Coronavirus Disease 2019: COSeSco - A Risk Assessment Score to Predict the Risk of Pulmonary Sequelae in COVID-19 Patients.

BACKGROUND: The presence of interstitial pneumonia in coronavirus disease 2019 (COVID-19) patients, as diagnosed through laboratory, functional, and radiological data, provides potential predicting factors of pulmonary sequelae. OBJECTIVES: The objectives were the creation of a risk assessment score for pulmonary sequelae at high-resolution computed tomography (HRCT) through the assessment of laboratory data, lung function, and radiological changes in patients after the onset of COVID-19 interstitial pneumonia and the identification of predictive factors. METHODS: We enrolled 121 subjects hospitalized due to COVID-19 pneumonia in our study. Clinical features, Charlson Comorbidity Index (CCI) score, HRCT score, and blood chemistry data at hospital admission, as well as HRCT score, pulmonary function testing values, exercise capacity by means of a 6-Minute Walk Test (6MWT), and dyspnea perception by the modified Medical Research Council (mMRC) at 4-month follow-up, were all recorded. The variables were elaborated in order to create a predictive model to identify patients at high risk of pulmonary sequelae at HRCT. RESULTS: At the time of follow-up visit, 63% of patients had functional abnormality (diffusion lung capacity and/or total lung capacity <80% of predicted). Age, BMI, CCI, D-dimer, 6MWT, and mMRC were included in the COVID-19 Sequelae Score (COSeSco, ranging 0-15), which was able to individuate COVID-19 patients with radiologic sequelae (HRCT score >10%) at follow-up. The most revelatory COSeSco value that was found to intercept the highest sensitivity (100%) and specificity (77%) was 2. CONCLUSION: The COSeSco - comprising age, BMI, comorbidities, D-dimer, walking distance, and dyspnea perception - makes it possible to identify particularly at-risk COVID-19 patients who are likely to develop pulmonary sequelae assessed by HRCT.

Sarcoid-like reaction mimicking disease progression in an ALK-positive lung cancer patient receiving lorlatinib.

The administration of target inhibitors is paramount to grant the longest survival in patients with ALK-positive non-small cell lung cancer (NSCLC). The eventual resistance to tyrosine kinase inhibitors (TKI) is monitored clinically and radiologically for prompt molecule shift to further generation TKI, if available. However, the early radiological detection of progression pattern (e.g. nodule onset) should be regarded with caution because overlaps exist with non-tumor cell proliferation and/or accumulation. Here we report the case of a stage IV ALK-rearranged NSCLC patient exposed to serial crizotinib, brigatinib, ceritinib, and lorlatinib (this latter brought to complete brain and leptomeningeal disease response), in a period of more than five years. During lorlatinib, the appearance of solid pulmonary nodules was obviously interpreted as disease progression. However, surgical biopsies of the pulmonary nodules revealed features of sarcoid-like granulomatous lymphadenitis, namely without tumor cell. This invasive approach, besides documenting for the first time a sarcoid-like reaction to ALK inhibitors, allowed to revert the radiological diagnosis and maintain lorlatinib, for the best patient outcome. The pragmatic relevance of these findings suggests a careful attitude towards the interpretation of radiologic patterns of disease progression in patients under TKI.

Decreased maturation of dendritic cells in the central airways of COPD patients is associated with VEGF, TGF-ß and vascularity.

BACKGROUND: Dendritic cells (DCs) have a pivotal role in the onset and regulation of innate and adaptive immune responses. Moreover, DCs can interact with angiogenic modulators, resulting in modification of their biology and participation in angiogenesis. OBJECTIVES: This study was designed to evaluate the relationship between the density of DCs, vascularity and expression of angiogenic factors [vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-ß and basic fibroblast growth factor (bFGF)] in the central airways of chronic obstructive pulmonary disease (COPD) patients. METHODS: The study included 20 patients with moderate/severe COPD and 8 healthy control subjects. Bronchial biopsies were evaluated by immunohistochemistry. Specimens were examined for CD83 and CD207 to mark mature and immature DCs, respectively, for collagen IV to evaluate vascularity, and for VEGF, TGF-ß and bFGF. RESULTS: Compared to controls, COPD patients had a significant reduction of CD83+ cells and an increased CD207/CD83 ratio (p < 0.05). Vascularity, VEGF, TGF-ß and bFGF were also significantly increased in COPD patients as compared to controls (p < 0.01). In COPD patients, CD83+ cells were inversely related to VEGF and TGF-ß expression (p < 0.05). Moreover, the CD207/CD83 ratio was positively related to VEGF, TGF-ß and vascularity (p < 0.05). Finally, CD207+ cells were inversely related to FEV1 (p < 0.05). CONCLUSION: Our results show a reduced maturation of DCs in COPD that was related to airway vascularity and angiogenic factors (VEGF and TGF-ß). Additionally, immature DCs were significantly related to disease severity. We propose that the interplay between airway vascular changes, on one hand, and DCs maturation on the other, may play a key role in the pathogenetic mechanisms of COPD.

Beyond the lung involvement in COVID-19 patients.

Since COVID-19 spread all over the world becoming a pandemic illness, researchers have better characterized route of virus transmissibility and clinical signs and symptoms of the disease. Since viral transmission occurs through the droplets emitted during coughing or sneezing, the lungs are primarily affected. However, SARS-CoV-2 can affect several human organs due to high expressions of ACE2 receptor which is the main viral target, and the virus may affect not only higher and lower respiratory tracts, but also heart, kidney, gastro enteric tract, liver, pancreas, nervous system and skin. This review focuses on extra pulmonary involvement underlying atypical presentation of COVID-19. There is a great body of evidence concerning several human organ abnormalities associated to the SARS-CoV-2, enough to consider COVID-19 as a multisystemic and polyhedral disease.

Sex-Related Differences in Long-COVID-19 Syndrome.

Background: Sex differences have been demonstrated in the acute phase of coronavirus disease 2019 (COVID-19). Women (F) were found to be less prone to develop a severe disease than men (M), but few studies have assessed sex-differences in Long-COVID-19 syndrome. Methods: The aim of this prospective/retrospective study was to characterize the long-term consequences of this infection based on sex. For this purpose, we enrolled 223 patients (89 F and 134 M) who were infected by SARS-CoV-2. In the acute phase of the illness, F reported the following symptoms more frequently than M: weakness, dysgeusia, anosmia, thoracic pain, palpitations, diarrhea, and myalgia-all without significant differences in breathlessness, cough, and sleep disturbance. Results: After a mean follow-up time of 5 months after the acute phase, F were significantly more likely than M to report dyspnea, weakness, thoracic pain, palpitations, and sleep disturbance but not myalgia and cough. At the multivariate logistic regression, women were statistically significantly likely to experience persistent symptoms such as dyspnea, fatigue, chest pain, and palpitations. On the contrary, myalgia, cough, and sleep disturbance were not influenced by sex. Conclusion: We demonstrated that F were more symptomatic than M not only in the acute phase but also at follow-up. Sex was found to be an important determinant of Long-COVID-19 syndrome because it is a significant predictor of persistent symptoms in F, such as dyspnea, fatigue, chest pain, and palpitations. Our results suggest the need for long-term follow-up of these patients from a sex perspective to implement early preventive and personalized therapeutic strategies.

Pulmonary Embolism as a Finding During Endobronchial Ultrasound: An Occasional Occurrence or a New Element to Be Staged?

In this report, we describe two cases of lung cancer-related pulmonary embolism (PE), both encountered while performing an endobronchial ultrasound (EBUS). We propose EBUS as a diagnostic and confirmatory method for PE detection during the staging of lung cancer.

Cryptogenic Fibrosing Pleuritis.

We report the case of a 46-year-old male patient who was referred for chest pain and bilateral pleural effusion. Despite treatment with antibiotics and steroids, the pleural effusion worsened over a few months until pulmonary function was halved. The CT scan showed bilateral pleural thickening with right basal opacity. Histology revealed extensive fibrotic tissue with focal collections of lymphocytes and giant cells without traces of asbestos bodies. Since no evidence of an infectious, embolic or occupational aetiology was found, this bilateral pleural effusion progressing to diffuse pleural thickening was diagnosed as cryptogenic fibrosing pleuritis, a rare pleural disease. LEARNING POINTS: Bilateral pleural effusion progressing to diffuse pleural thickening was diagnosed as cryptogenic fibrosing pleuritis, a rare pleural disease.Cryptogenic fibrosing pleuritis was treated with high-dose corticosteroids.The patient showed stable disease at 6-year follow-up.

Long-Term Cardiac Sequelae in Patients Referred into a Diagnostic Post-COVID-19 Pathway: The Different Impacts on the Right and Left Ventricles.

Most patients who had COVID-19 are still symptomatic after many months post infection, but the long-term outcomes are not yet well defined. The aim of our prospective/retrospective study was to define the cardiac sequelae of COVID-19 infection. This monocentric cohort study included 160 consecutive patients who had been discharged from the ward or from the outpatient clinic after a diagnosis of COVID-19 and subsequently referred for a follow-up visit. Clinical features' data about the acute phase along with information about the follow-up visit, including ECG and Echocardiographic parameters, were recorded. At an average follow-up of 5 months, echocardiography showed morpho-functional characteristics of both right (RV) and left (LV) ventricles, such as RV dilation, increased pressure in the pulmonary circulation, and bi-ventricular systolic-diastolic dysfunction. When examined using multivariate analysis, independent of age, sex, and co-morbidities, RV and LV changes were significantly associated with chest High-Resolution computed tomography score and hemodynamic Instability (HI), and with C-reactive protein, respectively. Our results suggest that COVID-19 may impact RV and LV differently. Notably, the extent of the pneumonia and HI may affect RV, whereas the inflammatory status may influence LV. A long-term follow-up is warranted to refine and customize the most appropriate therapeutic strategies.

Monitoring cfDNA in Plasma and in Other Liquid Biopsies of Advanced EGFR Mutated NSCLC Patients: A Pilot Study and a Review of the Literature.

In order to study alternatives at the tissue biopsy to study EGFR status in NSCLC patients, we evaluated three different liquid biopsy platforms (plasma, urine and exhaled breath condensate, EBC). We also reviewed the literature of the cfDNA biological sources other than plasma and compared our results with it about the sensitivity to EGFR mutation determination. Twenty-two EGFR T790M-mutated NSCLC patients in progression to first-line treatment were enrolled and candidate to osimertinib. Plasma, urine and EBC samples were collected at baseline and every two months until progression. Molecular analysis of cfDNA was performed by ddPCR and compared to tissue results. At progression NGS analysis was performed. The EGFR activating mutation detection reached a sensitivity of 58 and 11% and for the T790M mutation of 45 and 10%, in plasma and urine samples, respectively. Any DNA content was recovered from EBC samples. Considering the plasma monitoring study, the worst survival was associated with positive shedding status; both plasma and urine molecular progression anticipated the radiological worsening. Our results confirmed the role of plasma liquid biopsy in testing EGFR mutational status, but unfortunately, did not evidence any improvement from the combination with alternative sources, as urine and EBC.

Severe acute respiratory failure due to a multifactorial diffuse alveolar haemorrhage.

Diffuse alveolar haemorrhage (DAH) is a life-threatening syndrome caused by infection, coagulation disorders or autoimmune diseases. We here report the case of an 81-year-old male subject affected by a multifactorial DAH, in which the bleeding was related to the administration of clopidogrel and warfarin, both implicated in the context of a polycythaemia. He developed a severe acute respiratory failure treated with a ventilatory support by means of a continuous positive airway pressure (C-PAP) therapy. An improvement of patient's clinical conditions was observed only after clopidogrel and warfarin discontinuation.

What happens to people's lungs when they get coronavirus disease 2019?

The novel coronavirus SARS-CoV-2 was first identified in Wuhan in December 2019 as cause of the consequent novel coronavirus disease 2019 (COVID-19). The virus has since spread worldwide. The clinical presentation following human infection ranges from a mild upper respiratory tract infection to severe acute respiratory distress syndrome and sepsis. We reviewed literature using Pubmed to identify relevant English-language articles published until April 15, 2020. Search terms include novel coronavirus pneumonia, severe acute respiratory syndrome coronavirus 2, coronavirus and ventilation. We summarized what SARS-CoV-2 infection means for the lungs.

Systemic thromboembolism from a misdiagnosed non-bacterial thrombotic endocarditis in a patient with lung cancer: A case report.

Thromboembolic events are frequent in patients with cancer, commonly involving the venous and pulmonary circulation. The arterial system is rarely implicated in embolism and, when involved, a cardiogenic origin should always be excluded. In the present study, a case of a patient who developed multiple embolic events concomitantly with the diagnosis of locally-advanced non-small cell lung cancer with high expression levels of programmed death-ligand 1 (PD-L1) in >50% of tumor cells is reported. A cardiac defect interpreted as a patent foramen ovale required low molecular weight heparin administration. Despite the anti-coagulant therapy, before first-line anticancer treatment with pembrolizumab immunotherapy could be administered due to high PD-L1 expression levels, a new hospitalization was required due to the onset of novel ischemic manifestation. New transthoracic and transesophageal echocardiography revealed a previously misdiagnosed vegetation of the mitral valve that caused systemic embolization. The lack of any sign of infection led to the diagnosis of a non-bacterial thrombotic endocarditis (NBTE), whose embolic sprouting gave rise to the widespread ischemic events. No active anticancer treatment was feasible due to the rapid progression of the disease. NBTE can evolve quickly, eventually preventing any chance of treatment targeting the primary cause, which in the present study was lung cancer. If NBTE can be correctly diagnosed sooner then there may be the potential for anticancer therapy that does not worsen the hypercoagulability state, thus improving cancer-associated survival.

Optimizing PD-L1 evaluation on cytological samples from advanced non-small-cell lung cancer.

Aim: Programmed cell death-ligand 1 (PD-L1) predicts response to immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) patients. Most NSCLCs are diagnosed at an advanced stage and using minimally invasive diagnostic procedures that yield small biopsies or cytological samples. Methods: Cytological smears and paired histological samples from 52 advanced NSCLC patients were tested for PD-L1 expression by immunocyto/histochemistry (ICC/IHC) and for PD-L1 gene status by FISH. Results:PD-L1 was overexpressed in 9/52 (17%) cytological samples and in seven (13.5%) matched biopsies. The concordance between immunocytochemistry and IHC was 92.3% (48/52; p < 0.001). The concordance between PD-L1 gene status on cytology and histology was 69.2% (18/26; p < 0.001). No correlation between IHC and fluorescence in situ hybridization results was found. Conclusion: Our data support the feasibility and reliability of PD-L1 protein and PD-L1 gene assessment on direct cytological smears from NSCLC patients whenever histological sample are inadequate.

Early fatal hemoptysis after first-dose, first-line pembrolizumab in a central lung cancer: did tumor shrinkage matter?

A patient diagnosed with centrally located advanced lung adenocarcinoma with signs of large vessels infiltration, strongly expressing PD-L1, was candidate to first-line pembrolizumab. He had not complained of any bleeding manifestation before immunotherapy. 5 days after the first dose of pembrolizumab, the patient experienced massive, fatal hemoptysis. Given the central localization of the tumor and the strong PD-L1 expression, a contribution of rapid disease shrinkage is envisaged in determining the fatal hemorrhagic event. An attentive clinical attitude should be dedicated in centrally located and vessel-infiltrating tumors strongly expressing PD-L1 and candidate to anti-PD-1/PD-L1 agents.

Competence in pulmonary endoscopy emergencies.

In clinical practice, interventional pulmonologists face several situations which can lead to dramatic consequences especially regarding ventilation and require immediate intervention. We describe the main pathological conditions where an urgent bronchoscopy is crucial because they act through mechanisms such as airway obstructions or alteration of the anatomic integrity of the tracheobronchial tree. We point out the problems resulting from inhalation of foreign bodies, one of the most dramatic respiratory emergencies typical in childhood which needs not only the appropriate endoscopic equipment suitable for the age, but also great experience in the management of the possible related complications. Massive hemoptysis is then discussed in order to help to choose the right endoscope and to clarify the steps requested to face this dramatic event. Lastly, iatrogenic tracheal injuries are described, in spite of their low occurrence. The correct endoscopic assessment of the lesions enables to select the proper multidisciplinary therapeutic approach together with surgeons and anesthetists. Due to their peculiarities, emergencies do not allow classic training so it is difficult to estimate the procedure volume necessary to achieve an adequate endoscopic experience. We think, in this field, it is advisable to refer to numbers proposed for elections endoscopic procedures. For these reasons, we consider desirable the use of simulators and clinic case discussions during interventional pulmonologist's training.

Pleural tuberculosis: medical thoracoscopy greatly increases the diagnostic accuracy.

Our objective was to evaluate the efficacy of a standardised work-up in the diagnosis of pleural tuberculosis (TB) that included fibreoptic bronchoscopy and medical thoracoscopy. A consecutive series of 52 pleural TB patients observed during the period 2001-2015 was evaluated retrospectively. 20 females, mean (range) age 39.7 (18-74) years, and 32 males, mean (range) age 45.75 (21-83) years, were included (28 non-EU citizens (53.8%)). The diagnosis of TB infections was established by identification (using stains, culture or molecular tests) of Mycobacterium tuberculosis in the pleura, sputum and/or bronchial specimens, or by evidence of caseous granulomas on pleural biopsies. Patients with and without lung lesions were considered separately. The diagnostic yield of the microbiological tests on pleural fluid was 17.3% (nine out of 52 patients). Among the 18 patients with lung lesions, bronchial samples (washing, lavage or biopsy) were positive in 50% of cases (nine patients). Cultures of pleural biopsies were positive in 63% of cases (29 out of 46 patients); pleural histology was relevant in all patients. Without pleural biopsy, a diagnosis would have been reached in 15 out of 52 patients (28.6%) and in four of them only following culture at 30-40 days. An integrated diagnostic work-up that includes all the diagnostic methods of interventional pulmonology is required for a diagnosis of pleural TB. In the majority of patients, a diagnosis can be reached only with pleural biopsy.

Pulmonary metastases from low grade sarcoma in a patient with pulmonary sarcoidosis. Sarcoidosis or sarcoid-like reaction?

An asymptomatic man with previous histopatological diagnosis of pulmonary sarcoidosis in radiological follow-up (stable for about 4 years) presented massive right pleural effusion. After drainage, CT of the chest showed an increase in number and size of pulmonary nodules compared to the last check (8 months before). Surgical pulmonary biopsies were performed with the diagnosis of metastases from low grade sarcoma. The primary tumor was localized to the right buttock. Given the absence of symptoms, the extent of disease and many comorbidities the patient underwent only treatment with gemcitabine that was not tolerated and discontinued after the first few cycles 1 year ago. At the present the patientis still asymptomatic even if the CT of the chest shows a slow but continuous progression of the disease. The question is: is this an association between sarcoidosis and malignancy? or was this a sarcoid-like reaction during malignancy?

Conventional transbronchial needle aspiration with 23 gauge needle: a preliminary study.

BACKGROUND: Conventional transbronchial needle aspiration (cTBNA) is a safe and minimally invasive procedure with a high yield for the diagnosis of large lymph nodes (LNs) in favourable locations (LNs >1.5 cm in stations #4R and/or #7). However, it is usually underutilized by pulmonologist. One of the main reasons given for not performing cTBNA is the risk of puncturing vascular structures of the mediastinum. Recently, with the twofold objective of minimize the risk of bleeding and reduce the cTBNA cost, a thinner and less expensive needle has been commercialized. It is a 23 gauge (G) needle that costs 34, 37 €. The aim of our study was to analyze the sample adequacy, diagnostic accuracy and safety of this needle in comparison with 21 and 22 G needles (average cost: 6,400 €). METHODS: We retrospectively analysed medical records from patients who underwent bronchoscopy with cTBNA for the diagnosis of LNs >1.5 cm in stations #4R and/or #7 at the Thoracic Endoscopy Unit of the University Hospital of Parma from January 1st, 2007 to October 31(st), 2011. Five hundred patients underwent cTBNA from January 1(st), 2007 to October 31(st), 2011. In order to reduce the technical and personal bias for sampling procedure we analyzed only cases sampled by a single well-trained bronchoscopist, particularly skilful at cTBNA. RESULTS: A total of 222 patients (186 men; mean age 63 years±12, range 6-89) with LNs >1.5 cm in stations #4R and/or #7 were identified. A 23 G needle was used in 84 patients (38%), a 21 G needle in 88 patients (40%) and a 22 G needle in 50 patients (22%). No statistically significant differences between the 23 G group and the 21 or 22 G group in sample adequacy (P=0.78 and P=0.12, respectively) and diagnostic accuracy (P=0.9 and P=0.4, respectively) were found. There were no intraprocedural or postprocedural complications irrespective of the size of needle used. CONCLUSIONS: Transbronchial 23 G needle is as safe and effective as the 21 and 22 G needle for the sampling of LNs >1.5 cm in stations #4R and/or #7. For this reason, to obtain cytology specimens from large LNs in favourable locations, the 23 G needle may represent an alternative and less expensive choice compared to 21 and 22 G needles, even if our observation needs to be confirmed in a larger prospective study.

ALK and ROS1 rearrangements tested by fluorescence in situ hybridization in cytological smears from advanced non-small cell lung cancer patients.

BACKGROUND: The identification of ALK and ROS1 rearrangements and the availability of an effective target therapy, such as crizotinib, represent a new option in the treatment of advanced non-small cell lung cancer (NSCLC) patients. In light of recent advances in non-invasive diagnostic procedures, we aimed to demonstrate that direct cytological smears are suitable for assessing ALK and ROS1 rearrangements in patients with NSCLC. METHODS: Fifty-five patients with a cytological diagnosis of lung adenocarcinoma (ADC) were evaluated for ALK rearrangements by fluorescence in situ hybridization (FISH) and 12 patients for ROS1 FISH rearrangements. Seventeen of the 55 cytological samples tested for ALK were obtained from the primary tumor and 38 from metastatic lesions. Ten of 12 samples evaluated for ROS1 were obtained from metastatic sites and two from the primary tumor. RESULTS: ALK FISH was successful in 49/55 (89%) cytological ADC samples and ROS1 FISH in all 12 cytological samples. ALK rearrangements were found in 3/13 (23%) primary tumors and 7/36 (19%) metastatic sites. ROS1 rearrangements were found in one of the two primary tumors and in two of the 10 metastases. Two of the three rearranged cases were tested on cytology after knowing that they were rearranged on histology in order to increase representativeness of ROS1 rearranged cases in this study. CONCLUSION: Whenever cytology represents the only available material for diagnosis and biological characterization of NSCLC, minimally invasive procedures may provide an additional important source of cellular material for FISH assessment of ALK and ROS1 rearrangements.

Lipoid pneumonia as a complication of Lorenzo's oil therapy in a patient with adrenoleukodystrophy.

Lipoid pneumonia (LP) is a rare exogenous condition caused by inhalation or aspiration of lipid material into the lungs. It is often associated with the therapeutic use of different types of oil, and the diagnosis is based on the demonstration of lipid-laden macrophages in bronchoalveolar lavage fluid. We reported the case of a 39-year-old male with X-linked adrenoleukodystrophy who developed LP secondary to the use of Lorenzo's oil. To our knowledge, the association between the use of Lorenzo's oil and LP has never been reported in literature.