Long COVID in Children, Adults, and Vulnerable Populations: A Comprehensive Overview for an Integrated Approach.

Long COVID affects both children and adults, including subjects who experienced severe, mild, or even asymptomatic SARS-CoV-2 infection. We have provided a comprehensive overview of the incidence, clinical characteristics, risk factors, and outcomes of persistent COVID-19 symptoms in both children and adults, encompassing vulnerable populations, such as pregnant women and oncological patients. Our objective is to emphasize the critical significance of adopting an integrated approach for the early detection and appropriate management of long COVID. The incidence and severity of long COVID symptoms can have a significant impact on the quality of life of patients and the course of disease in the case of pre-existing pathologies. Particularly, in fragile and vulnerable patients, the presence of PASC is related to significantly worse survival, independent from pre-existing vulnerabilities and treatment. It is important try to achieve an early recognition and management. Various mechanisms are implicated, resulting in a wide range of clinical presentations. Understanding the specific mechanisms and risk factors involved in long COVID is crucial for tailoring effective interventions and support strategies. Management approaches involve comprehensive biopsychosocial assessments and treatment of symptoms and comorbidities, such as autonomic dysfunction, as well as multidisciplinary rehabilitation. The overall course of long COVID is one of gradual improvement, with recovery observed in the majority, though not all, of patients. As the research on long-COVID continues to evolve, ongoing studies are likely to shed more light on the intricate relationship between chronic diseases, such as oncological status, cardiovascular diseases, psychiatric disorders, and the persistent effects of SARS-CoV-2 infection. This information could guide healthcare providers, researchers, and policymakers in developing targeted interventions.

Impact of gender on patients hospitalized for SARS-COV-2 infection: A prospective observational study.

Biological sex could affect the natural history of severe acute respiratory syndrome coronavirus 2 infection. We enrolled all COVID-19 patients admitted to two COVID-19 hospitals in Milan in a prospective observational study. The primary outcome was death during the study period and the secondary outcome was critical disease at hospital admission. The association(s) between clinically relevant, noncollinear variables, and the primary outcome was assessed with uni- and multivariable Logistic regression models. A total of 520 patients were hospitalized of whom 349 (67%) were males with a median age 61 (interquartile range: 50-72). A higher proportion of males presented critically ill when compared to females (30.1% vs. 18.7%, p < .046). Death occurred in 86 (24.6%) males and 27 (15.8%) females (p = .024). In multivariable analysis age (per 10 years more) (adjusted odds ratio [AOR]: 1.83 [95% confidence interval {CI}: 1.42-2.35], p < .0001), obesity (AOR: 2.17 [95% CI: 1.10-4.31], p = .026), critical disease at hospital admission (AOR 6.34 [95% CI: 3.50-11.48], p < .0001) were independently associated to higher odds of death whereas gender was not. In conclusion, a higher proportion of males presented critically ill at hospital admission. Age, critical disease at hospital admission, obesity, anemia, D-dimer, estimated glomerular filtration rate, lactate dehydrogenase, and creatine kinase predicted death in hospitalized COVID-19 patients.

Sulphurous thermal water inhalation impacts respiratory metabolic parameters in heavy smokers.

Sulphurous thermal water inhalations have been traditionally used in the treatment of airway diseases. In vivo and in vitro studies reported that they ameliorate mucus rheology, mucociliary clearance and reduce inflammation. Cigarette smoking induces an inflammatory damage, with consequent remodeling of respiratory airways, which in turn affect pulmonary functions. Despite the anti-inflammatory effects of H2S are clinically documented in several airway inflammatory diseases, data on the effects of sulphurous thermal water treatment on pulmonary function and biomarkers of airways inflammation in smokers are still scant. Therefore, we investigated whether a conventional cycle of sulphurous thermal water inhalation produced changes in markers of respiratory inflammation and function. A cohort of 504 heavy current and former smokers underwent 10-day cycles of sulphurous thermal water inhalation. Pulmonary function and metabolic analyses on exhaled breath condensate were then performed at day 0 and after the 10-day treatment. Spirometric data did not change after spa therapy, while exhaled breath condensate analysis revealed that a single 10-day cycle of sulphurous water inhalation was sufficient to induce a statistically significant increase of citrulline levels along with a decrease in ornithine levels, thus shifting arginine metabolism towards a reduced nitric oxide production, i.e. an anti-inflammatory profile. Overall, sulphurous thermal water inhalation impacts on arginine catatabolic intermediates of airways cells, shifting their metabolic balance towards a reduction of the inflammatory activity, with potential benefits for smokers.

Primary sternal tuberculosis mimicking a lytic bone tumor lesion.

Tubercular sternal osteomyelitis is a rare manifestation of tuberculosis. We describe the case of a 51-years-old male patient, presenting with three months history of pain and swelling of the central chest wall, referred to our hospital with clinical diagnosis of chondrosarcoma of the sternum.

MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer.

The efficacy of computed tomography (CT) screening for early lung cancer detection in heavy smokers is currently being tested by a number of randomized trials. Critical issues remain the frequency of unnecessary treatments and impact on mortality, indicating the need for biomarkers of aggressive disease. We explored microRNA (miRNA) expression profiles of lung tumors, normal lung tissues and plasma samples from cases with variable prognosis identified in a completed spiral-CT screening trial with extensive follow-up. miRNA expression patterns significantly distinguished: (i) tumors from normal lung tissues, (ii) tumor histology and growth rate, (iii) clinical outcome, and (iv) year of lung cancer CT detection. Interestingly, miRNA profiles in normal lung tissues also displayed remarkable associations with clinical features, suggesting the influence of a permissive microenvironment for tumor development. miRNA expression analyses in plasma samples collected 1-2 y before the onset of disease, at the time of CT detection and in disease-free smokers enrolled in the screening trial, resulted in the generation of miRNA signatures with strong predictive, diagnostic, and prognostic potential (area under the ROC curve ≥ 0.85). These signatures were validated in an independent cohort from a second randomized spiral-CT trial. These results indicate a role for miRNAs in lung tissues and plasma as molecular predictors of lung cancer development and aggressiveness and have theoretical and clinical implication for lung cancer management.

Elevated levels of the acute-phase serum amyloid are associated with heightened lung cancer risk.

BACKGROUND: The authors investigated whether early stage lung cancer could be identified by proteomic analyses of plasma. METHODS: For the first case-control study, plasma samples from 52 patients with lung cancer and from a group of 51 controls were analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. In a second case-control study, a classifier of 4 markers (mass-to-charge ratio, 11,681, 6843, 5607, and 8762) also was tested for validation on plasma from 16 consecutive patients with screen-detected cancer versus 406 healthy individuals. The most relevant marker was identified, and an enzyme-linked immunosorbent assay-based analysis revealed that signal intensity was correlated with concentration. RESULTS: The classifier had a sensitivity of 94.23% and a specificity of 76.47% in the first study but lost predictive value in the second study. Nevertheless, the 11,681 cluster, which was identified as serum amyloid protein A (SAA), resulted in a multiple logistic regression model that indicated a strong association with lung cancer. When both studies were considered as a together, the odds ratio (OR) for an SAA intensity > or =0.5 was 10.27 (95% confidence interval [CI], 4.64-22.74), whereas an analysis restricted to stage I cancers (TNM classification) revealed an OR of 8.45 (95% CI, 2.76-25.83) for T1 lung cancer and 21.22 (95% CI, 5.62-80.14) for T2 lung cancer. CONCLUSIONS: SAA levels were predictive of an elevated risk of lung cancer, supporting the general view that inflammation is implicated in lung cancer development.

Bronchial diverticula in smokers on thin-section CT.

The objective was to determine the prevalence of bronchial diverticula in smokers on thin-section CT and the relationship to clinical and other morphological features on CT. Thin-section CT images of 503 cigarette smokers were assessed for the profusion and location of diverticula in the major airways. The extent of the bronchial diverticula was recorded as follows: grade 0, none; grade 1, one to three diverticula; grade 2, more than three diverticula. The extent of emphysema, bronchial wall thickness, clinical features, and pulmonary function were compared in the sub-groups stratified according to the extent of bronchial diverticula. A total of 229/503 (45.5%) smokers had bronchial diverticula, with 168/503 (33.3%) and 61/503 (12.2%) having grade 1 and 2 bronchial diverticula respectively. Subjects with grade 2 bronchial diverticula were heavier smokers, reported a history of coughing more frequently, and showed more severe functional impairment, greater extent of emphysema and more severe bronchial wall thickening compared with subjects with grade 1 and those individuals without bronchial diverticula (P < 0.05). Multivariate regression analysis revealed that only bronchial wall thickness predicted the extent of the bronchial diverticula (P < 0.0001). Bronchial diverticula are a frequent finding in the major airways of smokers, and they are associated with other markers of smoking-related damage.

Fluorodeoxyglucose uptake measured by positron emission tomography and standardized uptake value predicts long-term survival of CT screening detected lung cancer in heavy smokers.

BACKGROUND: Fluorodeoxyglucose-positron emission tomography (FDG-PET) has proven its value in the diagnosis of undetermined pulmonary lesions, lung cancer staging, and assessment of prognosis. Purpose of this study is to clarify whether standardized uptake value (SUV) can predict clinical outcome of computed tomography (CT) screening detected lung cancer. METHODS: We tested the predictive value of FDG-PET using SUV on long-term survival of 34 lung cancer patients, detected from 1035 heavy smokers > or = 50 years monitored by annual low-dose CT for 5 years, with a median follow-up of 75 months from diagnosis. FINDINGS: PET scan was performed in 34 (89%) of 38 lung cancer patients diagnosed during the 5 years of screening and was positive in 32 (94%). Complete resection was achieved in 30 cases (88%), 20 (59%) were pathologic stage I and 23 (68%) were adenocarcinoma. Median SUV was 5.0 overall, being significantly lower in stage I (2.5 vs. 10.1, p = 0.001) and in adenocarcinoma (2.5 vs. 13.0, p = 0.001). The 5-year survival of lung cancer patients was 100% for SUV levels < or = 2.5, 60% for SUV more than 2.5 and less than 8, and only 20% for SUV > or = 8 (p = 0.001). CONCLUSIONS: FDG-PET using SUV can predict long-term survival of screening detected lung cancer, in a noninvasive manner. Metabolic assessment of biologic behavior might improve the clinical management of CT-detected lung cancer and reduce the risk of unnecessary treatments for indolent disease.

Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment.

The identification of lung tumor-initiating cells and associated markers may be useful for optimization of therapeutic approaches and for predictive and prognostic information in lung cancer patients. CD133, a surface glycoprotein linked to organ-specific stem cells, was described as a marker of cancer-initiating cells in different tumor types. Here, we report that a CD133+, epithelial-specific antigen-positive (CD133+ESA+) population is increased in primary nonsmall cell lung cancer (NSCLC) compared with normal lung tissue and has higher tumorigenic potential in SCID mice and expression of genes involved in stemness, adhesion, motility, and drug efflux than the CD133(-) counterpart. Cisplatin treatment of lung cancer cells in vitro resulted in enrichment of CD133+ fraction both after acute cytotoxic exposure and in cells with stable cisplatin-resistant phenotype. Subpopulations of CD133+ABCG2+ and CD133+CXCR4+ cells were spared by in vivo cisplatin treatment of lung tumor xenografts established from primary tumors. A tendency toward shorter progression-free survival was observed in CD133+ NSCLC patients treated with platinum-containing regimens. Our results indicate that chemoresistant populations with highly tumorigenic and stem-like features are present in lung tumors. The molecular features of these cells may provide the rationale for more specific therapeutic targeting and the definition of predictive factors in clinical management of this lethal disease.

Pulmonary nodules: volume repeatability at multidetector CT lung cancer screening.

PURPOSE: To assess in vivo volumetric repeatability of an automated software algorithm in pulmonary nodules detected during a lung cancer screening trial. MATERIALS AND METHODS: This study was approved by an institutional review board. Written informed consent was obtained from all participants. Data were collected from the Multicentric Italian Lung Detection project, a randomized controlled lung cancer screening trial. The first 1236 consecutive baseline computed tomographic (CT) studies performed at the Istituto Nazionale Tumori of Milan were evaluated. Among the enrolled participants, those who underwent repeat low-dose CT after 3 months and had at least one indeterminate nodule with a volume of more than 60 mm(3) (diameter of 4.8 mm or greater) were considered. Nonsolid, part-solid, and pleural-based nodules were excluded from this study. A descriptive analysis was performed by calculating means and standard deviations of nodule volumes at three assessment times (at baseline and 3 and 12 months later). The volume measurement repeatability was determined by using the approach described by Bland and Altman. RESULTS: One hundred one subjects (70 men, 31 women; mean age, 58 years) with 233 eligible nodules (mean volume, 98.3 mm(3); range, 5-869 mm(3)) were identified. The 95% confidence interval for difference in measured volumes was in the range of +/-27%. About 70% of measurements had a relative difference in nodule volume of less than 10%. No malignant lesions were registered during the follow-up of these subjects. CONCLUSION: Semiautomatic volumetry is sufficiently accurate and repeatable and may be useful in assisting with lung nodule management in a lung cancer screening program.

FGFR4 Gly388Arg polymorphism may affect the clinical stage of patients with lung cancer by modulating the transcriptional profile of normal lung.

The association of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism with clinical stage and overall survival in a series of 541 Italian lung adenocarcinoma (ADCA) patients indicated a significantly decreased survival in patients carrying the rare Arg388 allele as compared to that in Gly/Gly homozygous patients [hazard ratio (HR) = 1.5; 95% confidence interval (CI) 1.1-1.9], with the decrease related to the association of the same polymorphism with clinical stage (HR = 1.8, 95% CI 1.3-2.6). By contrast, no significant association was detected in small series of either Norwegian lung ADCA patients or Italian lung squamous cell carcinoma (SQCC) patients. Single nucleotide polymorphisms of known FGFR4 ligands expressed in lung (FGF9, FGF18 and FGF19) were not associated with clinical stage or survival and showed no interaction with FGFR4. Analysis of gene expression profile in normal lungs according to FGFR4 genotype indicated a specific transcript pattern associated with the allele carrier status, suggesting a functional role for the FGFR4 polymorphism already detectable in normal lung. These findings confirm the significant association of the FGFR4 Gly388Arg polymorphism with clinical stage and overall survival in an Italian lung ADCA population and demonstrate a FGFR4 genotype-dependent transcriptional profile present in normal lung tissue.

Transcription deregulation at the 15q25 locus in association with lung adenocarcinoma risk.

PURPOSE: We characterized the candidacy of the six candidate genes mapping in the chromosome 15q25 locus, which was previously reported as associated with lung cancer risk, and confirmed the locus association with lung cancer risk in an Italian population of lung adenocarcinoma patients and controls. EXPERIMENTAL DESIGN: We did a quantitative analysis of mRNA levels of IREB2 (iron-responsive element-binding protein 2), LOC123688, PMSA4 [proteasome (prosome, macropain) subunit alpha type 4], CHRNB4 (cholinergic receptor nicotinic beta 4), CHRNA3 (cholinergic receptor nicotinic alpha 3), and CHRNA5 (cholinergic receptor nicotinic alpha 5) genes in paired normal lung and lung adenocarcinoma tissue, and an immunohistochemical localization of CHRNA3- and CHRNA5-encoded proteins. We also examined the association of CHRNA5 D398N polymorphism with lung cancer risk and with CHRNA5 mRNA levels in the normal lung. RESULTS: Expression analysis of the six candidate genes mapping in the lung cancer risk-associated chromosome 15q25 locus revealed a 30-fold up-regulation of the gene encoding the CHRNA5 subunit and a 2-fold down-regulation of the CHRNA3 subunit in lung adenocarcinoma as compared with the normal lung. The expression of the four other candidate genes resulted either unchanged or absent. The carrier status of the 398N allele at the D398N polymorphism of the CHRNA5 gene was associated with lung adenocarcinoma risk (odds ratio, 1.5; 95% confidence interval, 1.2-2.0) in a population-based series of lung adenocarcinoma patients (n=467) and healthy controls (n=739). Analysis of a family-based series of nonsmoker lung cancer cases (n=80) and healthy sib controls (n=80) indicated a similar trend. In addition, the same D398N variation correlated with CHRNA5 mRNA levels in normal lung of adenocarcinoma patients. CONCLUSIONS: Our results point to the candidacy of the CHRNA5 gene for the 15q25 locus.

Prolonged remission of disseminated atypical adenomatous hyperplasia under gefitinib.

Atypical adenomatous hyperplasia (AAH) is a putative precursor of bronchioloalveolar carcinoma (BAC) and adenocarcinoma of the lung, developing from terminal respiratory unit cells. AAH and BAC lesions typically present as ground-glass opacities at spiral chest computed tomography. Epidermal growth factor receptor polysomy/mutations, conferring higher sensitivity to Gefitinib, are frequent in BAC but less common in AAH. We describe an interesting case of disseminated AAH showing a sustained remission under Gefitinib therapy.

Fragile histidine triad gene inactivation in lung cancer: the European Early Lung Cancer project.

RATIONALE: Fragile histidine triad (FHIT) is a tumor suppressor gene involved in the pathogenesis of lung cancer. OBJECTIVES: The purpose of this study was to investigate the different molecular alterations leading to the inactivation of FHIT gene function and to validate their use as biomarkers of risk for progression of the disease in patients belonging to the multicentric European study for the Early detection of Lung Cancer (EUELC) who were resected for early-stage lung tumors. METHODS: FHIT immunostaining was performed on 305 tumor samples. The methylation status of FHIT promoter was assessed by nested methylation-specific polymerase chain reaction (MSP-PCR) in 232 tumor and 225 normal lung samples of which a subset of 187 patients had available normal/tumor DNA pairs. Loss of heterozygosity (LOH) at the FHIT locus was analyzed in 202 informative cases by D3S1300 and D3S1234 microsatellite markers. MEASUREMENTS AND MAIN RESULTS: Lost or reduced FHIT expression was found in 36.7 and 75.7% of the tumor samples, respectively. Methylation of the FHIT promoter was found in 36.7% of tumor and 32.7% of normal lung samples, whereas LOH was detected in 61.9% of the tumors. A strong association with complete loss of FHIT expression was present when methylation and LOH were analyzed together (P = 0.0064). Loss of FHIT protein expression was significantly more frequent in squamous cell carcinoma histotype (P < 0.0001) and in smokers (P = 0.008). FHIT methylation in normal lung was associated with an increased risk of progressive disease (OR, 2.27; P = 0.0415). CONCLUSIONS: Our results indicate that different molecular mechanisms interplay to inactivate FHIT expression and support the proposition that FHIT methylation in normal lung tissue could represent a prognostic marker for progressive disease.

Lung cancer stage is an independent risk factor for surgical mortality.

AIMS AND BACKGROUND: To study surgical mortality and evaluate major risk factors, with specific focus on the role of pathological stage in patients undergoing lung cancer resection. METHODS AND STUDY DESIGN: Age, gender, comorbidity, resection volume, experience of the hospital and surgical team have been reported as variables related to postoperative morbidity and mortality in lung cancer. The role of pathological tumor stage on postoperative mortality has never been fully evaluated. The study included 1418 consecutive lung cancer resections performed from 1998 to 2002 in two institutions. The effect of age, gender, comorbidity, resection volume, pathological stage and induction therapies on postoperative mortality was assessed by univariable and multivariable logistic regression analysis. RESULTS: Postoperative mortality was 1.8% overall, 3.7% (9/243) for pneumonectomy, 1.7% (17/1016) for lobectomy, and null (0/159) for sublobar resections (P = 0.020). At multivariable analysis, cardiovascular comorbidity (P = 0.008), resection volume (P = 0.036) and pathological stage (P = 0.027) emerged as significant predictors of surgical mortality. CONCLUSIONS: Early stage lung cancer resection has a favorable effect on surgical mortality, not only by preventing the need for pneumonectomy, but also by reducing mortality after lobectomy.

Reliability of quantitative computed tomography to predict postoperative lung function in patients with chronic obstructive pulmonary disease having a lobectomy.

OBJECTIVE: To verify the reliability of quantitative computed tomography (CT) to estimate the postoperative lung function in patients with mild to severe chronic obstructive pulmonary disease (COPD) who underwent a lobectomy. METHODS: Nine COPD patients with lung cancer having a lung lobectomy with preoperative CT were enrolled. By applying a density mask technique and a specific equation, predicted postoperative forced expiratory volume in 1 second (FEV1) and vital capacity (VC) were calculated. Predicted values were correlated with postoperative measured values. RESULTS: Estimated FEV1 and VC were always significantly lower than the corresponding postoperative values; however, CT-estimated postresection FEV1 values were better than the postresection VC values (biases between estimated and measured values were -0.14 and -0.536 L, respectively, according to the Bland-Altman method). Quantitative CT predicted postoperative FEV1 (r = 0.97, P < 0.001) and VC (r = 0.93, P < 0.001) well in all patients, however. CONCLUSIONS: Quantitative CT may be an alternative tool to perfusion scan to predict postresection lung function, even in patients with borderline pulmonary function undergoing a lobectomy.

Diagnostic imaging of diffuse infiltrative disease of the lung.

Plain chest radiography remains the first diagnostic approach to diffuse infiltrative lung disease but has limited diagnostic sensitivity and specificity. Many diseases remain occult or are not correctly assessed using chest X-ray, appearing as a nonspecific 'reticulonodular pattern'. High-resolution CT (HRCT) is actually the recommended imaging technique in the diagnosis, assessment, and follow-up of these diseases, allowing also the evaluation of the effectiveness of the medical therapy and the selection of the type and the location of the biopsy when required. Appropriate techniques must be used to acquire high-quality HRCT scans, with the thin collimation and high spatial reconstruction algorithm being the most important factors. A nodular pattern, linear and reticular opacities, cystic lesions, ground-glass opacities and consolidations are the most common HRCT patterns of diffuse infiltrative lung disease. This article reviews the role of chest radiography and HRCT in the diagnosis and assessment of these diseases, the technical aspects of HRCT, its clinical indications and the radiological pattern of the most common types of chronic diffuse infiltrative lung disease.