Does the severity of asthma affect exercise capacity and daily physical activity?

OBJECTIVE: Exercise capacity, daily physical activity, and psychological profile are crucial aspects in the management of asthmatic patients. Whether these features are expressed in a different way in mild-moderate (MMA) and severe asthma (SA) is unknown. METHODS: In this observational cross-sectional study, patients matching the American Thoracic Society/European Respiratory Society (ATS/ERS) definition for SA underwent incremental cardiopulmonary exercise testing (CPET), full lung function testing, and an evaluation of daily step count and physical activity. Questionnaires on quality of life, general fatigue, and presence of anxiety and depression traits (Hospital Anxiety and Depression Scale - HADS) were administered. Patients were compared with a cohort of age- and gender-matched MMA patients. RESULTS: We enrolled 16 SA, 17 MMA patients, and 16 healthy subjects. Compared to MMA, SA subjects showed a median (interquartile range) reduced peak oxygen consumption during CPET (20.4 (17.2-23.3) vs. 25.6 (18.5-30.3) ml/min/kg; p = 0.019), a reduced resting lung function (FEV1% of predicted 77 (67-84) vs. 96 (84-100); p < 0.001) and a pronounced anxiety trait at HADS (9.5 (3-11.7) vs. 4.0 (2.0-7.5); p = 0.023). In addition, SA patients showed a significantly higher reduction in inspiratory capacity from rest to peak (310 (160-520) vs. 110 (-65-325) ml; p = 0.031). We found no significant differences in mean daily step count or quality of life. CONCLUSIONS: Compared to MMA, SA patients present a reduced exercise capacity and a more pronounced anxiety trait, but not worse daily physical activity or quality of life. These aspects should be considered in the clinical management and research development of SA.

Surviving COVID-19 in Bergamo province: a post-acute outpatient re-evaluation.

Bergamo province was badly hit by the coronavirus disease 2019 (COVID-19) epidemic. We organised a public-funded, multidisciplinary follow-up programme for COVID-19 patients discharged from the emergency department or from the inpatient wards of 'Papa Giovanni XXIII' Hospital, the largest public hospital in the area. As of 31 July, the first 767 patients had completed the first post-discharge multidisciplinary assessment. Patients entered our programme at a median time of 81 days after discharge. Among them, 51.4% still complained of symptoms, most commonly fatigue and exertional dyspnoea, and 30.5% were still experiencing post-traumatic psychological consequences. Impaired lung diffusion was found in 19%. Seventeen per cent had D-dimer values two times above the threshold for diagnosis of pulmonary embolism (two unexpected and clinically silent pulmonary thrombosis were discovered by investigating striking D-dimer elevation). Survivors of COVID-19 exhibit a complex array of symptoms, whose common underlying pathology, if any, has still to be elucidated: a multidisciplinary approach is fundamental, to address the different problems and to look for effective solutions.

Covid-19 and gender: lower rate but same mortality of severe disease in women-an observational study.

BACKGROUND: Gender-related factors might affect vulnerability to Covid-19. The aim of this study was to describe the role of gender on clinical features and 28-day mortality in Covid-19 patients. METHODS: Observational study of Covid-19 patients hospitalized in Bergamo, Italy, during the first three weeks of the outbreak. Medical records, clinical, radiological and laboratory findings upon admission and treatment have been collected. Primary outcome was 28-day mortality since hospitalization. RESULTS: 431 consecutive adult patients were admitted. Female patients were 119 (27.6%) with a mean age of 67.0 ± 14.5 years (vs 67.8 ± 12.5 for males, p = 0.54). Previous history of myocardial infarction, vasculopathy and former smoking habits were more common for males. At the time of admission PaO2/FiO2 was similar between men and women (228 [IQR, 134-273] vs 238 mmHg [150-281], p = 0.28). Continuous Positive Airway Pressure (CPAP) assistance was needed in the first 24 h more frequently in male patients (25.7% vs 13.0%; p = 0.006). Overall 28-day mortality was 26.1% in women and 38.1% in men (p = 0.018). Gender did not result an independent predictor of death once the parameters related to disease severity at presentation were included in the multivariable analysis (p = 0.898). Accordingly, the Kaplan-Meier survival analysis in female and male patients requiring CPAP or non-invasive ventilation in the first 24 h did not find a significant difference (p = 0.687). CONCLUSION: Hospitalized women are less likely to die from Covid-19; however, once severe disease occurs, the risk of dying is similar to men. Further studies are needed to better investigate the role of gender in clinical course and outcome of Covid-19.

Lymphangioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia, and sarcoidosis: more pathological findings in the same chest CT, or a single pathological pathway?

BACKGROUND: Autoimmune hepatitis/primary biliary cirrhosis overlap syndrome, lymphangioleiomyomatosis/tuberous sclerosis complex (LAM-TSC), and sarcoidosis are three rare diseases. Here we present, to the best of our knowledge, the first description of a patient with the coexistence of these three diseases. CASE PRESENTATION: A 47-year-old woman affected by LAM-TSC and primary biliary cirrosis/autoimmune hepatitis overlap syndrome. During her follow up a high resolution chest CT scan (HRTC) confirmed the presence of both multiple cysts and micronodular opacities consistent with multifocal micronodular pneumocytes hyperlasia (MMPH), and revealed multiple hilar-mediastinal symmetrical lymphadenopathies suggestive of sarcoidosis. Simultaneously, subcutaneous nodules appeared on her forearm bilaterally. Cutaneous biopsy showed granulomatous dermatitis with sarcoid-like granulomas. A diagnosis of stage I pulmonary sarcoidosis was made. No treatment for sarcoidosis was initiated since the patient had neither systemic involvement, nor respiratory impairment. CONCLUSIONS: The presence of more than one rare disease should challenge the concept of a potential common underlying mechanism, since the a priori probability of the concomitant presence of different conditions with different pathogenic mechanisms - especially if rare diseases - is low. We speculate that the dysregulation of the pathway involving mTOR and MAPK and their interaction might play a role in the pathogenesis of other diseases, including sarcoidosis.

A Review of the Ultrasound Assessment of Diaphragmatic Function in Clinical Practice.

Ultrasonography is the only non-invasive, non-ionizing imaging technique widely available to directly assess diaphragmatic function. Two different sonographic approaches permit the assessment of muscle thickening in the zone of apposition and excursion of the dome of the diaphragm. Thanks to the new hand-held ultrasound instruments, the morphology and function of the diaphragm can be assessed in different settings, such as outpatient clinic, pulmonary function test laboratory, hospital department and intensive care unit, and under different conditions. Despite the existence of different acoustic views and several codified approaches, a comprehensive sonographic examination has never been standardized for clinical use. In this review, we summarize the clinical indications, methods and perspectives of the technique in adults.

Gas exchange abnormalities in Long COVID are driven by the alteration of the vascular component.

BACKGROUND: There are uncertainties whether the impairment of lung diffusing capacity in COVID-19 is due to an alteration in the diffusive conductance of the alveolar membrane (Dm), or an alteration of the alveolar capillary volume (Vc), or a combination of both. The combined measurement DLNO and DLCO diffusion, owing to NO higher affinity and faster reaction rate with haemoglobin compared to CO, enables the simultaneous and rapid determination of both Vc and Dm. The aim of the present study was to better identify the precise cause of post-COVID-19 diffusion impairment. METHODS: Using the combined NO and CO gas transfer techniques (DLNO and DLCO), it is possible to better understand whether gas exchange abnormalities are due to membrane or alveolar capillary volume components. The present study was aimed at evaluating pulmonary gas exchange one year after severe COVID-19.  Results: The cohort included 33 survivors to severe COVID-19 (median age 67 years, 70% male) with no pre-existing lung disease, who underwent clinical, lung function and imaging assessments at 12 months due to persistence of respiratory symptoms or radiological impairment. The gas exchange abnormalities were mainly determined by the compromise of the vascular component as demonstrated by vascular pattern of gas exchange impairment (i.e., DLNO/DLCO≥110%, 76% of the sample), and by a reduction of the Vc (73%), while the Dm was reduced only in 9% of the entire sample. We did not find a correlation between the gas exchange impairment and the extent of the chest CT alterations (DLCO p = 0.059 and DLNO p = 0.054), which on average were found to be mild (11% of the parenchyma). CONCLUSION: In COVID-19 survivors who are still symptomatic or have minimal CT findings at one year, gas exchange abnormalities are determined by impairment of the vascular component, rather than the diffusive component of the alveolar membrane.

Oscillometry in severe asthma: the state of the art and future perspectives.

INTRODUCTION: Approximately 3-10% of people with asthma have severe asthma (SA). Patients with SA have greater impairment in daily life and much higher costs. Even if asthma affects the entire bronchial tree, small airways have been recognized as the major site of airflow limitation. There are several tools for studying small airway dysfunction (SAD), but certainly the most interesting is oscillometry. Despite several studies, the clinical usefulness of oscillometry in asthma is still in question. This paper aims to provide evidence supporting the use of oscillometry to improve the management of SA in clinical practice. AREAS COVERED: In the ATLANTIS study, SAD was strongly evident across all severity. Various tools are available for evaluation of SAD, and certainly an integrated use of these can provide complete and detailed information. However, the most suitable method is oscillometry, implemented for clinical routine by using either small pressure impulses or small pressure sinusoidal waves. EXPERT OPINION: Oscillometry, despite its different technological implementations is the best tool for determining the impact of SAD on asthma and its control. Oscillometry will also be increasingly useful for choosing the appropriate drug, and there is ample room for a more widespread diffusion in clinical practice.

One-year mortality in COVID-19 is associated with patients' comorbidities rather than pneumonia severity.

BACKGROUND: In patients with pneumonia or acute respiratory distress syndrome who survived hospitalization, one-year mortality can affect up to one third of discharged patients. Therefore, significant long-term mortality after COVID-19 respiratory failure could be expected. The primary outcome of the present study was one-year all-cause mortality in hospitalized COVID-19 patients. METHODS: Observational study of COVID-19 patients hospitalized at Papa Giovanni XXIII Hospital (Bergamo, Italy), during the first pandemic wave. RESULTS: A total of 1326 COVID-19 patients were hospitalized. Overall one-year mortality was 33.6% (N 446/1326), with the majority of deaths occurring during hospitalization (N=412, 92.4%). Thirty-four patients amongst the 914 discharged (3.7%) subsequentely died within one year. A third of these patients died for advanced cancer, while death without a cause other than COVID-19 was uncommon (8.8% of the overall post-discharge mortality). In-hospital late mortality (i.e. after 28 days of admission) interested a population with a lower age, and fewer comorbidities, more frequentely admitted in ICU. Independent predictors of post-discharge mortality were age over 65 years (HR 3.19; 95% CI 1.28-7.96, p-value=0.013), presence of chronic obstructive pulmonary disease (COPD) (HR 2.52; 95% CI 1.09-5.83, p-value=0.031) or proxy of cardiovascular disease (HR 4.93; 95% CI 1.45-16.75, p-value=0.010), and presence of active cancer (HR 3.64; 95% CI 1.50-8.84, p-value=0.004), but not pneumonia severity. CONCLUSIONS: One-year post-discharge mortality depends on underlying patients' comorbidities rather than COVID-19 pneumonia severity per se. Awareness among physicians of predictors of post-discharge mortality might be helpful in structuring a follow-up program for discharged patients.

Small Airways: The "Silent Zone" of 2021 GINA Report?

Asthma is a chronic disease, affecting approximately 350 million people worldwide. Inflammation and remodeling in asthma involve the large airways, and it is now widely accepted that the small airways (those with an internal diameter <2 mm) are involved in the pathogenesis of asthma and are the major determinant of airflow obstruction in this disease. From a clinical perspective, small airways dysfunction (SAD) is associated with more severe bronchial hyperresponsiveness, worse asthma control and more exacerbations. Unlike the GOLD guidelines which, in their definition, identify COPD as a disease of the small airways, the Global Initiative for Asthma (GINA) guidelines do not refer to the prevalence and role of SAD in asthmatic patients. This decision seems surprising, given the growing body of compelling evidence accumulating pointing out the high prevalence of SAD in asthmatic patients and the importance of SAD in poor asthma control. Furthermore, and remarkably, SAD appears to possess the characteristics of a treatable pulmonary trait, making it certainly appealing for asthma control optimization and exacerbation rate reduction. In this mini-review article, we address the most recent evidence on the role of SAD on asthma control and critically review the possible inclusion of SAD among treatable pulmonary traits in international guidelines on asthma.

Structural and Functional Pulmonary Assessment in Severe COVID-19 Survivors at 12 Months after Discharge.

Long-term pulmonary sequelae in COVID-19 patients are currently under investigation worldwide. Potential relationships between blood sampling and functional and radiological findings are crucial to guide the follow-up. In this study, we collected and evaluated clinical status, namely symptoms and patients' reported outcome, pulmonary function tests (PFT), laboratory tests, and radiological findings at 3- and 12-months post-discharge in patients admitted between 25 February and 2 May 2020, and who survived severe COVID-19 pneumonia. A history of chronic pulmonary disease or COVID-19-unrelated complications were used as exclusion criteria. Unenhanced CTs were analyzed quantitatively (compromising lung volume %) and qualitatively, with main patterns of: ground-glass opacity (GGO), consolidation, and reticular configuration. Patients were subsequently divided into groups based on their radiological trends and according to the evolution in the percentage of compromised lung volume. At 12 months post-discharge, seventy-one patients showed significantly improved laboratory tests and PFT. Among them, 63 patients also underwent CT examination: all patients with negative CT findings at three months (n = 14) had negative CT also at 12 months; among the 49/63 patients presenting CT alterations at three months, 1/49 (2%) normalized, 40/49 (82%) improved, 7/49 (14%) remained stably abnormal, and 1/49 (2%) worsened. D-dimer values were low in patients with normal CT and higher in cases with improved or stably abnormal CT (median values 213 vs. 329 vs. 1000 ng/mL, respectively). The overall compromised lung volume was reduced compared with three months post-discharge (12.3 vs. 14.4%, p < 0.001). In stably abnormal CT, the main pulmonary pattern changed, showing a reduction in GGO and an increase in reticular configuration. To summarize, PFT are normal in most COVID-19 survivors 12 months post-discharge, but CT structural abnormalities persist (although sensibly improved over time) and are associated with higher D-dimer values.

Frequency, characteristics, and outcome of patients with COVID-19 pneumonia and "silent hypoxemia" at admission: a severity-matched analysis.

BACKGROUND: An aspect of COVID-19 baffling physicians is the presentation of patients with acute respiratory failure, but normal mental faculties and no perception of dyspnea (i.e. "silent hypoxemia"). The aim of this study was to investigate the frequency, characteristics, and outcome of COVID-19 patients with silent hypoxemic status and comparing them with a symptomatic severity-matched group. METHODS: This is a retrospective monocentric observational study involving all patients with PCR confirmed SARS-CoV-2 pneumonia, admitted at Papa Giovanni XXIII Hospital, Bergamo (Italy) from Emergency Department due to acute respiratory failure, during the first Italian pandemic peak (February-April 2020). RESULTS: Overall 28-day mortality in 1316 patients was 26.9%. Patients who did not report dyspnea at admission (N 469, 35.6%) had a lower 28-day mortality (22.6 vs. 29.3%, P=0.009). The severity matching analysis (i.e. PaO2/FiO2 and imaging) led to the identification of two groups of 254 patients that did not differ for sex prevalence, age, BMI, smoking history, comorbidities, and PaCO2 at admission. The use of CPAP during the first 24 hours, such as the need of endotracheal intubation (ETI) during the overall admission were significantly lower in matched patients with silent hypoxemia, whereas 28-day mortality resulted similar (P=0.21). CONCLUSIONS: Lack of dyspnea is common in patients suffering from severe COVID-19 pneumonia leading to respiratory failure, since up to a third of them could be asymptomatic on admission. Dyspnea per se correlates with pneumonia severity, and prognosis. However, dyspnea loses its predictive relevance once other findings to evaluate pneumonia severity are available such as PaO2/FiO2 and imaging. Silent hypoxemic patients are less likely to receive CPAP during the first 24 hours and ETI during the hospitalization, in spite of a comparable mortality to the dyspneic ones.

Artificial intelligence for quality control of oscillometry measures.

BACKGROUND: The forced oscillation technique (FOT) allows non-invasive lung function testing during quiet breathing even without expert guidance. However, it still relies on an operator for excluding breaths with artefacts such as swallowing, glottis closure and coughing. This manual selection is operator-dependent and time-consuming. We evaluated supervised machine learning methods to exclude breaths with artefacts from data analysis automatically. METHODS: We collected 932 FOT measurements (Resmon Pro Full, Restech) from 155 patients (6-87 years) following the European Respiratory Society (ERS) technical standards. Patients were randomly assigned to either a training (70%) or test set. For each breath, we computed 71 features (including anthropometric, pressure stimulus, breathing pattern, and oscillometry data). Univariate filter, multivariate filter and wrapper methods for feature selection combined with several classification models were considered. RESULTS: Trained operators identified 4333 breaths with- and 10244 without artefacts. Features selection performed by a wrapper method combined with an AdaBoost tree model provided the best performance metrics on the test set: Balanced Accuracy = 85%; Sensitivity = 79%; Specificity = 91%; AUC-ROC = 0.93. Differences in FOT parameters computed after manual or automatic breath selection was less than ∼0.25 cmH2O*s/L for 95% of cases. CONCLUSION: Supervised machine-learning techniques allow reliable artefact detection in FOT diagnostic tests. Automating this process is fundamental for enabling FOT for home monitoring, telemedicine, and point-of-care diagnostic applications and opens new scenarios for respiratory and community medicine.

Post-discharge chest CT findings and pulmonary function tests in severe COVID-19 patients.

PURPOSE: To evaluate chest computed tomography (CT) and pulmonary function test (PFT) findings in severe COVID-19 patients after discharge and correlate CT pulmonary involvement with PFT results. METHODS: COVID-19 patients admitted to our hospital between February 25 and May 2, 2020, were retrospectively included according to the following criteria: (a) COVID-19 defined as severe based on the WHO interim guidance (i.e., clinical signs of pneumonia plus respiratory rate > 30 breaths/min, severe respiratory distress, and/or SpO2 < 90 % on room air); (b) chest radiograph in the acute setting; (c) post-discharge unenhanced chest CT; and (d) post-discharge comprehensive PFT. Imaging findings were retrospectively evaluated in consensus by two readers, and volume of abnormal lung was measured on CT using 3D Slicer software. Differences between demographics, comorbidities, acute radiographic findings, PFT, and post-discharge clinical and laboratory data of patients with normal and abnormal CT findings were assessed by Mann-Whitney or Fisher tests, and the compromised lung volume-PFT association by Pearson correlation after removing possible outliers. RESULTS: At a median of 105 days from symptom onset, 74/91 (81 %) patients had CT abnormalities. The most common CT pattern was combined ground-glass opacity and reticular pattern (46/74, 62 %) along with architectural distortion (68/74, 92 %) and bronchial dilatation (66/74, 89 %). Compromised lung volume had a median value of 15 % [11-23], was higher in dyspneic patients, and negatively correlated with the percentage of predicted DLCO, VA, and FVC values (r = -0.39, -0.5, and -0.42, respectively). These PFT parameters were significantly lower in patients with CT abnormalities. Impairment of DLCO and KCO was found in 12 (13 %) cases, possibly implying an underlying pulmonary vasculopathy in this subgroup of patients. CONCLUSIONS: Most severe COVID-19 survivors still had physiologically relevant CT abnormalities about three months after the disease onset, with an impairment of diffusion capacity on PFT. A pulmonary vasculopathy was suggested in a minor proportion of patients.

Exploring the Role of Matrix Metalloproteinases as Biomarkers in Sporadic Lymphangioleiomyomatosis and Tuberous Sclerosis Complex. A Pilot Study.

Background: Lymphangioleiomyomatosis can develop in a sporadic form (S-LAM) or in women with tuberous sclerosis complex (TSC). The matrix metalloproteinases (MMPs) are extracellular matrix-degrading enzymes potentially involved in cystic lung destruction, and in the process of migration of LAM cells. The aim of the study was to explore the role of MMP-2 and MMP-7, such as vascular endothelial growth factor (VEGF) -C and -D in women with LAM, including patients with minor pulmonary disease (i.e., <10 lung cysts), and TSC with or without LAM. Methods: We evaluated 50 patients: 13 individuals affected by S-LAM, 20 with TSC-LAM, of whom six with minor pulmonary disease, and 17 with TSC without pulmonary involvement. Sixteen healthy women were used as controls. Results: MMP-2 resulted higher in LAM compared to healthy volunteers, and TSC patients (p = 0.040). MMP-7 was higher in TSC-LAM patient, with even greater values in patients with TSC-LAM minor pulmonary disease, than in S-LAM patients, and in controls (p = 0.001). VEGF-D level was lower than 800 pg/mL in all healthy controls and resulted higher in S-LAM and TSC-LAM than in TSC patients and controls (p < 0.001). VEGF-C values were not statistically different in the study population (p = 0.354). The area under ROC curves (AUCs) of MMP-2, and MMP-7 for predicting LAM diagnosis were of 0.756 ± 0.079 (p = 0.004), and 0.828 ± 0.060 (p < 0.001), respectively. Considering only patients with TSC, the AUCs for MMP-2, and MMP-7 in predicting LAM were 0.694 ± 0.088 (p = 0.044), and 0.713 ± 0.090 (p = 0.027), respectively. Conclusions: Our data suggest that MMP-2 and MMP-7 could be promising biomarkers for LAM diagnosis.

Natural history of incidental sporadic and tuberous sclerosis complex associated lymphangioleiomyomatosis.

Lymphangioleiomyiomatosis (LAM) is a rare disease affecting women in childbearing age. A sporadic form (S-LAM) affecting previously healthy women, and a form associated with Tuberous Sclerosis Complex (TSC-LAM) are described. Some data suggested that TSC-LAM could be a milder disease compared to S-LAM. To investigate whether the different disease behavior is real or due to overdiagnosis of screened TSC women, we compared the natural history of S-LAM and TSC-LAM in patients with incidental diagnosis. Clinical, and functional data from 52 patients (23 with S-LAM and 29 with TSC-LAM) were analysed. At diagnosis functional impairment was mild without differences between groups [FEV1 % pred was 97% (88-105) and 94% (82-106) in TSC-LAM and S-LAM, respectively, p = 0.125]. Patients with S-LAM had less renal angiomyolipoma, and lower VEGF-D serum levels than TSC-LAM. There was no difference in the baseline extent of pulmonary cysts on CT scan and no difference in yearly rate of functional decline between TSC-LAM, and S-LAM patients [e.g. yearly rate of decline of FEV1 % pred was -0.51 (-1.59-2.24) and -0.90 (-1.92--0.42) in TSC-LAM and S-LAM, respectively, p = 0.265]. In conclusion, the natural history of TSC-LAM and S-LAM, when a potential selection bias due to screening in the latter group is balanced, is similar. Our study suggests that the prevalence of S-LAM can be significantly underestimated due to a tendency to diagnosis more frequently patients with more severe impairment, without identifying several ones with asymptomatic disease.

Efficacy of Benralizumab in severe asthma in real life and focus on nasal polyposis.

INTRODUCTION: Severe asthma occurs in 5-10% of asthmatic patients, with nasal polyposis as one of the most frequent comorbidity. Benralizumab was recently marketed, thus we could analyse its effects in real-life in severe asthma, and compare the effects of the drug in patients with and without polyposis. METHODS: Patients with severe asthma, receiving Benralizumab were enrolled in Italian asthma centres. The efficacy criteria for asthma (exacerbation rate, oral corticosteroid intake, hospitalizations, pulmonary function, exhaled nitric oxide) were evaluated at baseline and after 24 weeks of treatment. Patients were then sub-analysed according to the presence/absence of nasal polyposis. RESULTS: Fifty-nine patients with severe uncontrolled asthma (21 males, age range 32-78) and treated with benralizumab for at least 24 weeks has been evaluated, showing significant improvements in asthma-related outcomes, except for pulmonary function and exhaled nitric oxide. This included a reduction in the sino-nasal outcome-22 score versus baseline of 13.7 points (p = .0037) in the 34 patients with nasal polyposis. Anosmia disappeared in 31% patients (p = .0034). When comparing the groups with and without nasal polyposis, a similar reduction of exacerbations was seen, with a greater reduction of the steroid dependence in patients with polyposis (-72% vs -53%; p < .0001), whereas lung function was significantly more improved (12% vs 34%, p = .0064) without polyposis patients. CONCLUSIONS: Benralizumab, after 6 months of treatment, confirmed its efficacy in severe asthma, and also in nasal polyposis, which is the most frequent comorbidity. The efficacy of Benralizumab in reducing steroid dependence was even higher in patients with polyposis.

Role of thoracic imaging in the management of lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare diffuse lung cystic disease (DLCD) that occurs sporadically or in association with Tuberous Sclerosis Complex (TSC). The diagnostic pathway is tracked on the identification of the disease hallmarks on chest High-Resolution Computed Tomography (HRCT). Aim of this review is to discuss the thoracic HRCT pathognomonic features, essential to rule out other DLCD. It also examines the new evidences emerging from Computed Tomography (CT) quantitative studies that, by demonstrating a specific cysts distribution and a pathological aspect of the parenchyma near the cysts, could improve our understanding of this rare disorder and supply pulmonologists with a new tool for a more appropriate long-term management. Finally, the contribution of other image techniques as low dose chest CT, Magnetic Resonance Imaging (MRI) and Ultrasound (US) is discussed.

Women with TSC: Relationship between Clinical, Lung Function and Radiological Features in a Genotyped Population Investigated for Lymphangioleiomyomatosis.

The advent of pharmacological therapies for lymphangioleiomyomatosis (LAM) has made early diagnosis important in women with tuberous sclerosis complex (TSC), although the lifelong cumulative radiation exposure caused by chest computer tomography (CT) should not be underestimated. We retrospectively investigated, in a cohort of TSC outpatients of San Paolo Hospital (Milan, Italy) 1) the role of pulmonary function tests (PFTs) for LAM diagnosis, 2) the association between LAM and other features of TSC (e.g. demography, extrapulmonary manifestations, genetic mutations, etc.), and 3) the characteristics of patients with multifocal micronodular pneumocyte hyperplasia (MMPH). Eighty-six women underwent chest CT scan; pulmonary involvement was found in 66 patients (77%; 49% LAM with or without MMPH, and 28% MMPH alone). LAM patients were older, with a higher rate of pneumothorax, presented more frequently with renal and hepatic angiomyolipomas, and tended to have a TSC2 mutation profile. PFTs, assessed in 64% of women unaffected by cognitive impairments, revealed a lower lung diffusion capacity in LAM patients. In multivariate analysis, age, but not PFTs, resulted independently associated with LAM diagnosis. Patients with MMPH alone did not show specific clinical, functional or genetic features. A mild respiratory impairment was most common in LAM-TSC patients: In conclusions, PFTs, even if indicated to assess impairment in lung function, are feasible in a limited number of patients, and are not significantly useful for LAM diagnosis in women with TSC.