Pneumothorax (PNX) and pneumomediastinum (PNM) are potential complications of COVID-19, but their influence on patients’ outcomes remains unclear. The aim of the study was to assess incidence, risk factors, and outcomes of severe COVID-19 complicated with PNX/PNM. Methods: A retrospective multicenter case-control analysis was conducted in COVID-19 patients admitted for respiratory failure in intermediate care units of the Treviso area, Italy, from March 2020 to April 2021. Clinical characteristics and outcomes of patients with and without PNX/PNM were compared. Results: Among 1213 patients, PNX and/or PNM incidence was 4.5%. Among these, 42% had PNX and PNM, 33.5% only PNX, and 24.5% only PNM. COVID-19 patients with PNX/PNM showed higher in-hospital (p = 0.02) and 90-days mortality (p = 0.048), and longer hospitalization length (p = 0.002) than COVID-19 patients without PNX/PNM. At PNX/PNM occurrence, one-third of subjects was not mechanically ventilated, and the respiratory support was similar to the control group. PNX/PNM occurrence was associated with longer symptom length before hospital admission (p = 0.005) and lower levels of blood lymphocytes (p = 0.017). Conclusion: PNX/PNM are complications of COVID-19 associated with a worse prognosis in terms of mortality and length of hospitalization. Although they are more frequent in ventilated patients, they can occur in non-ventilated, suggesting that mechanisms other than barotrauma might contribute to their presentation.

The clinical course in idiopathic pulmonary fibrosis (IPF) is highly heterogeneous, with some patients having a slow progression and others an accelerated clinical and functional decline. This study aims to clinically characterize the type of progression in IPF and to investigate the pathological basis that might account for the observed differences in disease behavior. Clinical and functional data were analyzed in 73 IPF patients, followed long-time as candidates for lung transplantation. The forced vital capacity (FVC) change/year (< or ≥10% predicted) was used to define "slow" or "rapid" disease progression. Pathological abnormalities were quantified in the explanted lung of 41 out of 73 patients undergoing lung transplantation. At diagnosis, slow progressors (n = 48) showed longer duration of symptoms and lower FVC than rapid progressors (n = 25). Eleven slow and 3 rapid progressors developed an acute exacerbation (AE) during follow-up. Quantitative lung pathology showed a severe innate and adaptive inflammatory infiltrate in rapid progressors, markedly increased compared to slow progressors and similar to that observed in patients experiencing AE. The extent of inflammation was correlated with the yearly FVC decline (r = 0.52, p = 0.005). In conclusion an innate and adaptive inflammation appears to be a prominent feature in the lung of patients with IPF and could contribute to determining of the rate of disease progression.

The clinical and functional course of IPF might deteriorate rapidly, rapid decliners (R) or slowly, slow decliners (S). Acute exacerbations (AE) are a feature of IPF. Lung pathology is considered to be similar in R and S; diffuse alveolar damage (DAD) is considered a common finding in AE. The aim of the study was a) determine the frequency of S and R phenotypes and incidence of AE in a IPF population followed before transplant, and b) correlate the clinical course with the quantitative lung pathology in the explanted lungs. 59 IPF patients referred for lung transplant were followed for 37 (12-156) months. A 10% FVC fall/year cutoff was used to define the R (>10%) and S ( 63% of patients were S and 37% were R. 74% of R and 73% of S were smokers. During the follow-up 23% of patients developed AE. The extension of lung abnormalities differed in the 3 groups; S had a significantly higher proportion of normal lung than R and AE (19 vs 9 vs 5% p R and S decliners are different not only clinically but also pathologically and fulfill the definition of phenotypes. The degree of inflammation seen in R is the key finding separating the phenotypes. Smoking does not singly predispose for the R phenotype neither to the type and degree of lung inflammation.

BACKGROUND:Pulmonary hypertension (PH) represents an important complication of idiopathic pulmonary fibrosis (IPF) with a negative impact on patient survival. Herpes viruses are thought to play an etiological role in the development and/or progression of IPF. The influence of viruses on PH associated with IPF is unknown. We aimed to investigate the influence of viruses in IPF patients focusing on aspects related to PH. A laboratory mouse model of gamma-herpesvirus (MHV-68) induced pulmonary fibrosis was also assessed.METHODS:Lung tissue samples from 55 IPF patients and 41 controls were studied by molecular analysis to detect various viral genomes. Viral molecular data obtained were correlated with mean pulmonary arterial pressure (mPAP) and arterial remodelling. Different clinical and morphological variables were studied by univariate and multivariate analyses at time of transplant and in the early post-transplant period. The same lung tissue analyses were performed in MHV-68 infected mice.RESULTS:A higher frequency of virus positive cases was found in IPF patients than in controls (p = 0.0003) and only herpes virus genomes were detected. Viral cases showed higher mPAP (p = 0.01), poorer performance in the six minute walking test (6MWT; p = 0.002) and higher frequency of primary graft (PGD) dysfunction after lung transplant (p = 0.02). Increased arterial thickening, particularly of the intimal layer (p = 0.002 and p = 0.004) and higher TGF-β expression (p = 0.002) were demonstrated in viral cases. The remodelled vessels showed increased vessel cell proliferation (Ki-67 positive cells) in the proximity to metaplastic epithelial cells and macrophages. Viral infection was associated with higher mPAP (p = 0.03), poorer performance in the 6MWT (p = 0.008) and PGD (p = 0.02) after adjusting for other covariates/intermediate factors. In MHV-68 infected mice, morphological features were similar to those of patients.CONCLUSION:Herpesviral infections may contribute to the development of PH in IPF patients.

Rationale Wheezing is the most frequent clinical manifestation of asthma early in life, however is not specific since infants can have episodes of wheezing associated with viral infections. Neither the pathogenesis of these episodes nor their relation to classic asthma has been completely elucidated. Aim The aim of this study was to compare the airway pathology of children with wheezing only during viral infections i.e “episodic wheeze”, to that of children with wheezing not only during viral infections but also in between i.e.“multitrigger wheeze” that often evolves into asthma. Methods Bronchial biopsies were taken in 7 children with episodic wheeze, 18 with multitrigger wheeze and 7 controls who underwent bronchoscopy for appropriate clinical indications and analyzed by immunohistochemistry. Results Eosinophil infiltration was increased in multitrigger wheeze compared to controls (90;0-267 vs 9; 0-50 cells/mm2;p=0.007), but not in episodic wheeze (25;0-586). Mast cells were increased in the multitrigger and episodic wheeze groups (410; 113-755 and 460;183-750 cells/mm2) when compared to controls (144; 63-612; p=0.03). Epithelial damage was present in higher proportion in episodic and multitrigger wheeze children than in controls (65 vs 92% vs 37%) but the difference was not statistically significant. In the population as a whole, the number of mast cells positively correlated with the degree of epithelial damage (r=0.5, p=0.005). Conclusion The presence of mast cells along with epithelial damage might represent the anatomical basis for the intermittent wheezing in childhood. The presence of eosinophils along with mast cells might predispose to multitrigger wheeze in childhood and eventually asthma.

Background. Lung inflammation is neither considered an important feature of IPF nor an important factor in its pathogenesis. However the degree and type of lung inflammation has never been carefully quantified and characterized in the different phenotypes of IPF. Aim. To quantify and define the type of inflammation in slow decliners (S), rapid decliners (R) and acute exacerbation (AE) phenotypes of IPF and relate it to the functional decline. Methods. 59 patients IPF, referred for lung transplant, were followed for 37 (12-156) months. A 10% FVC decline/year cut-off was used to define the R (>10%) and S ( Results. Total leukocytes were markedly increased in R (median; range: 653;428-973 cells/mm 2 ) and AE (682;513-921 cells/mm 2 ) when compared with S (213;91-252 cells/mm 2 ) (p Conclusions. A severe innate and adaptive inflammation differentiates the S from the R and AE phenotypes of IPF. The apparent correlation between inflammation and decline suggests a possible role for inflammation on the mechanism of rapid progression in IPF. Different phenotypes should be taken in consideration in the design of treatment trials.

A strong association between gastroesophageal reflux (GER) and idiopathic pulmonary fibrosis (IPF) has been reported. A significant proportion of patients may have signs of microaspiration and still remain asymptomatic. Videolaringoscopy can be a useful tool to detect silent microaspiration, which to date has never been investigated in IPF. The aim of the study was to assess signs of micro-aspiration by videolaryngoscopy in patients with IPF and to relate them with clinical findings. We recruited 20 IPF patients (mean age 52 + 7 yrs). We investigated the presence/absence of GER symptoms and performed videolaryngoscopy to evaluate abnormal laryngeal findings considered indirect signs of micro-aspiration. Three out of twenty patients (15%) had classic GER symptoms, while 17 (85%) did not report any kind of GER symptoms. Among asymptomatic patients, 5 (29%) had indirect signs of microaspiration at videolaryngoscopy while the remaining twelve had no such signs. Of interest, IPF patients with laryngeal abnormalities at videolaryngoscopy showed a lower FVC% at the diagnosis compared to patients without such abnormalities [46%(45-82) vs 75%(72-87) p=0,03]. Conversely, no differences in age, smoking history and BMI were found between the two groups of patients. In conclusion our study suggests that videolaryngoscopy may be a useful diagnostic tool to detect silent microaspiration in patients with IPF even in the absence of GER symptoms. These findings may have important therapeutic implications.

Among solid organ transplant recipients, lung transplant ones are at highest risk of cytomegalovirus (CMV) infection. The advent of CMV prophylaxis and changes in prophylactic protocols have contributed to a steady decline in CMV infection and mortality; however its potential impact on short-term outcome needs further investigation. The aim of the study is to evaluate the effect of combined CMV prophylaxis in reducing short term acute illness after transplant. A consecutive series of 52 CMV high-risk lung transplant recipients who had more than one year follow-up, were studied. The study group (n=26; age 44±2yrs) received ganciclovir or valganciclovir from postoperative day 15 and CMV-Immunoglobulins for six months, while the control group (n=26; 40±2yrs) was treated with pre-emptive therapy. Viral Infection Index (number of BAL with infection/total BAL number), acute rejection index (ARI, number of acute rejections/total transbronchial biopsies number), incidence of CMV pneumonia and early onset BOS were obtained. Viral Infection Index, infection index simply related to CMV as well as ARI were significantly reduced in the study group than in the control group (mean 33%Vs50% p=0.02; 14%Vs27% p=0.05 and 13%Vs26% p=0.04, respectively), while the incidence of CMV-pneumonia and BOS were similar in the two groups. A significant relationship between combined CMV prophylaxis and a reduced prevalence of acute rejection was observed by logistic regression analysis, even when considering grade A3 only (p=0.01). In conclusion our data underline the strong efficacy of combined CMV prophylaxis in reducing infections as well as acute rejections, particularly the most severe ones, in lung transplant recipients.

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with heterogeneous clinical course. Some patients experience an accelerated disease progression (rapid progressors) while other remain relatively stable over time (slow progressors). The aim was to investigate the different course of the disease in relation to survival. The study population included 55 IPF patients (age at diagnosis 53±1) categorized in rapid progressors and slow progressors by two distinct criteria: pre-diagnosis criteria (time from symptoms onset and IPF diagnosis) or by post-diagnosis criteria (decline in FVC%pr. over 12 months). When stratified by pre-diagnosis criteria 18% were rapid progressors while 66% were slow ones.When stratified according to post-diagnosis criteria 67% were rapid progressors and 33% were slow ones. The coefficient of agreement between the two criteria was 70% and 75% for slow and rapid progressors respectively indicating that up to 30%of patients did not maintain the same label. Stratification by pre-diagnosis criteria was not related to survival. Conversely, stratification by post-diagnosis criteria had a prognostic significance; indeed, rapid progressors had decreased survival as compared to slow ones (28±1Vs49±8mo.p=0.02). Of interest, rapid progressors according to post-diagnosis criteria, often display an unstable decline alternating periods of functional stability to a rapid deterioration. In conclusion our data suggest the need to be cautious in labelling IPF patients to a fixed phenotype from the beginning of symptoms till death. It is possible that IPF patients show a variable and unpredictable clinical course rather than a steady condition.

The critical shortage of donor lungs suitable for transplant significantly limits the number of potential recipients. Many questions regarding donor acceptability still remain unanswered. Regarding recipients, less is known about peri-operative factors affecting 1-year survival. To investigate how multiple risk factors influence short term survival we retrospectively reviewed clinical data of donors and their recipients, transplanted in our centre. We collected data from donors (n=174, mean age 35.7+1.0) focusing on age, Body Mass Index (BMI), orotracheal intubation (OTI) duration, marginality, cause of death, tracheal secretions and selected clinical information from their recipients (n= 200, mean age 46.8+1.0): native disease, BMI, type of transplant, intensive care unit (ICU) stay and OTI duration. Donor age, above 35 yrs, and overweight (BMI>25) were independent predictors of survival less 1 year (respectively p=0.004; p = 0.05). Instead OTI duration (> 3 days), marginality, death for traumatic/cardiovascular cause, presence of tracheal secretions did not affect survival (respectively p=0.73;p=0.92;p=0.40;p = 0.40; p=0.40). Concerning recipients, BMI between 18 to 20 (p=0.04) and age under 50yrs (p=0,005) predisposes to longer survival. Prolonged ICU stay (>20 days,p=0.007) and OTI duration (>3 days,p=0.00001) negatively affect short survival. Our data suggest that some peri-operative donor characteristics do not affect short survival and might help maximize lung availability from donor pool. Recipient evaluation confirm how crucial is to reduce OTI duration which, in our study, have influenced 1year survival.

Idiopathic pulmonary fibrosis (IPF) is known to be associated with increased risk of lung cancer but the potential pathological abnormalities that could precede the development of lung cancer are not well known. The aim of our study was to investigate the prevalence of high grade dysplasia/foci of neoplastic transformation (precancerous changes) and their relationship with metaplastic changes in honeycomb areas. The lungs of 66 patients who underwent lung transplantation for IPF were studied. Scores were used to quantitate the degree of honeycomb changes and squamous, cuboidal and bronchial cell metaplasia in honeycombed areas. The presence or absence of precancerous changes in the same areas was recorded. Twelve of the 66 patients (18%) showed foci of neoplastic transformation/high grade dysplasia (“cancer” group). The “cancer” group (mean age at transplant 53±9 years; F:M=3:9) had similar smoking history, age and duration of disease than the “no cancer” group (mean age at transplant 57±6 years; F:M=17:37). Although all lungs showed metaplasia, the score of squamous (p=0.0001), cuboidal (p=0.018) and bronchial cell (0.018) metaplasia was significantly higher in the “cancer” than in the “no cancer”, while the honeycomb score was similar in the two groups. In conclusion, contrary to previous reports, we have found that the presence of metaplasia, specially squamous, in the honeycombed areas, is associated to the development of precancerous changes in IPF, independently to smoking history.