Lung Cancer Screening with Low-Dose CT: What We Have Learned in Two Decades of ITALUNG and What Is Yet to Be Addressed.

The ITALUNG trial started in 2004 and compared lung cancer (LC) and other-causes mortality in 55-69 years-aged smokers and ex-smokers who were randomized to four annual chest low-dose CT (LDCT) or usual care. ITALUNG showed a lower LC and cardiovascular mortality in the screened subjects after 13 years of follow-up, especially in women, and produced many ancillary studies. They included recruitment results of a population-based mimicking approach, development of software for computer-aided diagnosis (CAD) and lung nodules volumetry, LDCT assessment of pulmonary emphysema and coronary artery calcifications (CAC) and their relevance to long-term mortality, results of a smoking-cessation intervention, assessment of the radiations dose associated with screening LDCT, and the results of biomarkers assays. Moreover, ITALUNG data indicated that screen-detected LCs are mostly already present at baseline LDCT, can present as lung cancer associated with cystic airspaces, and can be multiple. However, several issues of LC screening are still unaddressed. They include the annual vs. biennial pace of LDCT, choice between opportunistic or population-based recruitment. and between uni or multi-centre screening, implementation of CAD-assisted reading, containment of false positive and negative LDCT results, incorporation of emphysema. and CAC quantification in models of personalized LC and mortality risk, validation of ultra-LDCT acquisitions, optimization of the smoking-cessation intervention. and prospective validation of the biomarkers.

Moderate-severe coronary calcification predicts long-term cardiovascular death in CT lung cancer screening: The ITALUNG trial.

PURPOSE: Coronary artery calcifications (CAC) are very strong indicators for increased cardio-vascular (CV) risk and can be evaluated also in low-dose computed tomography (LDCT) for lung cancer screening. We assessed whether a simple and fast CAC visual score is associated with CV mortality. METHODS: CAC were retrospectively assessed by two observers using a 4-score (absent, mild, moderate and severe) scale in baseline LDCT obtained in 1364 participants to the ITALUNG trial who had 55-69 years of age and a smoking history ≥20 pack-years. Correlations with CV risk factors at baseline and with CV mortality after 11 years of follow-up were investigated. RESULTS: CAC were absent in 470 (34.5%), mild in 433 (31.7%), moderate in 357 (26.2%) and severe in 104 (7.6%) subjects. CAC severity correlated (≤0.001) with age, male sex, pack-years, history of arterial hypertension or diabetes, obesity and treated hypercholesterolemia. Twenty-one CV deaths occurred. Moderate or severe CAC were significantly associated with higher CV mortality after adjustment for all other known risk factors (ARR = 2.72; 95 %CI:1.04-7.11). Notably, also in subjects with none or one only additional CV risk factor, the presence of moderate-severe CAC allowed to identify a subgroup of subjects with higher CV death risk (RR = 3.66; CI95%:1.06-12.6). CONCLUSIONS: Moderate or severe CAC visually assessed in LDCT examinations for lung cancer screening are independently associated with CV mortality.

Decreased cardiovascular mortality in the ITALUNG lung cancer screening trial: Analysis of underlying factors.

OBJECTIVES: In the ITALUNG lung cancer screening trial after 9.3 years of follow-up we observed an unexpected significant decrease of cardiovascular (CV) mortality in subjects invited for low-dose CT (LDCT) screening as compared to controls undergoing usual care. Herein we extended the mortality follow-up and analyzed the potential factors underlying such a decrease. MATERIALS AND METHODS: The following factors were assessed in screenes and controls: burden of CV disease at baseline, changes in smoking habits, use of CV drugs and frequency of planned vascular procedures after randomisation. Moreover, in the screenes we evaluated inclusion of presence of coronary artery calcification (CAC) in the LDCT report form that was transmitted to the participant and his/her General Practitioner. RESULTS: The 2-years extension of follow-up confirmed a significant decrease of CV mortality in the subjects of the active group compared to control subjects (15.6 vs 34.0 per 10,000; p = 0.001) that was not observed in the drops-out of the active group. None of the explaining factors we considered significantly differed between active and control group. However, the subjects of the active group with reported CAC experienced a not significantly lower CV mortality and showed a significantly higher use of CV drugs and frequency of planned vascular procedures than the control group. CONCLUSIONS: LDCT screening for lung cancer offers the opportunity for detection of CAC that is an important CV risk factor. Although the underlying mechanisms are not clear, our results suggest that the inclusion of information about CAC presence in the LDCT report may represent a candidate factor to explain the decreased CV mortality observed in screened subjects of the ITALUNG trial, possibly resulting in intervention for patient care to prevent CV deaths. Further studies investigating whether prospective reporting and rating of CAC have independent impact on such interventions and CV mortality are worthy.

Screen-detected multiple primary lung cancers in the ITALUNG trial.

Occurrence of multiple primary lung cancers (MPLC) in individuals undergoing low-dose computed tomography (LDCT) screening has not been thoroughly addressed. We investigated MPLC in subjects recruited in the ITALUNG randomized clinical trial. Cases of cytologically/histologically proven MPLC detected at screening LDCT or follow-up CT were selected and pathologically re-evaluated according to the WHO 2015 classification. Overall 16 MPLC were diagnosed at screening LDCT (n=14, all present at baseline) or follow-up CT (n=2) in six subjects (4 in one subject, 3 in two and 2 in three subjects), representing 0.43% of the 1,406 screenees and 15.8% of the 38 subjects with at least one screen-detected primary lung cancer. MPLC included 9 adenocarcinomas in three subjects and a combination of 7 different tumour histotypes in three subjects. MPLC, mostly adenocarcinomas, are not uncommon in smokers and ex-smokers with at least one LDCT screen detected primary lung cancer.

Four-year results of low-dose CT screening and nodule management in the ITALUNG trial.

INTRODUCTION: Recruitment and nodule management are critical issues of lung cancer screening with low-dose computed tomography (LDCT). We report subjects' compliance and results of LDCT screening and management protocol in the active arm of the ITALUNG trial. METHODS: Three thousand two hundred six smokers or former smokers invited by mail were randomized to receive four annual LDCT (n = 1613) or usual care (n = 1593). Management protocol included follow-up LDCT, 2-[18F]fluoro-2-deoxy-D glucose positron emission tomography (FDG-PET), and CT-guided fine-needle aspiration biopsy (FNAB). RESULTS: One thousand four hundred six subjects (87%) underwent baseline LDCT, and 1263 (79%) completed four screening rounds. LDCT was positive in 30.3% of the subjects at baseline and 15.8% subsequently. Twenty-one lung tumors in 20 subjects (1.5% detection) were found at baseline, and 20 lung tumors in 18 subjects (0.5% detection) in subsequent screening rounds. Ten of 18 prevalent (55%) and 13 of 17 incident (76%) non-small-cell cancers were in stage I. Interval growth enabled diagnosis of lung cancer in 16 subjects (42%), but at least one follow-up LDCT was obtained in 741 subjects (52.7%) over the screening period. FDG-PET obtained in 6.5% of subjects had 84% sensitivity and 90% specificity for malignant lesions. FNAB obtained in 2.4% of subjects showed 90% sensitivity and 88% specificity. Positivity of both FDG-PET and FNAB invariably predicted malignancy. Surgery for benign lesions was performed on four subjects (10% of procedures) but followed protocol violations on three subjects. CONCLUSIONS: High-risk subjects recruited by mail who entered LDCT screening showed a high and stable compliance. Efficacy of screening is, however, weakened by low detection rate and specificity. Adhesion to management protocol might lessen surgery for benign lesions.

Molecular profile in body fluids in subjects enrolled in a randomised trial for lung cancer screening: Perspectives of integrated strategies for early diagnosis.

The aim of this study was to evaluate the diagnostic value of a grid of molecular genetic markers detectable in sputum and plasma samples of individuals enrolled in a lung cancer screening program with low-dose CT. Subjects enrolled in the baseline screening round of the ITALUNG (randomised) screening trial were invited to provide biological specimens for molecular analysis (1356 subjects out of 1406). We included 98 subjects in this analysis. There was a highly statistically significant difference between proportion of subjects with a negative baseline CT screening test who were positive to allelic imbalance, and those with a non-calcified nodule (NCN greater than or equal to 5mm), the reason of recall for all suspects at CT Scan (chi(2): 22.9; P<0.0001). Allelic imbalance showed good performance for screening of NCN > or = 5 mm. In subjects recalled for NCN > or = 5 mm, LOH, K-ras mutations and high levels of free plasma DNA (>5ng/ml plasma) might be important to support clinical decision making for further follow-up and repeated screening. This study, embedded in an early diagnosis randomised trial, suggests that a multi-screening approach integrating imaging technique and a biomolecular marker panel is worth of further investigation.

Design, recruitment and baseline results of the ITALUNG trial for lung cancer screening with low-dose CT.

BACKGROUND: Results of randomized clinical trials (RCTs) are needed to assess the efficacy of lung cancer screening with low-dose chest computed tomography (CT) in reducing lung cancer mortality. We report design and results of enrolment and baseline screening test in the ITALUNG trial, a RCT. METHODS: Invitation letters were sent to subjects of 55-69 years of age clients of 269 general practitioners. Smokers or former smokers of at least 20 pack/years were eligible and after written consent were randomized in an active arm undergoing a low-dose CT annually for 4 years and in a control arm receiving no screening. Management of positive screening test was carried out using follow-up low-dose CT, fluorodeoxyglucose positron emission tomography, fine needle aspiration cytology and fiber optic bronchoscopy. RESULTS: A sample of 3206 eligible subjects was achieved by sending 71,232 letters (enrolment efficacy = 4.5%). Subjects in control (n = 1593) and active (n = 1613) arm were balanced for age, gender and smoking history. Two-hundred and seven (12.8%) subjects did not undergo CT after randomization. The baseline screening test was positive in 426 (30.3%) of 1406 subjects. Twenty-one lung cancers (prevalence = 1.5%) were found in 20 subjects: 18 non-small cell lung cancer (NSCLC), 2 small cell lung cancer (SCLC) and a case of typical carcinoid. Ten NSCLC (47.6%) were in Stage I. Sixteen fine needle aspirations were performed in 15 lung cancers, with a positive result in 12 (75%) cases. One biopsy only (6.3%) was performed on a benign lesion. Seventeen lung cancers (81%) were treated with surgical resection in 16 subjects. One subject underwent surgery for a benign lesion (5.5% of all surgical resections). CONCLUSIONS: Recruitment by mail of high risk subjects for a lung cancer screening RCT is feasible but not efficient. Results of the baseline screening test in the active arm of the ITALUNG trial are substantially in line with those of RCT and observational studies.

MRI features of pleural endometriosis after catamenial haemothorax.

A 43-year-old multiparous woman with a history of pelvic endometriosis and myocardial infarction presented with acute onset of right hemithorax pain and dyspnoea coinciding with dysmenorrhoeic menstruation. A chest CT confirmed the presence of a right hydropneumothorax which was drained. A video-assisted thoracoscopy was unremarkable but at a subsequent menses, an MRI chest demonstrated a lesion in the right costophrenic angle. The patient underwent a hysterectomy and oophorectomy for treatment of endometriosis. Six months later, she was free of thoracic symptoms and a repeat MRI scan showed resolution of the right pleural abnormality.

Patterns of chest wall kinematics during volitional pursed-lip breathing in COPD at rest.

BACKGROUND: Analysis of chest wall kinematics can contribute to identifying the reasons why some patients benefit from pursed-lip breathing (PLB). MATERIAL AND METHODS: We evaluated the displacement of the chest wall and its compartments, the rib cage and abdomen, by optoelectronic plethysmography (OEP), during supervised PLB maneuver in 30 patients with mild to severe chronic obstructive pulmonary disease (COPD). RESULTS: OEP showed two different patterns. A first pattern characterized the 19 most severely obstructed and hyperinflated patients in whom PLB decreased end-expiratory volumes of the chest wall and abdomen, and increased end-inspiratory volumes of the chest wall and rib cage. Deflation of the abdomen and inflation of the rib cage contributed to increasing tidal volume of the chest wall. The second pattern characterized 11 patients in whom, compared to the former group, PLB resulted in the following: (i) increased end-expiratory volume of the rib cage and chest wall, (ii) greater increase in end-inspiratory volume of the rib cage and abdomen, and (iii) lower tidal volume of the chest wall. In the patients as a whole changes in end-expiratory chest wall volume were related to change in Borg score (r(2)=0.5, p<0.00002). CONCLUSIONS: OEP helps identifying the reason why patients with COPD may benefit from PLB at rest.

Is there a link between the qualitative descriptors and the quantitative perception of dyspnea in asthma?

BACKGROUND: There is no obvious link between qualitative descriptors and overall intensity of dyspnea during bronchoconstriction in patients with asthma. AIMS: To determine whether qualitative and quantitative perception of methacholine-induced bronchoconstriction independently contribute to characterizing clinically stable asthma. MATERIAL AND METHODS: We assessed changes in inspiratory capacity, and quantitative (by Borg scale) and qualitative (by a panel of eight dyspnea descriptors) sensations of dyspnea at 20 to 30% fall in FEV(1) during methacholine inhalation in 49 asthmatics. Furthermore, we calculated the level of perception of bronchoconstriction at 20% fall in FEV(1) (PB(20)). RESULTS: Descriptors selected by patients during methacholine inhalation allowed us to define three language subgroups: (1) chest tightness (subgroup A, n = 21); (2) work/effort (subgroup B, n = 7); and (3) both descriptors (subgroup C, n = 13). Eight of the 49 patients (subgroup D) were not able to make a clear-cut distinction among descriptors. The subgroups exhibited similar function at baseline and during methacholine inhalation. Most importantly, patients selected chest tightness to a greater extent (42.85%), and work/effort (14.3%) and both descriptors (26.5%) to a lesser extent at the lowest level of bronchoconstriction (FEV(1) fall < 10%) as at 20% fall in FEV(1). Thirty-two patients were normoperceivers (PB(20) > or = 1.4 to < 5 arbitrary units [au]), 7 patients were hyperperceivers (PB(20) > or = 5 au), and 10 patients were hypoperceivers (PB(20) < 1.4 au). Language subgroups were equally distributed across the perceiver subgroups. CONCLUSIONS: In patients with clinically stable asthma, PB(20) and language of dyspnea independently contribute to defining the condition of the disease. However, the possibility that this independence may be due to a beta-error should be taken into account.

Respiratory muscle energetics during exercise in healthy subjects and patients with COPD.

The energy expenditure required by the respiratory muscles during exercise is a function of their work rate, cost of breathing, and efficiency. During exercise, ventilatory requirements increase further exacerbating the potential imbalance between inspiratory muscle load and capacity. High level of exercise intensity in conjunction with contracting respiratory muscles is the reason for respiratory muscle fatigue in healthy subjects. Available evidence would suggest that fatigue of the diaphragm and other respiratory muscles is an important mechanism involved in redistribution of blood flow. Reflex mechanisms of sympathoexcitation are triggered in fatigued diaphragm during heavy exercise when cardiac output is not sufficient to adequately meet the high metabolic requirements of both respiratory and limb musculature. It is very likely that local changes in locomotor muscle blood flow may occur during exhaustive endurance exercise and that changes may have important effect on O2 transport to the working locomotor muscles and, therefore, on their fatigability. In a condition when the respiratory muscles receive their share of blood flow at the expense of limb locomotor muscles, minimizing mechanical work of breathing and therefore its metabolic cost allows a greater amount of cardiac output to be available to be delivered to working limb muscles. Malfunction in any of the multiple components responsible for circulatory flow and O2 delivery will limit the blood supply therefore inhibiting the supply of O2 and the energy substrate to the contracting muscles. Studies are needed to overcome these limitations.

Pathophysiology of exercise dyspnea in healthy subjects and in patients with chronic obstructive pulmonary disease (COPD).

In patients with a number of cardio-respiratory disorders, breathlessness is the most common symptom limiting exercise capacity. Increased respiratory effort is frequently the chosen descriptor cluster both in normal subjects and in patients with chronic obstructive pulmonary disease (COPD) during exercise. The body of evidence indicates that dyspnea may be due to a central perception of an overall increase in central respiratory motor output directed preferentially to the rib cage muscles. On the other hand, the disparity between respiratory motor output and mechanical response of the system is also thought to play an important role in the increased perception of exercise in patients. The expiratory muscles also contribute to exercise dyspnea: a decrease in Borg scores is related to a decrease in end-expiratory lung volume and to a decrease in end-expiratory gastric pressure at isowork after lung volume reduction surgery. Changes in respiratory mechanics and intrathoracic pressure surrounding the heart can reduce cardiac output by affecting the return of blood to the heart from the periphery, or by interfering with the ability of the heart to eject blood into the peripheral circulation. Change in arterial blood gas content may affect breathlessness via direct or indirect effects. Old and more recent data have demonstrated that hypercapnia makes an independent contribution to breathlessness. In hypercapnic COPD patients an increase in PaCO2 seems to be the most important stimulus overriding all other inputs for dyspnea. Hypoxia may act indirectly by increasing ventilation (VE), and directly, independent of change in VE. Finally, chemical (metabolic) ventilatory stimuli do not have a specific effect on breathlessness other than via their stimulation of VE. We conclude that exercise provides a stimulus contributing to dyspnea, which can be applied to many diseases.

Arm exercise and hyperinflation in patients with COPD: effect of arm training.

BACKGROUND: Unlike studies on leg exercise, reports on the regulation of dynamic hyperinflation during arm exercise are scanty. We ascertained the following in patients with COPD: (1) whether and to what extent upper-limb exercise results in dynamic hyperinflation, and (2) the mechanism whereby an arm-training program (ATP) reduces arm effort and dyspnea. PATIENTS: Twelve patients with moderate-to-severe COPD were tested during incremental, symptom-limited arm exercise after a non-intervention control period (pre-ATP) and after ATP. METHODS: Exercise testing (1-min increments of 5 W) was performed using an arm ergometer. Oxygen uptake (V(O2)), carbon dioxide output, minute ventilation (Ve), tidal volume, and respiratory rate (RR) were measured continuously during the tests. Inspiratory capacity (IC), exercise dyspnea, and arm effort using a Borg scale were assessed at each step of exercise. RESULTS: Arm exercise resulted in a significant decrease in IC and significant positive relationships of IC with an increase in V(O2) and exercise dyspnea and arm effort. The results of ATP were as follows: (1) a significant increase in exercise capacity (p < 0.001); (2) no change in the relationships of exercise dyspnea and arm effort with Ve and IC, and of IC with V(O2); (3) at a standardized work rate, Ve, exercise dyspnea, and arm effort significantly decreased, while the decrease in IC was significantly less (p < 0.01) than before the ATP; the decrease in Ve was accomplished primarily by a decrease in RR; and (4) at standardized Ve, exercise dyspnea and arm effort decreased significantly. CONCLUSIONS: Arm exercise results in the association of dynamic hyperinflation, exercise dyspnea, and arm effort in COPD patients. An ATP increases arm endurance, modulates dynamic hyperinflation, and reduces symptoms.

Dyspnea and leg effort during exercise.

Dyspnea and leg effort are the major symptoms limiting exercise in healthy subjects and in patients with a variety of respiratory disorders. Quantitative measurement of both symptoms may be obtained by category scales such as VAS and Borg, with the latter being widely used. Furthermore, descriptor clusters of dyspnea help to assess some of the reasons for stopping exercise. The intensity of dyspnea and leg effort are similar in different disease states; this symmetry suggests that the limiting discomfort is a function of the intensity of increased motor drive to peripheral and respiratory muscles. An alternative explanation for the factors which limit exercise is that the subjects stop exercise volitionally when the discomfort associated with continuing exercise exceeds that which they are willing to tolerate. Muscle strength contributes to the intensity of dyspnea and leg effort at a given power output: the greater the muscle force, the lower the symptom. Symptoms also correlate with intensity and duration of a task by a power function in such a way that when minimizing the intensity of a given muscular task by prolonging the duration of activity, the symptom is drastically reduced. Skeletal muscle fatigue may be a factor limiting exercise tolerance both in healthy subjects and in patients with cardiorespiratory disorders. In conclusion, symptom measurement complements physiological measurements, both being essential to a comprehensive understanding of exercise tolerance.

Respiratory muscles and dyspnea in obese nonsmoking subjects.

To our knowledge no data have been reported on the contribution to acute increase in dyspnea by the respiratory muscles in obese nonsmoking subjects. To better focus on this topic, we studied seven obese subjects and an age-matched normal control group, assessing baseline pulmonary function, breathing pattern, esophageal pressure (Pes), and gastric (Pga) and transdiaphragmatic (Pdi) pressures. Pes was also recorded during a sniff maneuver (Pessn). During a hypercapnic rebreathing test we recorded inspiratory swing in Pes (Pessw), expiratory changes in Pga, and inspiratory swings in Pdi (Pdisw). Change in inspiratory capacity was considered the mirror image of end-expiratory lung volume (EELV). Dyspnea was assessed by a modified Borg scale. Under control conditions, patients exhibited a reduced expiratory reserve volume and intrinsic positive end-expiratory pressure (PEEPi). At the end of hypercapnic stimulation, compared with controls our obese subjects exhibited greater respiratory frequency (Rf), shorter expiratory time, greater Pessw, and lower Pdisw. Increases in EELV and PEEPi were found in the obese subjects but not in controls. Changes in Borg correlated with changes in PETCO2, VE, Pessw (%Pessn), and Pdisw to a greater extent in patients than in controls. Stepwise regression analysis indicated the amount of variability in Borg that was predicted by both Pdisw (r2 = 0.31, p < 0.0004), and Pessw (%Pessn) (r2 = 0.09, p < 0.005) in controls, and by Pessw (%Pessn) (r2 = 0.40, p < 0.00001) in obese subjects. We conclude that the rib cage muscles contributed to dyspnea to a greater extent in this subset of obese subjects.

Chest wall kinematics and breathlessness during pursed-lip breathing in patients with COPD.

BACKGROUND: Pursed-lip breathing (PLB) is a strategy often spontaneously employed by patients with COPD during distress situations. Whether and to what extent PLB affects operational lung volume is not known. Also, conflicting reports deal with PLB capability of decreasing breathlessness. PARTICIPANTS AND MEASUREMENTS: Twenty-two patients with mild-to-severe COPD were studied. Volumes of chest wall (CW) compartments (rib cage [RC] and abdomen) were assessed using an optoelectronic plethysmograph. Dyspnea was assessed by a modified Borg scale. RESULTS: Compared to spontaneous breathing, patients with PLB exhibited a significant reduction (mean +/- SD) in end-expiratory volume of the CW (VCW) [VCWee; - 0.33 +/- 0.24 L, p < 0.000004], and a significant increase in end-inspiratory VCW (VCWei; + 0.32 +/- 0.43 L, p < 0.003). The decrease in VCWee, mostly due to the decrease in end-expiratory volume of the abdomen (VAbee) [- 0.25 +/- 0.21 L, p < 0.00002], related to baseline FEV(1) (p < 0.02) and to the increase in expiratory time (TE) [r(2) = 0.49, p < 0.0003] and total time of the respiratory cycle (TTOT) [r(2) = 0.35, p < 0.004], but not to baseline functional residual capacity (FRC). Increase in tidal volume (VT) of the chest wall (+ 0.65 +/- 0.48 L, p < 0.000004) was shared between VT of the abdomen (0.31 +/- 0.23 L, p < 0.000004) and VT of the rib cage (+ 0.33 +/- 0.29 L, p < 0.00003). Borg score decreased with PLB (p < 0.04). In a stepwise multiple regression analysis, decrease in VCWee accounted for 27% of the variability in Borg score at 99% confidence level (p < 0.008). CONCLUSIONS: Changes in VCWee related to baseline airway obstruction but not to hyperinflation (FRC). By lengthening of TE and TTOT, PLB decreases VCWee and reduces breathlessness.

Dissociation between respiratory effort and dyspnoea in a subset of patients with stroke.

Dyspnoea is not a prominent complaint of resting patients with recent hemispheric stroke (RHS). We hypothesized that, in patients with RHS presenting abnormalities in respiratory mechanics, increased respiratory motor output could translate into an increased perception of dyspnoea. We studied eight wheelchair-bound patients with RHS (mean age 62.4 years), previously evaluated by computerized tomography scanning, and a control group of normal subjects, matched for age and sex. We assessed routine spirometry, inspiratory and expiratory muscle pressures, breathing pattern and dyspnoea using a modified Borg scale. In six patients, we also measured oesophageal pressure during the maximal sniff manoeuvre and tidal inspiratory swing, and mechanical characteristics of the lung in terms of dynamic elastance during both quiet breathing and a hypercapnic/hyperoxic rebreathing test. During room air breathing, ventilation and tidal volume were similar in patients and controls, while tidal inspiratory swings of oesophageal pressure, an index of inspiratory motor output, were greater in patients ( P =0.005). Patients also exhibited a greater dynamic elastance ( P =0.013). During rebreathing, dynamic elastance remained higher ( P =0.01) and a greater than normal inspiratory motor output was found ( P =0.03). Responses of ventilation and tidal volume to carbon dioxide tension were normal, and in all patients but one a lower Borg score for the unit change in carbon dioxide tension and ventilation was found. In conclusion, a higher than normal inspiratory motor output was unexpectedly associated with a blunted perception of dyspnoea in this subset of RHS patients. This is likely to be due to the modulation of the integration process of respiratory sensation.