Assessing value of contrast-enhanced ultrasound vs. conventional transthoracic ultrasound in improving diagnostic yield of percutaneous needle biopsy of peripheral lung lesions.

OBJECTIVE: The aim of the present study was to systematically assess the value of contrast-enhanced ultrasound (CEUS) vs. conventional transthoracic ultrasound (TUS) in improving diagnostic accuracy of percutaneous needle biopsy (PTNB) for subpleural lung lesions. PATIENTS AND METHODS: 232 patients with subpleural lesions were 1:1 randomly assigned to a group were CEUS was performed (n=116, mean age=65.5±5.6, M=69) or not (n=116, mean age=66.0±5.3, M=70). For CEUS study was used an injection of 4.8 mL of SonoVue (Bracco, Italy). For PTNB was employed a Menghini-modified technique with a semi-automatic 18-gauge needle. RESULTS: The mean diameter of subpleural lesions was 2.85±0.7 cm in the CEUS+ group and 2.95±0.6cm in the CEUS- group. Only 3 lesions, 1 in the CEUS+ group and 2 in the CEUS- group measured >5 cm. CEUS showed no superiority in terms of diagnostic accuracy compared to conventional TUS (p=0.34). Similar results were obtained in the sub-analysis of lesions sized between 1-2 cm (p=1.00) and 2-5 cm (p=0.08). As the lesion size increased, the detection rate of necrosis in lesions increased by CEUS (from 8% to 31%). CEUS showed no superiority in terms of diagnostic accuracy in the sub-analysis of necrotic lesions at CECT (p=0.38). AUC values for both the groups assessed an excellent diagnostic yield for TUS-PTNB (≥0.80). CONCLUSIONS: CEUS study does not improve the diagnostic accuracy of TUS-guided PTNB for peripheral lung lesions <5 cm of diameter. Further studies evaluating CEUS guidance for larger (>5 cm) and necrotic lesions are needed prior that its potential can be clarified.

A case of severe allergic eosinophilic asthma with nasal polyposis in a patient affected by Birt-Hogg-Dubé syndrome successfully treated with benralizumab.

SUMMARY: Birt-Hogg-Dubé (BHD) syndrome is a rare genetic pathology characterized by cutaneous fibrofolliculomas, pulmonary cysts and kidney tumours. Severe asthma is the most serious form of asthma that does not respond to standard treatments. We present the case of a 68 years-old male patient who had frequent respiratory tract infections, shortness of breath and decline in lung function, nasal polyposis and hypertrophy of the nasal turbinates, for this reason was treated as a severe asthmatic patient for several years with ICS + LABA and high doses of OCS. When we tried to reduce OCS the patient had worsening of the symptoms, we requested a HRTC scan that showed presence of several cysts spread ubiquitously. The patient had a family history of pneumothorax, for this reason we requested a genetic test that resulted in a heterozygous point mutation on exon 12 (c.1429 C > T) of FLCN gene. Despite the diagnosis of BHD syndrome, the patient's clinical condition kept on suggesting an underlying severe asthma and the blood tests we requested pointed out a high percentage of eosinophils, for this reason we opted for the administration of benralizumab that resulted in an excellent asthma control and increased quality of life.

The prevalence of sleep impairments and predictors of sleep quality among patients with asthma.

BACKGROUND: Sleep is a significant dimension of daily life. However, only a few studies have examined the sleep quality of asthmatics in a real-world clinical settings. OBJECTIVE: This study is aimed to estimate the prevalence of sleep impairments among asthmatic patients and examine the relationship between sleep quality, asthma control, rhinitis symptoms, and sociodemographic characteristics. METHODS: The present study adopted the observational cross-sectional research design that has been designed by the Italian Respiratory Society and used valid assessments to measure the study variables. RESULTS: Data from 1150 asthmatic patients (mean age 51.01 years ± 16.03) were subjected to analysis. 58.3% of the patients had impaired sleep quality (Pittsburgh Sleep Quality Index [PSQI] total scores > 5), and their mean PSQI score was 5.68 (SD = 3.4). A significant correlation emerged between sleep quality and asthma control (p = 0.0001) and a significant albeit weak correlation emerged between PSQI total scores and Total 5 Symptoms Score (r = 0.24, p = 0.0001). Sleep quality was significantly associated health-related quality of life [HRQoL]. (r = 0.50, p < 0.001). After exclusion of patients at risk for Obstructive Sleep Apnea Syndrome (OSAS) and Gastro Esophageal Reflux Disease (GERD), the most important determinants of PSQI score were HRQoL, In the entire sample asthma control is the strongest predictor of both sleep quality and HRQoL. CONCLUSIONS: The results of this real-world study highlight the prevalence, impact and predictors of sleep disturbances in asthmatic patients and suggest the need for physicians to detect poor sleep quality.

A New SERPINA-1 Missense Mutation Associated with Alpha-1 Antitrypsin Deficiency and Bronchiectasis.

Alpha-1-antitrypsin deficiency (AATD) is a genetic condition caused by SERPINA1 mutations, which culminates into lower protease inhibitor activity in the serum and predisposes to emphysema. Clinical manifestations of AATD are often associated to ZZ (p.Glu342Lys) and SZ (p.Glu264Val) genotypes and less frequently to rare deficiency or null alleles in heterozygous and homozygous states. We report a case of a 52-year-old woman with bronchiectasis without other potential causes other than an electrophoresis that showed a decrease of alpha-1 globin band and AAT levels below the normal value (78 mg/dl; v.n. 90-200 mg/dl). No S or Z mutation was identified, but sequencing analysis found a novel missense variant Ile74Asn (c.221T > A) in heterozygous state on an M3 allele (Glu400Asp) in the exon 2 of the SERPINA-1gene, probably leading to a dysfunctional protein. This mutation has never been previously identified, and it is interesting to note the association with bronchiectasis in the absence of emphysema.

Exhaled breath temperature measurement: influence of circadian rhythm.

Exhaled breath temperature (EBT) is an expression of airway inflammation, an event that drives several lung diseases. The measurement of the exhaled breath temperature has recently been proposed as a popular tool in the diagnosis and monitoring of inflammatory lung diseases due to the fact that it is a non-invasive method. The influence of external factors on EBT, its reproducibility, and its sensitivity to treatment have already been explored. However, to reach clinical practice, EBT requires a complete validation that is still lacking. The aim of this study was to analyse the possible influence of an important internal variable, i.e the circadian rhythm on EBT values in a group of 24 healthy adult volunteers. We repeated measurement of EBT at different hours of the day: 8.00 AM, 12.00 AM, 4.00 PM, 8.00 PM and analysed the correlation with axillary temperature measurement at these times. The EBT resulted significantly different during daily measurements (8.00 AM vs 12.00 AM vs 4.00 PM vs 8.00 PM: 28.01±1.64°C vs 28.8±1.82°C vs 29.34±1.79°C vs 28.06±1.34°C). The highest EBT was reported at 4.00 PM and the lowest at 8.00 AM. For the first time we found an influence of the circadian rhythm on EBT. These data support the validation of the EBT necessary for its promotion in clinical practice.

How strong is the association between IPF and lung cancer? An answer from airway's DNA.

Idiopathic pulmonary fibrosis is a chronic progressive disease of lung interstitium of unknown etiology with poor prognosis. In patients with IPF, the incidence of lung cancer is much higher than that in the general population. The identification of noninvasive biomarkers for early diagnosis of IPF is of great relevance in consideration of the management of these patients. Among the noninvasive omic markers, an increasing interest has been directed toward the study of genetic alterations of microsatellites (MAs) in exhaled breath condensate (EBC). The aim of this preliminary study was to investigate the MAs, located in chromosomal regions 8p21.3-q11.1 and 17q11.2-q21, that harbor tumor suppressor genes, in EBC and in the paired whole blood (WB) of IPF patients. Eleven IPF patients were compared with 10 healthy control subjects. All subjects underwent collection of the EBC and WB. The EBC was collected using a condenser. Four microsatellite markers (THRA1, D17S579, D17S250 and D8S137) were used for the analysis of MAs. The EBC-DNA and WB-DNA were amplified by PCR; PCR products were analyzed using the ABI Prism 310 DNA. Microsatellite alterations were found in 58.82 % of EBC-DNA and 12.50 % of WB-DNA in patients with IPF (p < 0.01). None of the healthy subjects exhibited MAs in the studied markers. Our findings suggest that these genetic alterations, studied in EBC, may play an important role in the complex genetic basis of IPF. Since these MAs are frequently detected in cancer, they might explain the higher relative risk of tumorigenesis in this disease.

Study of mitochondrial DNA alteration in the exhaled breath condensate of patients affected by obstructive lung diseases.

Mitochondrial DNA (MtDNA) has been studied as an expression of oxidative stress in asthma, COPD, lung cancer and obstructive sleep apnea, but it has been mainly investigated systemically, although the pathogenetic mechanisms begin in the airways and only later progress to systemic circulation. The aim of this study was to investigate the MtDNA alterations in the exhaled breath condensate (EBC) of patients with asthma, COPD and asthma-COPD overlap syndrome (ACOS). In order to analyze better what happens to mitochondria, both locally and systemically, we compared MtDNA/nDNA in blood and EBC of paired patients. Thirteen (13) COPD patients, 14 asthmatics, 23 ACOS (10 according to Spanish guidelines, 13 in line with GINA guidelines) and 12 healthy subjects were enrolled. Patients underwent clinical and functional diagnostic tests as foreseen by the guidelines. They underwent blood and EBC collection. Content of MtDNA and nuclear DNA (nDNA) was measured in the blood cells and EBC of patients by Real Time PCR. The ratio between MtDNA/nDNA was calculated. For the first time we were able to detect MtDNA/nDNA in the EBC. We found higher exhaled MtDNA/nDNA in COPD, asthmatic and ACOS patients respectively compared to healthy subjects (21.9 ± 4.9 versus 6.51 ± 0.21, p < 0.05; 7.9 ± 2.5 versus 6.51 ± 0.21, p = 0.06; 18.3 ± 3.4 versus 6.51 ± 0.21, p < 0.05). The level of exhaled MtDNA/nDNA was positively correlated with the plasmatic one. The levels of MtDNA/nDNA in the EBC, as expression of oxidative stress, are increased in COPD, asthmatic and ACOS patients compared to healthy subjects. These are preliminary results in a small number of well characterized patients that requires confirmation on a larger population. We support new studies directed toward the analysis of exhaled MtDNA/nDNA as a new exhaled non-invasive marker in other inflammatory/oxidative airways diseases.

Analysis of mitochondrial DNA alteration in new phenotype ACOS.

BACKGROUND: Mitochondria contain their own DNA (MtDNA) that is very sensitive to oxidative stress and as a consequence could be damaged in quantity. Oxidative stress is largely recognized to play a key role in the pathogenesis of asthma and COPD and might have a role in the new intermediate phenotype ACOS (asthma-COPD overlap syndrome). The aim of this study was to investigate MtDNA alterations, as an expression of mitochondrial dysfunction, in ACOS and to verify whether they might help in the identification of this new phenotype and in its differentiation from asthma and COPD. METHODS: Ten (10) ACOS according to Spanish guidelines, 13 ACOS according to GINA guidelines, 13 COPD, 14 asthmatic patients and ten normal subjects were enrolled. They further underwent a blood, induced sputum and exhaled nitric oxide collection. Content of MtDNA and nuclear DNA (nDNA) were measured in the blood cells of patients by Real Time PCR. RESULTS: ACOS patients showed an increase of MtDNA/nDNA ratio. Dividing ACOS according to guidelines, those from the Spanish showed a higher value of MtDNA/nDNA compared to those from GINA/GOLD (92.69 ± 7.31 vs 80.68 ± 4.16). Spanish ACOS presented MtDNA/nDNA ratio closer to COPD than asthma. MtDNA was higher in asthmatic, COPD, GINA and Spanish ACOS patients compared to healthy subjects (73.30 ± 4.47-137.0 ± 19.45-80.68 ± 4.16-92.69 ± 7.31 vs 65.97 ± 20.56). CONCLUSION: We found an increase of MtDNA/nDNA ratio in ACOS subjects that led us to conclude that there is presence of mitochondrial dysfunction in this disease, that makes it closer to COPD than to asthma. Although the MtDNA/nDNA ratio results are a useful marker for differential diagnosis from asthma, COPD and ACOS, further studies are needed to confirm the potentiality of MtDNA/nDNA ratio and to a better characterization of ACOS.

Pulmonary hypertension in COPD and lung transplantation: timing and procedures.

The prevalence of pulmonary hypertension (PH) in the general chronic obstructive pulmonary disease (COPD) population is undefined because stable COPD patients do not routinely undergo screening echocardiogram and right heart catheterization. Most studies published on this topic are focused on a highly selected group of patients with moderate to severe disease awaiting lung transplantation, since hemodynamic data from cardiac catheterization are part of the standard transplant evaluation. In a very recent article, Hurdman et al. studied the characteristics and outcomes, with a particular focus on mortality, of extensively phenotyped, consecutive patients with PH-COPD over a 9-year period. This article offers the opportunity to update the role of PH in COPD as a timer to propose lung transplantation, based on solid literature data on survival, and to select the best procedure (single or double lung transplant), since the outcome indexes based on the old GOLD classification according to FEV1 (1-4) and the new GOLD classification (A-D) have failed in purpose to define the correct timing, due to the lack of functional (6 minutes walking test) and nutritional (Body Mass Index) data. After a revision of available literature including the recent paper of Hurdman et al. we conclude that the timing for lung transplantation is easy to manage in case of severe PH-COPD. On the other hand mild and moderate PH-COPD are still object of debate for therapy, procedure timing and choice and rehabilitation. In other words, we have some confirms for a little percentage of patients, whilst many doubts still exist for the rest.

Daytime PaO2 in OSAS, COPD and the combination of the two (overlap syndrome).

BACKGROUND: OSAS and COPD are often associated with day-time hypoxemia. Overlap Syndrome (OS), the association between both diseases, increases the risk of day-time hypoxemia. The aim of this study was to investigate the mechanisms which could justify the low oxygen level and the effect of CPAP. METHODS: We performed a retrospective analysis in all patients referred to our institutes for suspected OSAS and who also underwent spirometry and blood gas analysis during our evaluation. Thus, 720 patients were selected. According to pulmonary function test parameters they were divided into 3 groups: OSAS (N = 466,65%); OS (N = 168,23%) and COPD (N = 86,12%). In order to evaluate the differences between the three groups, ANOVA analyses were carried out, whereas a multivariate analysis was performed in order to evaluate which factors determine the diurnal PaO(2). In 90 patients we also have the data on blood gas analysis after one year of CPAP treatment, so we evaluate the PaO(2) improvement in accordance with compliance to treatment in these patient subgroups. RESULTS: The OS group showed a lower level of daytime PaO(2) compared with OSAS patients and T90 was higher in OS compared with OSAS. A multivariate analysis showed that in the OS diurnal PaO(2) correlated with age (ß = -0.20) and moreover with FEV(1) (ß = 0.31) and T90 (ß = 0.37), while in the OSAS a correlation was found with FEV(1) (ß = -0.11) and mostly with BMI (ß = 0.25), age and T90. In all patients with good compliance to CPAP day-time PaO(2) improved. CONCLUSIONS: Our data suggest that day-time hypoxemia in OSA patients is largely determined by the increase of body weight and severity of nocturnal hypoxia. However, CPAP therapy has been shown to improve daytime PaO(2) values both in OSAS and in OS.

Effect of CPAP-therapy on bronchial and nasal inflammation in patients affected by obstructive sleep apnea syndrome.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) has been shown to be associated to upper and lower airways inflammation. Continuous positive airway pressure (CPAP) is the elective treatment of OSAS. The aim of the present study was to assess the effect of CPAP-therapy on airway and nasal inflammation. METHODS: In 13 non-smoking subjects affected by untreated OSAS and in 11 non-smoking normal volunteers, airway inflammation was detected by analyses of the induced sputum. In the OSAS group measurements were repeated after 1, 10 and 60 days of the appropriate CPAP treatment. In addition, in 12 subjects of the OSAS group, nasal inflammation was detected by the analysis of induced nasal secretions at baseline, and after 1, 10 and 60 days of CPAP treatment. RESULTS: OSAS patients, compared to normal controls, showed at baseline a higher percentage of neutrophils and a lower percentage of macrophages in the induced sputum. One, 10 and 60 days of appropriate CPAP-therapy did not change the cellular profile of the induced sputum. In addition, in the OSAS patients, the high neutrophilic nasal inflammation present under baseline conditions was not significantly modified by CPAP-therapy. Finally, no patients developed airway hyper-responsiveness after CPAP therapy. CONCLUSIONS: In OSAS subjects, the appropriate CPAP-therapy, while correcting the oxygen desaturation, does not modify the bronchial and nasal inflammatory profile.

Severe obstructive sleep apnoea exacerbates the microvascular impairment in very mild hypertensives.

BACKGROUND: Different studies have shown that obstructive sleep apnoea syndrome (OSAS), frequently associated with hypertension, represents a harmful and independent risk for cardiovascular diseases. The aim of our study was to ascertain whether the occurrence of OSAS could worsen microcirculatory impairment in very mild hypertensives. MATERIALS AND METHODS: One hundred untreated very mild hypertensives underwent polysomnography and subdivided into 32 non-OSAS, 33 mild OSAS and 35 severe OSAS patients on standardized criteria. They underwent routine blood chemistry, ambulatory blood pressure monitoring and anthropometric analysis. Skin capillary density (n mm(-2)) of forearm (FAC) and periungueal (PUC) fields was obtained through videocapillaroscopy. By a venous congestion manoeuvre, PUC was maximized (CVC) and secondary capillary recruitment (GAIN) was calculated. These measurements served as indices of structural and functional capillary rarefaction, respectively. RESULTS: Severe OSAS hypertensives showed reduced FAC (P < 0.001) and PUC (P < 0.001) as compared to those with mild OSAS and non-OSAS, but a greater CVC (P < 0.01) and GAIN (P < 0.001). Multiple regression analysis showed that PUC was inversely related to total sleep time with oxyhaemoglobin saturation at < 90% (TST90) (P < 0.001) and FAC to the apnoea-hypopnoea index (AHI) (P < 0.001) and to the sleep propensity (P < 0.01). CVC was positively associated to AHI (P < 0.001) and GAIN to TST90 (P < 0.05). CONCLUSIONS: The findings suggest that OSAS, by means of reduced basal and functional capillarity rarefaction, might pose an additional risk of impaired peripheral perfusion in very mild hypertensives. A microcirculation study therefore should be a part of the clinical approach in patients at high cerebro-cardiovascular risk such as hypertensives and patients with OSAS.

Long-term evaluation of mental fatigue by Maastricht Questionnaire in patients with OSAS treated with CPAP.

BACKGROUND: Patients with obstructive sleep apnoea syndrome (OSAS) suffer from disrupted sleep. Impaired nightly sleep leads to increase physical and mental fatigue. The effect of long term continuous positive airway pressure (CPAP) on mental fatigue in OSAS patients, assessed by Maastricht Questionnaire (MQ), has not been investigated yet. METHODS: In order to evaluate the role of CPAP in improving mental fatigue of patients with OSAS, we studied 35 patients (26 males, age < 65 years at the time of the diagnosis) affected by OSAS, established by polysomnography (PSG). Patients were divided into two groups; 19 subjects (15 males), who refused CPAP therapy, and 16 patients (11 males) well matched for sex, age, body mass index (BMI), neck circumference, duration of follow up, and severity of disease, who had been treated with CPAP for at least two years. RESULTS: All patients had severe OSAS with Respiratory Disturbance Index (RDI), of 48 +/- 20.9 (range 22-90) and 61.48 +/- 18.6 (range 34-101) respectively, for group one (untreated patients) and group two (CPAP treatment). In addition, all patients had severe impairment of mental fatigue and of daytime sleepiness, demonstrated by high values of MQ score (32.17 +/- 15.33 and 37.36 +/- 12.4, respectively) and Epworth Sleepiness Scale (ESS) (14.21 +/- 4.77 and 15.06 +/- 6.07 respectively). There was no statistical significant difference in the group one at baseline and after follow-up, in terms of BMI, MQ score, ESS, and RDI. In the CPAP group (group two), the patients reported a significant improvement of the quality of their mental health (MQ 37.36 +/- 12.4 vs. 16.41 +/- 9.02; p < 0.0001) and sleepiness (ESS 15.06 +/- 6.07 vs. 4.13 +/- 3.93; p < 0.0001) with a stable BMI. There was significant correlation between the severity of sleep apnoea, expressed as RDI, and MQ at admission compared to at the end of follow-up (r = 0.4, p < 0.05). CONCLUSIONS: This study demonstrates an evident deterioration of mental fatigue in patients with OSAS, directly correlated to the severity of nocturnal disorder breathing; however supports the hypothesis that long-term CPAP therapy significantly improves sleepiness and mental fatigue.

Gender difference in sleep profile of severely obese patients with obstructive sleep apnea (OSA).

OBJECTIVES: Few papers addressed the gender difference in the polisomnographic features of obstructive sleep apnea (OSA). In this paper we investigated the sleep architecture and the nocturnal respiratory pattern in a group of severely obese women with OSA compared with a group of men with OSA matched by age and weight. DESIGN: A cross-sectional study. SETTING: Primary-care setting. SUBJECTS, MAIN OUTCOME MEASURES: Anthropometric parameters, respiratory function data and a full night polisomnography were evaluated in a group of 45 obese subjects, 20 females and 25 males, with a previous diagnosis of OSA. RESULTS: The group of the severely obese women with OSA presented greater disturbances of the sleep architecture than the group of the men does (wake time after sleep onset 92.6+/-52.4 vs 58.2+/-45.2 min, P<0.05; total wake time 104.8+/-51.4 vs 67.8+/-47.4, P<0.05; number of awakenings 15.5+/-3.6 vs 10.2+/-6.215, P<0.001; OSA that occurred almost exclusively during REM sleep (REM OSA) 35% vs 4%, P<0.05) and a reduced sleep efficiency (69.6+/-15.9 vs 80.3+/-14.0%, P<0.05). CONCLUSIONS: Severely obese women with OSA, even with milder OSA, present greater disturbances of the sleep architecture with a more severe sleep disruption and more frequently REM OSA in comparison with men matched by age and weight.

Influence of subclinical hypothyroidism and T4 treatment on the prevalence and severity of obstructive sleep apnoea syndrome (OSAS).

BACKGROUND: Obstructive sleep apnoea (OSA) and subclinical hypothyroidism are relatively frequent disorders that may be causally linked. However, discordant results exist on the prevalence and severity of OSA in subclinical hypothyroidism. The aim of this study was to compare the prevalence and severity of sleep-disordered breathing in individuals with or without subclinical hypothyroidism, and to investigate the possible effect of levothyroxine treatment on these patients. PATIENTS AND METHODS: One hundred and eight subjects were consecutively enrolled and divided in 3 groups, according to the TSH levels and levothyroxine therapy. The first group (Group A) was represented by 63 subjects with normal TSH and thyroid function. The other two groups included patients affected by subclinical hypothyroidism; one group (Group B) treated with levothyroxine, while the other group (Group C) was never treated with levothyroxine. Anthropometric, respiratory and polysomnographic data were evaluated in all individuals. RESULTS: The percentage of OSA, neck circumference, and body mass index (BMI) were not statistically different among the 3 groups. Respiratory disturbance index (RDI) as well as the percentage of the total number of events (apnoea-hypopnoea) by total sleep time (TST) with <90% oxyhemoglobin saturation (TSTSaO2 <90%) were not different among the groups. When we observed OSA patients, the only significant difference between groups B and C was represented by the Epworth Sleepiness Scale (ESS) (p=0.005). CONCLUSION: This study shows that subclinical hypothyroidism and treatment with levothyroxine do not influence the prevalence and severity of OSA, while sleep propensity is increased by untreated subclinical hypothyroidism.