Chest CT Lung Abnormalities 1 Year after COVID-19: A Systematic Review and Meta-Analysis.

Background Radiological lung sequelae may explain the persistence of respiratory complaints in post-COVID-19 condition (long-COVID). Purpose To perform a systematic review and meta-analysis of the prevalence and type of COVID-19 residual lung abnormalities at 1-year chest CT. Materials and Methods A literature search of PubMed, Web of Science, Embase, and Medline databases was performed from January 2020 to January 2023. Full-text reports of CT lung sequelae in adults (≥18 years) with confirmed COVID-19 at 1-year follow-up were included. The prevalence of any residual lung abnormality and type (fibrotic or not) was analyzed according to the Fleischner Glossary. The meta-analysis included studies with chest CT data assessable in no less than 80% of individuals. A random-effects model was used to estimate pooled prevalence. Multiple sub-group (country, journal category, methodological quality, study setting, outcomes) and meta-regression analyses were performed to identify potential sources of heterogeneity. I2 statistics estimated low (25%), moderate (26-50%) and high (>50%) heterogeneity. 95% Prediction Intervals (95% PIs) were computed to describe the expected estimates range. Results Of 22 709 records, 21 studies were reviewed (20 prospective, 9 from China, and 7 in radiology journals). The meta-analysis included 14 studies with chest CT data in 1854 of 2043 individuals (M/F: 1109/934). Estimates of lung sequelae were highly heterogeneous (7.1-96.7%), with a pooled frequency of 43.5% (I2=94%; 95% PI: 5.9%, 90.4%). This also applied to single non-fibrotic changes, including ground glass opacity, consolidations, nodules/masses, parenchymal bands, and reticulations. The prevalence range of fibrotic traction bronchiectasis/bronchiolectasis was 1.6-25.7% (I2=93%; 95% PI: 0.0%, 98.6%;); honeycombing was unremarkable (0-1.1%; I2=58%; 95% PI: 0%, 60%). Lung sequelae were unrelated to any characteristics of interest. Conclusion The prevalence of COVID-19 lung sequelae at 1-year chest CT is highly heterogeneous among studies. Heterogeneity determinants remain unknown suggesting caution in data interpretation with no convincing evidence. PROSPERO (CRD42022341258) Keywords: COVID-19 pneumonia, pulmonary fibrosis, chest CT, long-COVID, systematic review, metaanalysis See also the editorial by Parraga and Svenningsen in this issue.

Chest CT-based Assessment of 1-year Outcomes after Moderate COVID-19 Pneumonia.

BACKGROUND: COVID-19 pneumonia may lead to pulmonary fibrosis in the long term. Chest CT is useful to evaluate changes in the lung parenchyma over time. PURPOSE: To illustrate the temporal change of lung abnormalities on chest CT scans associated with COVID-19 pneumonia over 1 year. MATERIALS AND METHODS: In this prospective study, patients previously hospitalized due to COVID-19 pneumonia who visited the radiology department of a tertiary care center for imaging follow-up were consecutively enrolled between March 2020 and July 2021. Exclusion criteria were acute respiratory distress syndrome, requirement of intubation and/or mechanical ventilation, pulmonary embolism, and any interstitial lung disease. High-resolution volumetric noncontrast chest CT scans were acquired at 3, 6, and 12 months from the first diagnosis and were compared with baseline CT scans. The imaging features analyzed were ground-glass opacity (GGO), consolidation, pleuroparenchymal band, linear atelectasis, bronchiectasis and/or bronchiolectasis, reticulation, traction bronchiectasis and/or bronchiolectasis, and honeycombing. The prevalence distribution of lung abnormalities was recorded at all time points. RESULTS: Eighty-four participants (56 men; mean age, 61 years ± 11 [SD]) were studied. GGOs and consolidations represented the main baseline lung abnormalities, accounting for a median severity score of 9 (IQR, 7-12.7; maximum possible score, 20), which indicates moderate lung involvement. The baseline prevalence of GGOs decreased from 100% to 2% of participants at 1 year, and that of consolidations decreased from 71% to 0% at 6 months. Fibrotic-like abnormalities (pleuroparenchymal bands, linear atelectasis, bronchiectasis and/or bronchiolectasis) were detected at 3 months (50% of participants), 6 months (42% of participants), and 1 year (5% of participants). Among these, pleuroparenchymal bands were the most represented finding. Fibrotic changes (reticulation and traction bronchiectasis and/or bronchiolectasis) were detected at 3-6 months (2%) and remained stable at 1 year, with no evidence of honeycombing. At 1 year, lung abnormalities due to COVID-19 pneumonia were completely resolved in 78 of 84 (93%) participants. CONCLUSION: Residual lung abnormalities in individuals hospitalized with moderate COVID-19 pneumonia were infrequent, with no evidence of fibrosis at 1-year chest CT. © RSNA, 2022.

A bird's eye view on the role of dendritic cells in SARS-CoV-2 infection: Perspectives for immune-based vaccines.

Coronavirus disease-19 (COVID-19) is a complex disorder caused by the pandemic diffusion of a novel coronavirus named SARS-CoV-2. Clinical manifestations vary from silent infection to severe pneumonia, disseminated thrombosis, multi-organ failure, and death. COVID-19 pathogenesis is still not fully elucidated, while increasing evidence suggests that disease phenotypes are strongly related to the virus-induced immune system's dysregulation. Indeed, when the virus-host cross talk is out of control, the occurrence of an aberrant systemic inflammatory reaction, named "cytokine storm," leads to a detrimental impairment of the adaptive immune response. Dendritic cells (DCs) are the most potent antigen-presenting cells able to support innate immune and promote adaptive responses. Besides, DCs play a key role in the anti-viral defense. The aim of this review is to focus on DC involvement in SARS-CoV-2 infection to better understand pathogenesis and clinical behavior of COVID-19 and explore potential implications for immune-based therapy strategies.

Lesson by SARS-CoV-2 disease (COVID-19): whole-body CT angiography detection of "relevant" and "other/incidental" systemic vascular findings.

OBJECTIVES: Increasing evidence suggests that SARS-CoV-2 infection may lead to severe and multi-site vascular involvement. Our study aimed at assessing the frequency of vascular and extravascular events' distribution in a retrospective cohort of 42 COVID-19 patients. METHODS: Patients were evaluated by whole-body CT angiography between March 16 and April 30, 2020. Twenty-three out of the 42 patients evaluated were admitted to the intensive care unit (ICU). Vascular and extravascular findings were categorized into "relevant" or "other/incidental," first referring to the need for immediate patient care and management. Student T-test, Mann-Whitney U test, or Fisher exact test was used to compare study groups, where appropriate. RESULTS: Relevant vascular events were recorded in 71.4% of cases (n = 30). Pulmonary embolism was the most frequent in both ICU and non-ICU cases (56.5% vs. 10.5%, p = 0.002). Ischemic infarctions at several sites such as the gut, spleen, liver, brain, and kidney were detected (n = 20), with multi-site involvement in some cases. Systemic venous thrombosis occurred in 30.9% of cases compared to 7.1% of systemic arterial events, the first being significantly higher in ICU patients (p = 0.002). Among incidental findings, small-sized splanchnic arterial aneurysms were reported in 21.4% of the study population, with no significant differences in ICU and non-ICU patients. CONCLUSIONS: Vascular involvement is not negligible in COVID-19 and should be carefully investigated as it may significantly affect disease behavior and prognosis. KEY POINTS: • Relevant vascular events were recorded in 71.4% of the study population, with pulmonary embolism being the most frequent event in ICU and non-ICU cases. • Apart from the lung, other organs such as the gut, spleen, liver, brain, and kidneys were involved with episodes of ischemic infarction. Systemic venous and arterial thrombosis occurred in 30.9% and 7.1% of cases, respectively, with venous events being significantly higher in ICU patients (p = 0.002). • Among incidental findings, small-sized splanchnic arterial aneurysms were reported in 21.4% of the whole population.

Circulating dendritic cells are severely decreased in idiopathic pulmonary fibrosis with a potential value for prognosis prediction.

Dendritic cells (DCs) accumulate in the lung of patients affected by idiopathic pulmonary fibrosis (IPF). We measured the frequencies of circulating conventional CD1c + and CD141+ cells (namely, cDC2 and cDC1) and of plasmacytoid CD303+ DCs in a cohort of 60 therapy naive IPF patients by flow cytometry. Peripheral levels of reactive oxygen species (ROS) and of pro-inflammatory and Th1/Th2 polarizing cytokines were also analyzed. All blood DC subtypes were significantly reduced in IPF patients in comparison to age- and sex-matched controls, while ROS and interleukin (IL-6) levels were augmented. IL-6 expression increased along with disease severity, according to the gender-age-physiology index, and correlated with the frequency of cDC2. IL-6 and cDC2 were not influenced by anti-fibrotic therapies but were associated with a reduced survival, the latter being an independent predictive biomarker of worse prognosis. Deciphering the role of DCs in IPF might provide information on disease pathogenesis and clinical behavior.

The Dysregulation of the Monocyte-Dendritic Cell Interplay Is Associated with In-Hospital Mortality in COVID-19 Pneumonia.

Background: The monocyte-phagocyte system (MPS), including monocytes/macrophages and dendritic cells (DCs), plays a key role in anti-viral immunity. We aimed to analyze the prognostic value of the MPS components on in-hospital mortality in a cohort of 58 patients (M/F; mean age ± SD years) with COVID-19 pneumonia and 22 age- and sex-matched healthy controls. Methods: We measured frequencies and absolute numbers of peripheral blood CD169+ monocytes, conventional CD1c+ and CD141+ (namely cDC2 and cDC1), and plasmacytoid CD303+ DCs by means of multi-parametric flow cytometry. A gene profile analysis of 770 immune-inflammatory-related human genes and 20 SARS-CoV-2 genes was also performed. Results: Median frequencies and absolute counts of CD169-expressing monocytes were significantly higher in COVID-19 patients than in controls (p 0.04 and p 0.01, respectively). Conversely, percentages and absolute numbers of all DC subsets were markedly depleted in patients (p < 0.0001). COVID-19 cases with absolute counts of CD169+ monocytes above the median value of 114.68/µL had significantly higher in-hospital mortality (HR 4.96; 95% CI: 1.42-17.27; p = 0.02). Interleukin (IL)-6 concentrations were significantly increased in COVID-19 patients (p < 0.0001 vs. controls), and negatively correlated with the absolute counts of circulating CD1c+ cDC2 (r = -0.29, p = 0.034) and CD303+ pDC (r = -0.29, p = 0.036) subsets. Viral genes were upregulated in patients with worse outcomes along with inflammatory mediators such as interleukin (IL)-1 beta, tumor necrosis-α (TNF-α) and the anticoagulant protein (PROS1). Conversely, surviving patients had upregulated genes related to inflammatory and anti-viral-related pathways along with the T cell membrane molecule CD4. Conclusions: Our results suggest that the dysregulated interplay between the different components of the MPS along with the imbalance between viral gene expression and host anti-viral immunity negatively impacts COVID-19 outcomes. Although the clinical scenario of COVID-19 has changed over time, a deepening of its pathogenesis remains a priority in clinical and experimental research.

Machine Learning and BMI Improve the Prognostic Value of GAP Index in Treated IPF Patients.

Patients affected by idiopathic pulmonary fibrosis (IPF) have a high mortality rate in the first 2-5 years from diagnosis. It is therefore necessary to identify a prognostic indicator that can guide the care process. The Gender-Age-Physiology (GAP) index and staging system is an easy-to-calculate prediction tool, widely validated, and largely used in clinical practice to estimate the risk of mortality of IPF patients at 1-3 years. In our study, we analyzed the GAP index through machine learning to assess any improvement in its predictive power in a large cohort of IPF patients treated either with pirfenidone or nintedanib. In addition, we evaluated this event through the integration of additional parameters. As previously reported by Y. Suzuki et al., our data show that inclusion of body mass index (BMI) is the best strategy to reinforce the GAP performance in IPF patients under treatment with currently available anti-fibrotic drugs.

Disease stage-related survival in idiopathic pulmonary fibrosis patients treated with nintedanib and pirfenidone: An exploratory study.

BACKGROUND: GAP (gender-age-physiology) and TORVAN are multi-parametric prognostication scores for idiopathic pulmonary fibrosis (IPF). We compared their prognostic value in patients treated with nintedanib or pirfenidone and explored their effect on patient survival in relation to disease staging. STUDY DESIGN AND PATIENTS: Retrospective evaluation of 235 naïve IPF patients (M = 179; mean age 69.8 yrs±7.1; 102 treated with nintedanib and 133 with pirfenidone), referred to two Italian academic centers between February 2012 and December 2019. RESULTS: During a median follow-up of 4.2 years, the incidence rate of death was 14.5 per 100 person-years (95% CI: 12 to 17.4), with no differences between nintedanib and pirfenidone (log-rank p = 0.771). According to time-ROC analysis, GAP and TORVAN showed a similar discrimination performance at 1, 2, and 5 years. Survival of GAP-2/GAP-3 IPF patients treated with nintedanib was worse than that of patients in GAP-1 (HR 4.8, 95% CI: 2.2 to 10.5 and HR 9.4, 95% CI: 3.8 to 23.2). TORVAN I patients treated with nintedanib exhibited better survival than those in stages III (HR 3.1, 95% CI: 1.4 to 6.6) and IV (HR 10.5, 95% CI: 3.5 to 31.6). A significant treatment x stage interaction was observed for both disease staging indexes (p = 0.042 for treatment by GAP interaction and p = 0.046 for treatment by TORVAN interaction). A better survival was associated with nintedanib in patients with mild disease (GAP-1 or TORVAN I stage) and with pirfenidone in GAP-3 or TORVAN IV cases, although these findings did not always reach statistical significance. CONCLUSIONS: GAP and TORVAN similarly perform in IPF patients on anti-fibrotic therapy. However, the survival of patients treated with nintedanib and pirfenidone appears to be differently affected by disease staging.

Poor Nutritional Status and Dynapenia Are Highly Prevalent in Post-Acute COVID-19.

Poor nutritional status is common (estimated prevalence 5-69%) in acute coronavirus disease-2019 (COVID-19), and has been associated with hospitalization, the need for intensive care, and mortality. Body composition (BC) and muscle function have also been related in such patients to poor disease outcomes. As the evidence in the literature is limited, a cross-sectional study was carried out to determine the frequency of malnutrition in a cohort of post-acute COVID-19 patients referred to a rehabilitation center after hospital discharge. BC and muscle strength were assessed and the differences between bedridden and not bedridden patients were specifically evaluated. The study sample was composed of 144 post-acute COVID-19 patients (mean age 64.8 years; males = 95), 37% of whom were bedridden (males = 60%). Nutritional status was evaluated with Mini-Nutritional Assessment (MNA) and Controlling Nutritional status (CONUT). Fat-free mass (FFM) and skeletal muscle mass (SM) were estimated using bioelectrical impedance analysis (BIA). Raw BIA variables (phase angle = PhA and impedance ratios = IRs) were also determined and handgrip strength (HGS) was measured. Dynapenia was identified according to the 2019 EWGSOP criteria. According to MNA, 18% (n. 26) of patients were malnourished and 62% (n. 89) were at risk of malnutrition. As for CONUT, 21% (n. 31) of cases had moderate-severe malnutrition and 58% (n. 83) had light malnutrition. Abnormalities of raw BIA variables (low PhA and high IRs) and low HGS were more common in bedridden patients, in those who were malnourished, or had low FFM or SM. Dynapenic patients were 65% men and 47% women. In conclusion, malnutrition, BC alterations, and low HGS occur in post-acute COVID-19 patients and are more common in bedridden patients. Further studies are needed to identify reliable algorithms for assessing nutritional status in post-acute COVID-19 patients undergoing rehabilitation.

A Phase II Study on the Effect of Taurisolo® Administered via AEROsol in Hospitalized Patients with Mild to Moderate COVID-19 Pneumonia: The TAEROVID-19 Study.

BACKGROUND: Polyphenols are the largest class of bioactive compounds in plants, which are synthesized as secondary metabolites. In the last few years, interesting studies have demonstrated the efficacy of polyphenols against coronavirus infections. METHODS: we conducted a phase II multicentric clinical trial (TAEROVID-19) during the first wave of the COVID-19 pandemic in order to assess the safety and feasibility of Taurisolo® aerosol formulation in hospitalized patients suffering from SARS-CoV-2 pneumonia. RESULTS: we observed a rapid decline of symptoms and a low rate of intensive care in patients treated with Taurisolo®, with a faster decline of symptoms. CONCLUSIONS: This is the first trial assessing the safety and feasibility of Taurisolo® aerosol formulation. We could argue that this treatment could act as an add-on therapy in the treatment of COVID-19 patients, owing to both its anti-inflammatory and antioxidant effects. Further controlled trials are needed, which may be of interest to evaluate the compound's efficacy.

Dendritic Cells Are the Intriguing Players in the Puzzle of Idiopathic Pulmonary Fibrosis Pathogenesis.

Idiopathic pulmonary fibrosis (IPF) is the most devastating progressive interstitial lung disease that remains refractory to treatment. Pathogenesis of IPF relies on the aberrant cross-talk between injured alveolar cells and myofibroblasts, which ultimately leads to an aberrant fibrous reaction. The contribution of the immune system to IPF remains not fully explored. Recent evidence suggests that both innate and adaptive immune responses may participate in the fibrotic process. Dendritic cells (DCs) are the most potent professional antigen-presenting cells that bridge innate and adaptive immunity. Also, they exert a crucial role in the immune surveillance of the lung, where they are strategically placed in the airway epithelium and interstitium. Immature DCs accumulate in the IPF lung close to areas of epithelial hyperplasia and fibrosis. Conversely, mature DCs are concentrated in well-organized lymphoid follicles along with T and B cells and bronchoalveolar lavage of IPF patients. We have recently shown that all sub-types of peripheral blood DCs (including conventional and plasmacytoid DCs) are severely depleted in therapy naïve IPF patients. Also, the low frequency of conventional CD1c+ DCs is predictive of a worse prognosis. The purpose of this mini-review is to focus on the main evidence on DC involvement in IPF pathogenesis. Unanswered questions and opportunities for future research ranging from a better understanding of their contribution to diagnosis and prognosis to personalized DC-based therapies will be explored.

Dynapenia is highly prevalent in older patients with advanced idiopathic pulmonary fibrosis.

Body composition and muscle strength are emerging aspects in idiopathic pulmonary fibrosis (IPF) clinical assessment. We aimed to study the relationships of handgrip strength (HGS) with anthropometric variables, body composition, and disease staging, and to evaluate the prevalence of dynapenia in 102 clinically stable IPF patients (70 M; mean age: 69.4 years). Fat-free mass (FFM), skeletal muscle (SM) were estimated with bioimpedance analysis. HGS was measured with a digital handle dynamometer for both dominant and non-dominant body sides. Dynapenia was identified according to six recognized criteria sets. Mean body mass index (BMI) was 28.2 ± 4.7 kg/m2, with a prevalence of overweight (BMI > 25 and < 30 kg/m2) and obesity (BMI ≥ 30 kg/m2) of 35% and 37%, respectively. FFM and SM were greater in males, whereas percentage body fat was higher in women. HGS was higher and declined with age slightly more rapidly in men, showing a stronger correlation with FFM and SM. Dynapenia prevalence ranged from 20.6 to 56.9%, depending on the criteria used, and was more frequent in older patients and advanced disease. Dynapenia is highly prevalent in IPF. HGS is a promising proxy marker of muscle function to be used in clinical evaluation and follow-up programs.

Liquid Biopsy Is a Promising Tool for Genetic Testing in Idiopathic Pulmonary Fibrosis.

Liquid biopsy, which allows the isolation of circulating cell-free (ccf) DNA from blood, is an emerging noninvasive tool widely used in oncology for diagnostic and prognosis purposes. Previous data have shown that serum cfDNA discriminates idiopathic pulmonary fibrosis (IPF) from other interstitial lung diseases. Our study aimed to measure plasma levels of ccfDNA in 59 consecutive therapy-naive and clinically stable IPF patients. The single nucleotide polymorphism (SNP) of the MUC5B gene promoter (rs35705950), associated with increased susceptibility of developing IPF, has been sought in plasma cfDNA and genomic DNA for comparison. Thirty-five age- and sex-matched healthy volunteers were recruited as the control group. Our results show that concentrations of small-size ccfDNA fragments were significantly higher in IPF patients than in controls and inversely correlated with lung function deterioration. Moreover, the median level of 104 ng/mL allowed discriminating patients with mild disease from those more advanced. The rs35705950 polymorphism was found in 11.8% of IPF patients and 8% of controls, with no differences. Complete concordance between ccfDNA and genomic DNA was detected in all control samples, while four out of seven IPF cases (57%) carrying the rs35705950 polymorphism were discordant from genomic DNA (7% of total IPF). Liquid biopsy is a suitable tool with optimistic expectations of application in the field of IPF. In analogy with cancer biology, finding some discrepancies between ccfDNA and genomic DNA in IPF patients suggests that the former may convey specific genetic information present in the primary site of the disease.

Alpha-1-Antitrypsin Deficiency and Bronchiectasis: A Concomitance or a Real Association?

Alpha-1-antitrypsin deficiency (AATd) is a hereditary disease, mainly characterized by early onset and the lower lobes' predominant emphysema. Bronchiectasis is characterized by dilatation of the bronchial wall and a clinical syndrome whose features are a cough, sputum production and frequent respiratory exacerbations. In the literature, there are many papers concerning these two clinical entities, but there is still a lot of debate about a possible association between them, in particular about the frequency of their association and causal links. The aim of this short communication is to show the literature reports about the association between AATd and bronchiectasis to establish the state of the art and possible future developments in this research field.