VEGF-A plasma levels are associated with impaired DLCO and radiological sequelae in long COVID patients.

BACKGROUND: Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is characterized by persistent clinical symptoms following COVID-19. OBJECTIVE: To correlate biomarkers of endothelial dysfunction with persistent clinical symptoms and pulmonary function defects at distance from COVID-19. METHODS: Consecutive patients with long COVID-19 suspicion were enrolled. A panel of endothelial biomarkers was measured in each patient during clinical evaluation and pulmonary function test (PFT). RESULTS: The study included 137 PASC patients, mostly male (68%), with a median age of 55 years. A total of 194 PFTs were performed between months 3 and 24 after an episode of SARS-CoV-2 infection. We compared biomarkers evaluated in PASC patients with 20 healthy volunteers (HVs) and acute hospitalized COVID-19 patients (n = 88). The study found that angiogenesis-related biomarkers and von Willebrand factor (VWF) levels were increased in PASC patients compared to HVs without increased inflammatory or platelet activation markers. Moreover, VEGF-A and VWF were associated with persistent lung CT scan lesions and impaired diffusing capacity of the lungs for carbon monoxide (DLCO) measurement. By employing a Cox proportional hazards model adjusted for age, sex, and body mass index, we further confirmed the accuracy of VEGF-A and VWF. Following adjustment, VEGF-A emerged as the most significant predictive factor associated with persistent lung CT scan lesions and impaired DLCO measurement. CONCLUSION: VEGF-A is a relevant predictive factor for DLCO impairment and radiological sequelae in PASC. Beyond being a biomarker, we hypothesize that the persistence of angiogenic disorders may contribute to long COVID symptoms.

Automated computed tomographic scoring of lung disease in adults with primary ciliary dyskinesia.

BACKGROUND: The present study aimed to develop an automated computed tomography (CT) score based on the CT quantification of high-attenuating lung structures, in order to provide a quantitative assessment of lung structural abnormalities in patients with Primary Ciliary Dyskinesia (PCD). METHODS: Adult (≥18 years) PCD patients who underwent both chest CT and spirometry within a 6-month period were retrospectively included. Commercially available lung segmentation software was used to isolate the lungs from the mediastinum and chest wall and obtain histograms of lung density. CT-density scores were calculated using fixed and adapted thresholds based on various combinations of histogram characteristics, such as mean lung density (MLD), skewness, and standard deviation (SD). Additionally, visual scoring using the Bhalla score was performed by 2 independent radiologists. Correlations between CT scores, forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were evaluated. RESULTS: Sixty-two adult patients with PCD were included. Of all histogram characteristics, those showing good positive or negative correlations to both FEV1 and FVC were SD (R = - 0.63 and - 0.67; p < 0.001) and Skewness (R = 0.67 and 0.67; p < 0.001). Among all evaluated thresholds, the CT-density score based on MLD + 1SD provided the best negative correlation with both FEV1 (R = - 0.68; p < 0.001) and FVC (R = - 0.71; p < 0.001), close to the correlations of the visual score (R = - 0.60; p < 0.001 for FEV1 and R = - 0.62; p < 0.001, for FVC). CONCLUSIONS: Automated CT scoring of lung structural abnormalities lung in primary ciliary dyskinesia is feasible and may prove useful for evaluation of disease severity in the clinic and in clinical trials.

Macrophage Migration Inhibitory Factor (MIF) Inhibition in a Murine Model of Bleomycin-Induced Pulmonary Fibrosis.

BACKGROUND: Pulmonary hypertension (PH) is a common complication of idiopathic pulmonary fibrosis (IPF) that significantly contributes to morbidity and mortality. Macrophage migration inhibitory factor (MIF) is a critical factor in vascular remodeling of the pulmonary circulation. OBJECTIVES: We tested the effects of two small molecules targeting MIF on bleomycin (BLM)-induced collagen deposition, PH, and vascular remodeling in mouse lungs. METHODS: We examined the distribution pattern of MIF, CD74, and CXCR4 in the lungs of patients with IPF-PH and the lungs of BLM-injected mice. Then, treatments were realized with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) and N-(3-hydroxy-4-fluorobenzyl)-5 trifluoromethylbenzoxazol-2-thione 31 (20 mg/kg/day per os for 3 weeks) started 24 h after an intratracheal BLM administration. RESULTS: More intense immunoreactivity was noted for MIF, CD74, and CXCR4 in lungs from IPF-PH patients and BLM-injected mice. Furthermore, we found that treatments of BLM-injected mice with ISO-1 or compound 31 attenuated lung collagen deposition and right ventricular systolic pressure increase. Additionally, reduced pulmonary inflammatory infiltration and pulmonary arterial muscularization were observed in the lungs of BLM-injected mice treated with ISO-1 or compound 31. CONCLUSIONS: Treatments with ISO-1 or compound 31 attenuates BLM-induced inflammation and fibrosis in lung, and prevents PH development in mice, suggesting that MIF is an important factor for IPF-PH development.

Combined measurement of carbon monoxide and nitric oxide lung transfer does not improve the identification of pulmonary hypertension in systemic sclerosis.

Screening is important to determine whether patients with systemic sclerosis (SSc) have pulmonary hypertension because earlier pulmonary hypertension treatment can improve survival in these patients. Although decreased transfer factor of the lung for carbon monoxide (TLCO) is currently considered the best pulmonary function test for screening for pulmonary hypertension in SSc, small series have suggested that partitioning TLCO into membrane conductance (diffusing capacity) for carbon monoxide (DMCO) and alveolar capillary blood volume (VC) through combined measurement of TLCO and transfer factor of the lung for nitric oxide (TLNO) is more effective to identify pulmonary hypertension in SSc patients compared with TLCO alone. Here, the objective was to determine whether combined TLCO-TLNO partitioned with recently refined equations could more accurately detect pulmonary hypertension than TLCO alone in SSc.For that purpose, 572 unselected consecutive SSc patients were retrospectively recruited in seven French centres.Pulmonary hypertension was diagnosed with right heart catheterisation in 58 patients. TLCO, TLNO and VC were all lower in SSc patients with pulmonary hypertension than in SSc patients without pulmonary hypertension. The area under the receiver operating characteristic curve for the presence of pulmonary hypertension was equivalent for TLCO (0.82, 95% CI 0.79-0.85) and TLNO (0.80, 95% CI 0.76-0.83), but lower for VC (0.75, 95% CI 0.71-0.78) and DMCO (0.66, 95% CI 0.62-0.70).Compared with TLCO alone, combined TLCO-TLNO does not add capability to detect pulmonary hypertension in unselected SSc patients.

RhoA/Rho-kinase activation promotes lung fibrosis in an animal model of systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a connective-tissue disease characterized by vascular injury, immune-system disorders, and excessive fibrosis of the skin and multiple internal organs. Recent reports found that RhoA/Rho-kinase (ROCK) pathway is implicated in various fibrogenic diseases. Intradermal injection of hypochlorous acid (HOCl)-generating solution induced inflammation, autoimmune activation, and fibrosis, mimicking the cutaneous diffuse form of SSc in humans. Our study aimed firstly to describe pulmonary inflammation and fibrosis induced by HOCl in mice, and secondly to determine whether fasudil, a selective inhibitor of ROCK, could prevent lung and skin fibroses in HOCl-injected mice. METHODS: Female C57BL/6 mice received daily intradermal injection of hypochlorous acid (HOCl) for 6 weeks to induce SSc, with and without daily treatment with fasudil (30 mg·kg(-1)·day(-1)) by oral gavage. RESULTS: HOCl intoxication induced significant lung inflammation (macrophages and neutrophils infiltration), and fibrosis. These modifications were prevented by fasudil treatment. Simultaneously, HOCl enhanced ROCK activity in lung and skin tissues. Inhibition of ROCK reduced skin fibrosis, expression of α-smooth-muscle actin and 3-nitrotyrosine, as well as the activity of ROCK in the fibrotic skin of HOCl-treated mice, through inhibition of phosphorylation of Smad2/3 and ERK1/2. Fasudil significantly decreased the serum levels of anti-DNA-topoisomerase-1 antibodies in mice with HOCl-induced SSc. CONCLUSIONS: Our findings confirm HOCl-induced pulmonary inflammation and fibrosis in mice, and provide further evidence for a key role of RhoA/ROCK pathway in several pathological processes of experimental SSc. Fasudil could be a promising therapeutic approach for the treatment of SSc.

Increased alveolar nitric oxide concentration is related to nocturnal oxygen desaturation in obstructive sleep apnoea.

PURPOSE: To assess distal/alveolar inflammation in patients with suggestive symptoms of obstructive sleep apnoea (OSA) using exhaled nitric oxide (NO) measured by two-compartment model (2-CM) after correction for axial NO back-diffusion (trumpet model). METHODS: Ninety five patients suspected for OSA prospectively underwent pulmonary function test, overnight polysomnography (PSG), and exhaled NO measurement. Patients with apnoea-hypopnoea index (AHI) < 5/hour were included in non-OSA group. Exhaled NO was repeatedly measured after PSG in 21 OSA patients and 8 non-OSA subjects. RESULTS: Alveolar NO concentration (C(ANO)) was significantly higher in OSA patients (n = 71; 4.07 ± 1.7 ppb) as compared with non-OSA subjects (n = 24; 2.24 ± 1.06 ppb; p < 0.0001) whilst maximal bronchial NO flux (J'awNO) and fractional exhaled NO (F(ENO)) did not differ between the two groups. C(ANO) was strongly associated to AHI (r = 0.701; p < 0.0001) and to recording time with SaO2 < 90% (ST-90%; r = 0.659; p < 0.0001) in OSA patients but not in non-OSA persons. The area under ROC curve for screening patients with OSA and significant nocturnal oxygen desaturation (ST-90% > 1%) was 0.865 ± 0.036 (95% IC, 0.793-0.937; p < 0.0001). C(ANO) at 4.5 ppb could detect these patients with specificity of 94% and sensitivity of 46%. Increase of C(ANO) measured after PSG was significantly related to oxygen desaturation index (ST-90%) in OSA patients. CONCLUSIONS: Increased alveolar NO concentration was related to the severity of nocturnal oxygen desaturation in patients with OSA, linking the distal airway inflammation to intermittent hypoxia. (250 words).

Cardiovascular comorbidities in obstructive sleep apnoea according to age: a sleep clinic population study.

PURPOSE: To describe the features of obstructive sleep apnoea (OSA) and its association with arterial hypertension (HT), coronary artery disease (CAD), and arrhythmias in elderly (≥65 years) versus younger patients. METHODS: All adult patients referred to our Sleep Research Unit for suspected OSA were included and underwent a thorough medical examination and an in-laboratory polysomnography. The severity of OSA was defined by the apnoea-hypopnoea index (AHI) as mild [5-15/h), moderate [15-30/h), and severe (≥30/h). RESULTS: Elderly patients (n = 136) and really old patients (>75 years) had higher prevalence of OSA (89 %) and severe OSA (36.8 %) as compared to younger patients (n = 439; 79.5 and 27.6 %, respectively, p < 0.05). In patients with OSA, the elderly group had a poorer sleep quality and more severe nocturnal oxygen desaturation than the younger group. Elderly patients presented higher percentages of HT (47.8 %), CAD (19.8 %), and arrhythmias (16.2 %) as compared to younger patients (p < 0.01). The odds ratio (OR) for HT increased with OSA severity from 1.0 to 1.65 (95 % confidence interval 0.83-3.27), 1.0 to 2.5 (95 % CI 1.25-5.00), and 1.0 to 3.77 (1.95-7.29) in younger patients, but not in elderly ones where the OR increased from 1.0 to 0.6 (0.17-2.04), 1.0 to 1.14 (0.34-3.82), and 1.0 to 1.46 (0.46-4.63), respectively. CONCLUSION: Stronger relation of HT and OSA severity in younger patients should encourage us to screen OSA in these patients at very young age. Increased OSA severity without obesity in very old patients needs to be confirmed and further studied.

Exhaled NO predicts cyclophosphamide response in scleroderma-related lung disease.

Cyclophosphamide (CYC) is not always effective in patients with scleroderma-related interstitial lung disease (SSc-ILD), hence the need for biomarkers able to predict beneficial responses to CYC therapy. We therefore assessed whether baseline alveolar concentration of nitric oxide (CANO) could predict the favourable response to CYC therapy in patients with SSc-ILD. Nineteen non-smoker patients with SSc-ILD, were enrolled and treated with 6 courses of CYC (0.75 g/m2/monthly) for lung function decline the year before inclusion, and followed-up for 2 years period. We assessed the proportion of favourable response to CYC, defined as improvement of forced vital capacity (FVC) or total pulmonary capacity (TLC) more than 10% between the inclusion and each following visit, according to the validated cut-off of CANO at 8.5 ppb identifying progressive SSc-ILD subset. At inclusion, 7 patients out of 19 had CANO >8.5 ppb. Clinical parameters were comparable between patients with high (>8.5 ppb) and low level of CANO (≤8.5 ppb). After CYC therapy, and during the follow-up, 9 out of 19 patients had favourable response to CYC therapy, 10 did not meet responder's criteria, from whom 4 patients died from respiratory failure. Six out of 7 patients with CANO >8.5 ppb at inclusion had favourable response to CYC therapy, while only 3 out of 12 patients with CANO ≤8.5 ppb responded favourably to CYC therapy (p=0.001). High level of CANO >8.5 ppb reflecting alveolar inflammation identify SSc patients with a greater chance to benefit from CYC treatment with a significant lung function improvement.

Amelioration of systemic fibrosis in mice by angiotensin II receptor blockade.

OBJECTIVE: Systemic sclerosis (SSc) is characterized by microvascular damage, fibrosis of skin and visceral organs, and autoimmunity. Previous studies have shown that angiotensin II is involved in the synthesis of type I collagen. We investigated whether the blockade of angiotensin II receptor type I (AT1 ) by irbesartan reduces skin and lung fibrosis in 2 murine models of SSc. METHODS: SSc was induced by daily intradermal injection of HOCl into the backs of BALB/c mice (HOCl-induced SSc). Mice were treated daily with irbesartan by oral gavage. RESULTS: Irbesartan reduced dermal thickness, collagen concentration, Smad2/3, and α-smooth muscle actin expression, as well as fibroblast proliferation and H-Ras expression in the skin of mice with HOCl-induced SSc. Mice treated with irbesartan also displayed less lung fibrosis, less inflammation, and a lower concentration of collagen in the lungs than untreated mice. Exhaled nitric oxide, inducible nitric oxide synthase, and 3-nitrotyrosine expression in the lungs were decreased following irbesartan treatment. Moreover, irbesartan reduced the number and the proliferation of splenic B and T cells and the serum levels of anti-DNA topoisomerase I autoantibodies. CONCLUSION: Irbesartan, an AT1 antagonist, prevents fibrosis and inflammation and inhibits nitric oxide production in HOCl-induced models of systemic fibrosis. Our findings extend the indication of an AT1 antagonist to SSc patients with diffuse fibrosis, especially those with lung involvement.

Cardiopulmonary Exercise Testing Provides Prognostic Information in Advanced Cystic Fibrosis Lung Disease.

Rationale: Cardiopulmonary exercise testing (CPET) provides prognostic information in cystic fibrosis (CF); however, its prognostic value for patients with advanced CF lung disease is unknown. Objectives: To determine the prognostic value of CPET on the risk of death or lung transplant (LTX) within 2 years. Methods: We retrospectively collected data from 20 CF centers in Asia, Australia, Europe, and North America on patients with a forced expiratory volume in 1 second (FEV1) ⩽ 40% predicted who performed a cycle ergometer CPET between January 2008 and December 2017. Time to death/LTX was analyzed using mixed Cox proportional hazards regression. Conditional inference trees were modeled to identify subgroups with increased risk of death/LTX. Results: In total, 174 patients (FEV1, 30.9% ± 5.8% predicted) were included. Forty-four patients (25.5%) died or underwent LTX. Cox regression analysis adjusted for age, sex, and FEV1 revealed percentage predicted peak oxygen uptake ([Formula: see text]o2peak) and peak work rate (Wpeak) as significant predictors of death/LTX: adjusted hazard ratios per each additional 10% predicted were 0.60 (95% confidence interval, 0.43-0.90; P = 0.008) and 0.60 (0.48-0.82; P < 0.001). Tree-structured regression models, including a set of 11 prognostic factors for survival, identified Wpeak to be most strongly associated with 2-year risk of death/LTX. Probability of death/LTX was 45.2% for those with a Wpeak ⩽ 49.2% predicted versus 10.9% for those with a Wpeak > 49.2% predicted (P < 0.001). Conclusions: CPET provides prognostic information in advanced CF lung disease, and Wpeak appears to be a promising marker for LTX referral and candidate selection.

High alveolar concentration of nitric oxide is associated with alveolitis in scleroderma.

Alveolar concentration of nitric oxide (C(A)NO) is a non invasive prognostic marker of systemic sclerosis (SSc) lung disease. There is, however, as yet no direct evidence showing concomitant increase of C(A)NO and the presence of inflammatory cells in alveoli. We have therefore measured C(A)NO and performed broncho-alveolar lavage (BAL) in SSc patients. Exhaled NO was measured, by the means of two different models, the two-compartment model (2CM) and the trumpet model with axial diffusion (TMAD), in 22 SSc patients and compared with 15 healthy controls. BAL was performed in all SSc patients. Alveolitis was defined as lymphocytes >14%, polymorphonuclears >4%, or eosinophils >3% on cell count in BAL fluid. Comparisons of C(A)NO levels were made between SSc patients with, and without, alveolitis. Levels of C(A)NO were significantly higher in SSc patients as compared with controls (p<0.001). Median C(A)NO was significantly higher in SSc patients with alveolitis as compared with SSc patients without alveolitis (8.4ppb; 1st and 3rd interquartile range: 6.0-10.5 vs 3.3ppb; 2.2-3.5; p=0.004 for 2CM and 5.4ppb; 3.2-9.2 vs 3.2ppb; 1.4-3.3, p=0.02 for TMAD), while bronchial airway output of NO (J'awNO, p=0.19), and fractional exhaled NO (F(E)NO, p=0.12) were comparable. C(A)NO was consistently high in SSc patients with alveolitis irrespective of the methods chosen (TMAD or 2CM). Our findings showed that increased C(A)NO was associated with alveolitis in patients with SSc. We submit that C(A)NO could be used as a reliable non-invasive surrogate biomarker of alveolitis in scleroderma lung disease.

Long-term treatment with fasudil improves bleomycin-induced pulmonary fibrosis and pulmonary hypertension via inhibition of Smad2/3 phosphorylation.

Pulmonary hypertension (PH) associated with pulmonary fibrosis (PF) considerably worsens prognosis of interstitial lung diseases (ILD). RhoA/Rho-kinases (ROCK) pathway is implicated in high pulmonary vascular tone and pulmonary fibrosis but the effect of ROCK inhibitors on PH associated with PF is not known. We therefore aimed to determine whether long-term treatment with fasudil, a selective ROCK inhibitor, could attenuate PF and PH induced by bleomycin in mice. Male C57BL/6 mice received a single dose of intratracheal bleomycin (3.3 U/kg) to induce PF. Treatment with fasudil (30 mg kg(-1) day(-1)) was given intraperitoneally for 7, 14 or 21 days until mice underwent hemodynamic measurements. Right ventricular systolic pressure (RVSP) and RV/(LV + S) ratio were assessed. Lung inflammatory cells profiles, including macrophages, neutrophils, lymphocytes B and lymphocytes T were assessed by immunohistochemistry. Lung fibrosis was evaluated by histological and biochemical methods. Pulmonary arteriole muscularization and medial wall thickness (MWT) were evaluated by immunohistochemical staining for α-SMA. Bleomycin induced severe PF and PH in mice, associated with an increased RhoA/ROCK activity in the lung. Fasudil reduced lung inflammation and lung collagen content, and attenuated the increased RVSP, RV hypertrophy, and pulmonary vascular remodeling in bleomycin-intoxicated mice. Fasudil inhibited the increased activity of RhoA/ROCK pathway, and partly altered bleomycin-associated activation of TGF-ß1/Smad pathway, via inhibition of Smad2/3 phosphorylation. The efficacy of long-term treatment with fasudil suggests that the blockade of RhoA/ROCK pathway may be a promising therapy for patients with ILD-associated PH.

Recovery of Endothelium-dependent vascular relaxation impairment in convalescent COVID-19 patients: Insight from a pilot study.

BACKGROUND: Endothelial dysfunction is a key-feature in acute COVID-19. However, follow-up data regarding endothelial dysfunction and injury after COVID-19 infection are lacking. We aimed to investigate the changes in endothelium-dependent vasorelaxation at baseline and four months after hospital discharge in COVID-19 patients. METHODS: Twenty COVID-19 patients were compared to 24 healthy controls. Clinical and morphological data were collected after hospital admission for SARS-CoV-2 infection and reactive hyperaemia index (RHI) measurement was performed with a delay between 24 and 48 h after hospital admission and four months after hospital discharge in the outpatient clinics. Blood tests including inflammatory markers and measurement of post-occlusive vasorelaxation by digital peripheral arterial tonometry were performed at both visits. RESULTS: At baseline, COVID-19 patients exhibited reduced RHI compared to controls (p < 0.001), in line with an endothelial dysfunction. At four months follow-up, there was a 51% increase in the RHI (1.69 ± 0.32 to 2.51 ± 0.91; p < 0.01) in favor of endothelium-dependent vascular relaxation recovery. RHI changes were positively correlated with baseline C-reactive protein (r = 0.68; p = 0.02). Compared to COVID-19 patients with a decrease in RHI, COVID-19 patients with an increase in RHI beyond the day-to-day variability (i.e. >11%) had less severe systemic inflammation at baseline. CONCLUSION: Convalescent COVID-19 patients showed a recovery of systemic artery endothelial dysfunction, in particular patients with lower inflammation at baseline. Further studies are needed to decipher the interplay between inflammation and endothelial dysfunction in COVID-19 patients.

Alveolar concentration of nitric oxide predicts pulmonary function deterioration in scleroderma.

BACKGROUND: Respiratory failure is a life-threatening and unpredictable complication of systemic sclerosis (SSc). A study was undertaken to assess the value of alveolar nitric oxide (NO) in predicting the risk of lung function deterioration leading to respiratory failure or death in patients with SSc. METHODS: 105 patients with SSc were enrolled in this prospective cohort and were followed longitudinally over a 3-year period during which the risk of occurrence of deleterious events was analysed according to alveolar concentration (C(A)NO), conducting airway output (J'(aw)NO) and fractional concentration (F(E)NO(0.05)) of exhaled NO measured at inclusion. Comparison was made between each NO parameter to predict the occurrence of deleterious events, defined as a 10% decrease in total lung capacity or forced vital capacity from baseline, or death. RESULTS: The area under the receiver operating characteristic curve of C(A)NO to predict the occurrence of the combined events was 0.84 (95% CI 0.76 to 0.92; p<0.001), which was significantly higher than those of J'(aw)NO and F(E)NO(0.05) (p<0.001). A cut-off of C(A)NO of 5.3 ppb had a sensitivity of 88% and a specificity of 62% for the prediction of the occurrence of combined events during follow-up, and was validated in an independent cohort of patients with SSc. Combined events occurred more frequently in patients whose C(A)NO was >5.3 ppb. The adjusted HR for patients with C(A)NO >5.3 ppb was 6.06 (95% CI 2.36 to 15.53; p<0.001). C(A)NO accurately predicted the occurrence of combined events irrespective of forced vital capacity values or the presence of interstitial lung disease at baseline. CONCLUSIONS: Increased C(A)NO accurately identifies patients with SSc with a high risk of developing lung function deterioration and may help to initiate early appropriate treatment.

Distal Lung Inflammation Assessed by Alveolar Concentration of Nitric Oxide Is an Individualised Biomarker of Severe COVID-19 Pneumonia.

Pulmonary sequelae as assessed by pulmonary function tests (PFTs) are often reported in patients infected by SARS-CoV-2 during the post-COVID-19 period. Little is known, however, about the status of pulmonary inflammation during clinical recovery after patients' discharge from the hospitals. We prospectively measured PFTs coupled with the exhaled nitric oxide (NO) stemming from the proximal airways (FeNO) and the distal lung (CaNO) in 169 consecutive patients with varying degrees of the severity of COVID-19 six weeks to one year after acute infection by SARS-CoV-2. The proportions of patients with abnormal PFTs, defined as the presence of either obstructive/restrictive patterns or impaired lung gas transfer, or both, increased with the severity of the initial lung disease (15, 30, and 52% in patients with mild, moderate, and severe COVID-19). FeNO values remained within normal ranges and did not differ between the three groups of patients. CaNO, however, was significantly higher in patients with severe or critical COVID-19, compared with patients with milder forms of the disease. There was also an inverse relationship between CaNO and DLCO. We conclude that the residual inflammation of the distal lung is still present in the post-COVID-19 follow-up period, in particular, in those patients with an initially severe form of COVID-19. This long-lasting alveolar inflammation might contribute to the long-term development of pulmonary fibrosis and warrants the regular monitoring of exhaled NO together with PFTs in patients with COVID-19.

Chronic Lung Allograft Dysfunction Post Lung Transplantation: A Review of Computed Tomography Quantitative Methods for Detection and Follow-Up.

Chronic lung allograft dysfunction (CLAD) remains the leading cause of morbidity and mortality after lung transplantation. The term encompasses both obstructive and restrictive phenotypes, as well as mixed and undefined phenotypes. Imaging, in addition to pulmonary function tests, plays a major role in identifying the CLAD phenotype and is essential for follow-up after lung transplantation. Quantitative imaging allows for the performing of reader-independent precise evaluation of CT examinations. In this review article, we will discuss the role of quantitative imaging methods for evaluating the airways and the lung parenchyma on computed tomography (CT) images, for an early identification of CLAD and for prognostic estimation. We will also discuss their limits and the need for novel approaches to predict, understand, and identify CLAD in its early stages.