assessed by sequential SPECT and Patlak analysis in six COPD patients and three healthy nonsmoking subjects. RESULTS: Whole body (111)In counts, expressed as percentages of 24 h counts, decreased in all subjects. Losses at 7 days (mean ± SD) were similar in healthy nonsmoking subjects (5.5 ± 1.5%), smoking subjects (6.5 ± 4.4%) and ex-smoking COPD patients (5.8 ± 1.5%). In contrast, currently smoking COPD patients showed higher losses (8.0 ± 3.0%) than healthy nonsmokers (p = 0.03). Two bronchiectatic patients lost 25% and 26%, indicating active disease; mean loss in the remaining eight was 6.9 ± 2.5%. The rate of accumulation of (99m)Tc-neutrophils in the lungs, determined by sequential SPECT, was increased in COPD patients (0.030-0.073 min(-1)) compared with healthy nonsmokers (0-0.002 min(-1); p = 0.02). CONCLUSION: In patients with COPD, sequential SPECT showed increased lung accumulation of (99m)Tc-labelled neutrophils, while whole-body counting demonstrated subsequent higher losses of (111)In-labelled neutrophils in patients who continued to smoke. Sequential SPECT as a means of quantifying neutrophil migration deserves further evaluation.

Pulmonary elimination rate of inhaled 99mTc-sestamibi radioaerosol is delayed in healthy cigarette smokers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Very little is known about the physiology of P-glycoprotein (P-gp) expression in the lungs. * Ex vivo evidence based on resected lung tissue suggests that pulmonary P-gp is upregulated by cigarette smoke, but there are no in vivo studies to date. WHAT THIS STUDY ADDS: * The novel observation that healthy cigarette smokers have a delayed pulmonary elimination rate of inhaled (99m)Tc-sestamibi, a P-gp substrate, provides for the first time a potential method for quantifying functional pulmonary P-gp expression that may inform about drug therapy by inhalation as well as provide a non-invasive, quantitative, human biomarker for assessing P-gp modulators. AIM: To explore inhaled technetium-99m-labelled hexakis-methoxy-isobutyl isonitrile ((99m)Tc-sestamibi) for quantifying pulmonary P-glycoprotein (P-gp) expression. METHODS: The elimination rate from the lungs of (99m)Tc-sestamibi was recorded scintigraphically for 30 min following inhalation as an aerosol in healthy smokers, nonsmokers and patients with lung disease. RESULTS: (99m)Tc-sestamibi elimination rates [% min(-1) (SD; P vs. healthy nonsmokers)] were: healthy nonsmokers, 0.43 (0.083); healthy smokers, 0.19 (0.056; P < 0.001); chronic obstructive pulmonary disease patients, 0.26 (0.077; P < 0.001). Elimination rates in three patients with interstitial lung disease were not accelerated. CONCLUSION: Cigarette smoke upregulates lung P-gp. (99m)Tc-sestamibi elimination in normal smokers could be used to test new P-gp modulators. The findings also have implications for inhaled drug delivery.

Healthy passive cigarette smokers have increased pulmonary alveolar permeability.

QUESTION: Does passive smoking have a measurable effect on lung function in otherwise healthy subjects? There is current interest concerning passive smoking but no objective evidence showing that it has any impact on lung function. METHODS: The pulmonary clearance rate of (99m)Tc-DTPA was measured in 21 healthy volunteers after inhalation as a radio-aerosol and compared between healthy cigarette smokers, passive smokers and non-smokers. All volunteers had normal lung function. RESULTS: Clearance half-times in healthy passive smokers (n=5) were longer than in healthy smokers (n=6) but clearly shorter compared with healthy non-smokers (n=10) with respective mean values of 45.2 (SD 8.3), 24.3 (8.6) and 80.3 (20) min. CONCLUSION: Passive smoking has a functional impact on the lung blood/gas barrier.

Does P-glycoprotein have a role in the lung clearances of inhaled 99mTc-sestamibi and 99mTc-tetrofosmin?

OBJECTIVE: The clearance rate of inhaled 99mTc-sestamibi from the lungs of healthy nonsmoking individuals is much slower than would be expected from its physical properties. The clearance rate is even slower in healthy cigarette smokers. As 99mTc-sestamibi is a substrate for P-glycoprotein (P-gp), pulmonary P-gp may be influential in 99mTc-sestamibi clearance and may be upregulated in smokers. 99mTc-tetrofosmin is also a substrate for P-gp, therefore we hypothesized that it would display similar kinetics to 99mTc-sestamibi and support a role for P-gp. We also hypothesized that administration of P-gp modulators would accelerate clearance of 99mTc-sestamibi. METHODS: We measured clearance rates of 99mTc-tetrofosmin in four healthy smokers and four healthy nonsmokers and of 99mTc-sestamibi in six otherwise healthy patients with psoriasis before and after 2 weeks of therapy with cyclosporine A (2.5-5 mg/kg/day) and two healthy women taking the oral contraceptive pill, as both cyclosporine and steroids are known to be P-gp modulators. RESULTS: The clearance rate of 99mTc-tetrofosmin in nonsmokers ranged from 0.38 to 0.63%/min, similar to the previously recorded rate for 99mTc-sestamibi [0.43 (SD 0.083)%/min], but it was not delayed in smokers (range 0.42-0.97%/min). Cyclosporine had no significant effect on 99mTc-sestamibi clearance, although clearance rates in the two women taking the oral contraceptive pill were both fast (0.58 and 0.62%/min). CONCLUSION: Although the role of P-gp expression in the clearance of 99mTc-sestamibi remains unproven, we conclude that 99mTc-tetrofosmin is not as P-gp-avid as 99mTc-sestamibi. A role for P-gp expression in the clearance of 99mTc-sestamibi remains unproven. Higher doses of P-gp inhibitors will be required and clearance rates correlated with immunohistochemical expression of P-gp.

Quantification of disease activity in patients undergoing leucocyte scintigraphy for suspected inflammatory bowel disease.

PURPOSE: Whole-body gamma camera counting is an alternative to faecal 111In collection for quantifying disease activity in inflammatory bowel disease (IBD) but requires administration of imaging activities of 111In. The aim of this study was to explore a dedicated whole-body counter which requires 20-fold less activity than gamma camera counting. METHODS: Thirty patients with known or suspected IBD received 99mTc-granulocytes (approximately 200 MBq) and 111In-granulocytes (approximately 0.5 MBq). The 99mTc-cells were injected 45 min after the 111In-cells and immediately after a baseline 111In whole-body count. The decay-corrected count at 120 h was expressed as a fraction of baseline to give whole-body 111In retention (WBR). One patient was excluded as the injected cells were non-viable. RESULTS: Median 45-min intravascular 111In recovery was 35% in patients compared with 43% in six normal volunteers (p<0.05). WBR in normals ranged from 91% to 93% and in 11 patients with negative 99mTc imaging from 87% to 96%. Only one of 11 patients with negative imaging had WBR <90% while 11/12 patients with WBR <90% had abnormal imaging. Ten of 13 patients with Crohn's disease (CD) had abnormal imaging. The lowest WBR in these ten was 77% and six had values of >90%. There was a significant association between WBR and 99mTc image grade (Rs=0.73, p<0.002) in 16 patients without CD, but not in 13 patients with CD (Rs=0.54, p>0.05). CONCLUSION: Dedicated whole-body counting is able to quantify disease activity in IBD but may give normal values in active CD.