An immunometabolic pathomechanism for chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is an inflammatory condition associated with abnormal immune responses, leading to airflow obstruction. Lungs of COPD subjects show accumulation of proinflammatory T helper (Th) 1 and Th17 cells resembling that of autoreactive immune responses. As regulatory T (Treg) cells play a central role in the control of autoimmune responses and their generation and function are controlled by the adipocytokine leptin, we herein investigated the association among systemic leptin overproduction, reduced engagement of glycolysis in T cells, and reduced peripheral frequency of Treg cells in different COPD stages. These phenomena were also associated with an impaired capacity to generate inducible Treg (iTreg) cells from conventional T (Tconv) cells. At the molecular level, we found that leptin inhibited the expression of forkhead-boxP3 (FoxP3) and its splicing variants containing the exon 2 (FoxP3-E2) that correlated inversely with inflammation and weakened lung function during COPD progression. Our data reveal that the immunometabolic pathomechanism leading to COPD progression is characterized by leptin overproduction, a decline in the expression of FoxP3 splicing forms, and an impairment in Treg cell generation and function. These results have potential implications for better understanding the autoimmune-like nature of COPD and the pathogenic events leading to lung damage.

Standardized exercise training is feasible, safe, and effective in pulmonary arterial and chronic thromboembolic pulmonary hypertension: results from a large European multicentre randomized controlled trial.

AIMS: This prospective, randomized, controlled, multicentre study aimed to evaluate efficacy and safety of exercise training in patients with pulmonary arterial (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS AND RESULTS: For the first time a specialized PAH/CTEPH rehabilitation programme was implemented in 11 centres across 10 European countries. Out of 129 enrolled patients, 116 patients (58 vs. 58 randomized into a training or usual care control group) on disease-targeted medication completed the study [85 female; mean age 53.6 ± 12.5 years; mean pulmonary arterial pressure 46.6 ± 15.1 mmHg; World Health Organization (WHO) functional class II 53%, III 46%; PAH n = 98; CTEPH n = 18]. Patients of the training group performed a standardized in-hospital rehabilitation with mean duration of 25 days [95% confidence interval (CI) 17-33 days], which was continued at home. The primary endpoint, change of 6-min walking distance, significantly improved by 34.1 ± 8.3 m in the training compared with the control group (95% CI, 18-51 m; P < 0.0001). Exercise training was feasible, safe, and well-tolerated. Secondary endpoints showed improvements in quality of life (short-form health survey 36 mental health 7.3 ± 2.5, P = 0.004), WHO-functional class (training vs. control: improvement 9:1, worsening 4:3; χ2P = 0.027) and peak oxygen consumption (0.9 ± 0.5 mL/min/kg, P = 0.048) compared with the control group. CONCLUSION: This is the first multicentre and so far the largest randomized, controlled study on feasibility, safety, and efficacy of exercise training as add-on to medical therapy in PAH and CTEPH. Within this study, a standardized specialized training programme with in-hospital start was successfully established in 10 European countries.

A multicentric quality-control study of exercise Doppler echocardiography of the right heart and the pulmonary circulation. The RIGHT Heart International NETwork (RIGHT-NET).

PURPOSE: This study was a quality-control study of resting and exercise Doppler echocardiography (EDE) variables measured by 19 echocardiography laboratories with proven experience participating in the RIGHT Heart International NETwork. METHODS: All participating investigators reported the requested variables from ten randomly selected exercise stress tests. Intraclass correlation coefficients (ICC) were calculated to evaluate the inter-observer agreement with the core laboratory. Inter-observer variability of resting and peak exercise tricuspid regurgitation velocity (TRV), right ventricular outflow tract acceleration time (RVOT Act), tricuspid annular plane systolic excursion (TAPSE), tissue Doppler tricuspid lateral annular systolic velocity (S'), right ventricular fractional area change (RV FAC), left ventricular outflow tract velocity time integral (LVOT VTI), mitral inflow pulsed wave Doppler velocity (E), diastolic mitral annular velocity by TDI (e') and left ventricular ejection fraction (LVEF) were measured. RESULTS: The accuracy of 19 investigators for all variables ranged from 99.7 to 100%. ICC was > 0.90 for all observers. Inter-observer variability for resting and exercise variables was for TRV = 3.8 to 2.4%, E = 5.7 to 8.3%, e' = 6 to 6.5%, RVOT Act = 9.7 to 12, LVOT VTI = 7.4 to 9.6%, S' = 2.9 to 2.9% and TAPSE = 5.3 to 8%. Moderate inter-observer variability was found for resting and peak exercise RV FAC (15 to 16%). LVEF revealed lower resting and peak exercise variability of 7.6 and 9%. CONCLUSIONS: When performed in expert centers EDE is a reproducible tool for the assessment of the right heart and the pulmonary circulation.

Cardiovascular Magnetic Resonance in Right Heart and Pulmonary Circulation Disorders.

Right heart and pulmonary circulation disorders are generally caused by right ventricle (RV) pressure overload, volume overload, and cardiomyopathy, and they are associated with distinct clinical courses and therapeutic approaches, although they often may coexist. Cardiac magnetic resonance (CMR) provides a noninvasive accurate and reproducible multiplanar anatomic and functional assessment, tissue characterization, and blood flow evaluation of the right heart and pulmonary circulation. This article reviews the current status of the CMR, the most recent techniques, the new parameters and their clinical utility in diagnosis, prognosis, and therapeutic management in the right heart and pulmonary circulation disorders.

Pulmonary Embolism: A Practical Guide for the Busy Clinician.

Acute pulmonary embolism (PE) is the third most common acute cardiovascular condition, and its prevalence increases over time. D-dimer has a very high negative predictive value, and if normal levels of D-dimer are detected, the diagnosis of PE is very unlikely. The final diagnosis should be confirmed by computed tomographic scan. However, echocardiography is the most available, bedside, low-cost, diagnostic procedure for patients with PE. Risk stratification is of utmost importance and is mainly based on hemodynamic status of the patient. Patients with PE and hemodynamic stability require further risk assessment, based on clinical symptoms, imaging, and circulating biomarkers.

Echocardiography in Pulmonary Arterial Hypertension.

PURPOSE OF REVIEW: Pulmonary arterial hypertension (PAH) is a devastating disease which can result in right heart (RH) failure and death. Herein, we discuss the current clinical applications of echocardiography in PAH. RECENT FINDINGS: Advanced echocardiographic techniques (strain, strain rate, 2D-speckle tracking strain, and three-dimensional echocardiography) may reveal in the near future additional important insights into RH structure and function. Although right-heart catheterization is mandatory for a definitive diagnosis, echocardiography (resting and exercise) represents a key noninvasive imaging test on the diagnostic-prognostic-therapeutic PAH algorithm.

Reference Ranges and Determinants of Tricuspid Regurgitation Velocity in Healthy Adults Assessed by Two-Dimensional Doppler-Echocardiography.

BACKGROUND: Tricuspid regurgitation velocity (TRV) is the most widely used parameter by transthoracic echocardiography (TTE) in the evaluation of patients with suspected pulmonary hypertension (PH). OBJECTIVES: To explore the physiologic range of TRV in healthy adults and to investigate its clinical determinants. METHODS: In the first part of the study, 614 healthy individuals (age 45.7± 14.7 years, 60.26% women) were prospectively assessed by TTE. In the second part, a pooled meta-analysis of 16 already published studies with TRV values in healthy subjects (n = 981) was performed. Statistical analysis included the calculation of 95% quantiles for defining reference ranges. RESULTS: In the prospectively enrolled cohort, mean TRV was 2.01 ± 0.29 m/s (5-95% CI 1.987-2.033 m/s). It was significantly but weakly positively correlated with age, body mass index, systolic blood pressure, diastolic blood pressure, left atrial volume and negative with mitral inflow E/A ratio. No significant differences were found between males and females. The prospectively enrolled data revealed similar values to the literature-based datasets resulting in a mean TRV of 1.96 m/s (95% CI 1.91-2.02 m/s) and a 95% quantile of 2.55 m/s. CONCLUSIONS: To the best of our knowledge, this is the largest dataset to describe reference ranges of TRV and their clinical determinants in healthy adults years. The determined cut-off value of 2.55 m/s of this study has to be confirmed in specific pathologies such as patients at risk of PH.

Reference values and correlates of right atrial volume in healthy adults by two-dimensional echocardiography.

BACKGROUND: Right atrial (RA) volume is an important parameter in the evaluation of patients with pulmonary hypertension. Aim of this study was to define reference ranges for RA volume by two-dimensional echocardiography (2DE) in healthy adults. METHODS: A total of 596 healthy subjects [mean age 45.7 ± 14.6 years, range 18-88 years; 60.1% women] underwent a transthoracic echocardiography. In addition, a meta-analysis was performed of published studies measuring RA volume in healthy subjects, using 2DE single plane area-length (A-L) and/or method of disks (MOD) at end-systole in apical four-chamber view. RESULTS: In our cohort, RA volume was higher in men than women but did not vary with age. Body surface area (BSA), stroke volume (SV), and tricuspid annular plane systolic excursion (TAPSE) were the only independent variables associated with RA volume (ß coefficient 0.569, 0.123, and 0.131, respectively; all P < .001). In the pooled analysis, normalized RA volume was 25.7 ± 7.0 mL/m2 in men and 21.2 ± 5.8 mL/m2 in women for A-L, 21.6 ± 5.6 mL/m2 in men and 18.2 ± 5.4 mL/m2 in women for MOD (all P values < .0001). The upper limit was about 36 mL/m2 in men and 31 mL/m2 in women for A-L and 31 mL/m2 in men and 27 mL/m2 in women for MOD. CONCLUSIONS: RA volume was found to be higher in men but not influenced by age. It was mainly correlated with larger BSA, indices of preload (SV) and RV longitudinal function (TAPSE). A statistically significant difference was found between A-L and MOD.

Pulmonary Hypertension: The Role of Lung Transplantation.

Despite advances in targeted medical therapy, pulmonary arterial hypertension (PAH) remains a fatal disease because of progressive right ventricular dysfunction. For patients who are refractory to medical therapy, heart-lung and lung transplantation are important treatment options. Because of longer waiting time, surgical interventions including extracorporeal lung support and atrial septostomy can be used in PAH patients bridging to transplantation.

Pulmonary Hypertension Related to Chronic Obstructive Pulmonary Disease and Diffuse Parenchymal Lung Disease: A Focus on Right Ventricular (Dys)Function.

Diffuse pulmonary lung disease and chronic obstructive pulmonary disease is a heterogeneous population that can manifest pulmonary hypertension. These subgroups are classified as primarily World Health Organization group 3. Available data suggest that the impact of pulmonary hypertension targeted therapy in diffuse pulmonary lung disease and chronic obstructive pulmonary disease is limited and survival is poor despite attempted treatment.

The Right Heart International Network (RIGHT-NET): Rationale, Objectives, Methodology, and Clinical Implications.

The Right Heart International Network is a multicenter international study aiming to prospectively collect exercise Doppler echocardiography tests of the right heart pulmonary circulation unit (RHPCU) in large cohorts of healthy subjects, elite athletes, and individuals at risk of or with overt pulmonary hypertension. It is going to provide standardization of exercise stress echocardiography of RHPCU and explore the full physiopathologic response.

The earlier, the better: Impact of early diagnosis on clinical outcome in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a complex disease with a highly variable clinical course and generally poor prognosis. Classified as a rare disease, significant increases in incidence have been recorded worldwide in recent years. Left untreated IPF is extremely debilitating with substantial personal, social and economic implications. OBJECTIVES: To discuss how IPF is diagnosed and managed in real life clinical practice with particular reference to Italy and to determine how new and effective therapies can be incorporated into a patient-centred management approach in order to improve the lives of patients with IPF. OUTCOMES: Barriers to early diagnosis are discussed. Cited reasons for delays in diagnosing IPF in Italy include: inherent difficulties in diagnosis; lack of knowledge/awareness of the condition among point-of-contact healthcare professionals; delays in referral to centres of excellence and underestimation of symptoms by both patients and healthcare workers. Valid therapeutic options with demonstrated efficacy in slowing the decline in lung function are now available for patients with IPF. The ASCEND trial confirmed the effects of pirfenidone, approved for the treatment of IPF on the basis of the four phase III trials. Nintedanib, a tyrosine kinase inhibitor that targets the PDGF receptors α/ß, FGF receptors 1 to 3, and VEGF receptors 1-3, is approved in the USA and the EU for the treatment of IPF. The TOMORROW and the INPULSIS placebo controlled trials in patients with IPF confirm the efficacy and safety of nintedanib and recent interim analyses endorse its long-term effects in slowing disease progression. CONCLUSIONS: The importance of early and accurate diagnosis of IPF cannot be underestimated and it is the duty of all healthcare professionals to be vigilant to the symptoms of IPF and to involve a multidisciplinary team in diagnosing and managing IPF early in the course of disease.

Imaging the right heart pulmonary circulation unit: Insights from advanced ultrasound techniques.

The right heart pulmonary circulation unit (RH-PCU) is a key determinant of prognosis in several cardiorespiratory diseases. Although right heart catheterization is considered the gold standard for pulmonary hemodynamic assessment, a comprehensive cardiovascular ultrasound approach is an essential step in the diagnostic-prognostic clinical pathway of patients with suspect or overt pulmonary hypertension. The exponential development of advanced ultrasound techniques (strain, 3-dimensional echocardiography and lung ultrasound) has led to new insights into the evaluation of RH-PCU structure and function, overcoming some limitations of standard Doppler echocardiography. In the near future, exercise Doppler echocardiography may become a useful technique for detecting a latent stage of pulmonary hypertension and for evaluating right ventricular contractile reserve.

Effect of CArbocisteine in Prevention of exaceRbation of chronic obstructive pulmonary disease (CAPRI study): An observational study.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a chronic and progressive lung disease characterized by irreversible airflow obstruction, airway inflammation, oxidative stress and, often, mucus hypersecretion. The aim of this study is to determine if carbocisteine, a mucolytic and antioxidant agent, administered daily for 12 months, can reduce exacerbation frequency in COPD patients. METHODS: This observational study was conducted in Naples (population approximately 1000,000), Italy. It included 85 out-patients (mean age of 67.8 ± 8.6 years) followed by Clinic of Respiratory Diseases of the University Federico II. Every patient underwent spirometry demonstrating airflow obstruction not fully reversible according to ERS/ATS criteria for COPD diagnosis (Tiffenau index less than 70% after administration of salbutamol, a beta2 agonist drug). Patients enrolled had diagnosed COPD since 2 years and suffered at least one exacerbation in the previous year. None of the patients had been treated with carbocisteine or other mucolytic agent for a longer period of time than 7 days and no more than 4 times in the previous year to the enrollment. All of them assumed daily 2.7 g of carbocisteine lysine salt for a year in addition to their basic therapy. RESULTS: The comparison of exacerbation frequency between the previous year (T0) and the end of study treatment (T12), documents a statistically significant reduction of exacerbations(number of exacerbations at T0: 2 [1,3] vs number of exacerbations at T12: 1 [1,2]; p < 0.001).Quality of life was also reported and showed a statistically significant improvement at the end of the study (p < 0.001).We did not find correlation between reducing exacerbation frequency and exposure to cigarette smoking, passive smoking exposure in childhood, the use of inhaled steroids, the level of education of our patients and the GOLD stadium. INTERPRETATION: Daily administration of a mucolytic drug such as carbocisteine for prolonged periods in addition to the bronchodilator therapy can be considered a good strategy for reducing exacerbation frequency in COPD.

Right Ventricular Structure and Function in Idiopathic Pulmonary Fibrosis with or without Pulmonary Hypertension.

AIMS: To elucidate right ventricular (RV) function in patients with idiopathic pulmonary fibrosis (IPF) with and without pulmonary hypertension (PH) and its relation to other features of the disease. METHODS AND RESULTS: Clinical evaluation, standard Doppler echo, Doppler myocardial imaging (DMI), and 2D strain echocardiography (STE) of RV septal and lateral walls were performed in 52 IPF patients (66.5 ± 8.5 years; 27 males) and in 45 age- and sex-comparable controls using a commercial US system (MyLab Alpha, Esaote). Pulmonary artery mean pressure (mPAP) was estimated by standard echo Doppler. RV global longitudinal strain (RV GLS) was calculated by averaging RV local strains. The IPF patients were divided into 2 groups by noninvasive assessment of PH: no PH (mPAP<25 mmHg; 36 pts) and PH (mPAP ≥25 mmHg; 16 pts). Left ventricular diameters and ejection fraction were comparable between controls and IPF, while GLS was impaired in IPF (P < 0.01). RV end-diastolic diameters, wall thickness andmPAP were increased in IPF patients with PH. In addition, pulsed DMI detected in PH IPF impaired myocardial RV early diastolic (Em) peak velocity. Also peak systolic RV strain was reduced in basal and middle RV lateral free walls in IPF, as well as RV GLS (P < 0.0001). The impairment in RV wall strain was more evident when comparing controls with the no PH group than comparing the no PH group with the PH group. By multivariate analysis, independent association of RV strain with both six-minute walking test distance (P < 0.001), mPAP (P < 0.0001), as well as with forced vital capacity (FVC) % (P < 0.005) in IPF patients were observed. CONCLUSIONS: Impaired RV diastolic and systolic myocardial function were present even in IPF patients without PH, which indicates an early impact on RV function and structure in patients with IPF.

NMR metabolomic analysis of exhaled breath condensate of asthmatic patients at two different temperatures.

Exhaled breath condensate (EBC) collection is a noninvasive method to investigate lung diseases. EBC is usually collected with commercial/custom-made condensers, but the optimal condensing temperature is often unknown. As such, the physical and chemical properties of exhaled metabolites should be considered when setting the temperature, therefore requiring validation and standardization of the collecting procedure. EBC is frequently used in nuclear magnetic resonance (NMR)-based metabolomics, which unambiguously recognizes different pulmonary pathological states. Here we applied NMR-based metabolomics to asthmatic and healthy EBC samples collected with two commercial condensers operating at -27.3 and -4.8 °C. Thirty-five mild asthmatic patients and 35 healthy subjects were included in the study, while blind validation was obtained from 20 asthmatic and 20 healthy different subjects not included in the primary analysis. We initially analyzed the samples separately and assessed the within-day, between-day, and technical repeatabilities. Next, samples were interchanged, and, finally, all samples were analyzed together, disregarding the condensing temperature. Partial least-squares discriminant analysis of NMR spectra correctly classified samples, without any influence from the temperature. Input variables were either integral bucket areas (spectral bucketing) or metabolite concentrations (targeted profiling). We always obtained strong regression models (95%), with high average-quality parameters for spectral profiling (R(2) = 0.84 and Q(2) = 0.78) and targeted profiling (R(2) = 0.91 and Q(2) = 0.87). In particular, although targeted profiling clustering is better than spectral profiling, all models reproduced the relative metabolite variations responsible for class differentiation. This warrants that cross comparisons are reliable and that NMR-based metabolomics could attenuate some specific problems linked to standardization of EBC collection.

Peripheral depletion of NK cells and imbalance of the Treg/Th17 axis in idiopathic pulmonary fibrosis patients.

The immune response plays an unsettled role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), the contribution of inflammation being controversial as well. Emerging novel T cell sub-populations including regulatory T lymphocytes (Treg) and interleukin (IL)-17 secreting T helper cells (Th17) may exert antithetical actions in this scenario. Phenotype and frequency of circulating immune cell subsets were assessed by multi-parametric flow cytometry in 29 clinically stable IPF patients and 17 healthy controls. The interplay between Treg lymphocytes expressing transforming growth factor (TGF)-ß and Th17 cells was also investigated. Proportion and absolute number of natural killer (NK) cells were significantly reduced in IPF patients in comparison with controls (p<0.001). Conversely, the proportion and absolute number of CD3(+)CD4(+)CD25(high)Foxp-3(+) cells were significantly increased in IPF patients (p=0.000). As in controls, almost the totality of cells (>90%) expressed TGF-ß upon stimulation. Interestingly, the frequency of Th17 cells was significantly compromised in IPF patients (p=0.000) leading to an increased TGF-ß/IL-17 ratio (4.2±2.3 vs 0.5±0.3 in controls, p=0.000). Depletion of NK and Th17 cells along with a not compromised Treg compartment delineate the existence of an "immune profile" that argue against the recent hypothesis of IPF as an autoimmune disease. Our findings along with the imbalance of the Treg/Th17 axis more closely suggest these immune perturbations to be similar to those observed in cancer. Clinical relevance, limitations and perspectives for future research are discussed.

Real-life efficacy and safety of nintedanib in systemic sclerosis-interstitial lung disease: data from an Italian multicentre study.

INTRODUCTION: Nintedanib (NTD) has been shown to be effective in systemic sclerosis (SSc)-interstitial lung disease (ILD). Here we describe the efficacy and safety of NTD in a real-life setting. METHODS: Patients with SSc-ILD treated with NTD were retrospectively evaluated at 12 months prior to NTD introduction; at baseline and at 12 months after NTD introduction. The following parameters were recorded: SSc clinical features, NTD tolerability, pulmonary function tests and modified Rodnan skin score (mRSS). RESULTS: 90 patients with SSc-ILD (65% female, mean age 57.6±13.4 years, mean disease duration 8.8±7.6 years) were identified. The majority were positive for anti-topoisomerase I (75%) and 77 (85%) patients were on immunosuppressants. A significant decline in %predicted forced vital capacity (%pFVC) in the 12 months prior to NTD introduction was observed in 60%. At 12 months after NTD introduction, follow-up data were available for 40 (44%) patients and they showed a stabilisation in %pFVC (64±14 to 62±19, p=0.416). The percentage of patients with significant lung progression at 12 months was significantly lower compared with the previous 12 months (60% vs 17.5%, p=0.007). No significant mRSS change was observed. Gastrointestinal (GI) side effects were recorded in 35 (39%) patients. After a mean time of 3.6±3.1 months, NTD was maintained after dose adjustment in 23 (25%) patients. In nine (10%) patients, NTD was stopped after a median time of 4.5 (1-6) months. During the follow-up, four patients died. CONCLUSIONS: In a real-life clinical scenario, NTD, in combination with immunosuppressants, may stabilise lung function. GI side effects are frequent and NTD dose adjustment may be necessary to retain the drug in patients with SSc-ILD.

Exercise Stress Echocardiography of the Right Ventricle and Pulmonary Circulation.

BACKGROUND: Exercise echocardiography is used for assessment of pulmonary circulation and right ventricular function, but limits of normal and disease-specific changes remain insufficiently established. OBJECTIVES: The objective of this study was to explore the physiological vs pathologic response of the right ventricle and pulmonary circulation to exercise. METHODS: A total of 2,228 subjects were enrolled: 375 healthy controls, 40 athletes, 516 patients with cardiovascular risk factors, 17 with pulmonary arterial hypertension, 872 with connective tissue diseases without overt pulmonary hypertension, 113 with left-sided heart disease, 30 with lung disease, and 265 with chronic exposure to high altitude. All subjects underwent resting and exercise echocardiography on a semirecumbent cycle ergometer. All-cause mortality was recorded at follow-up. RESULTS: The 5th and 95th percentile of the mean pulmonary artery pressure-cardiac output relationships were 0.2 to 3.5 mm Hg.min/L in healthy subjects without cardiovascular risk factors, and were increased in all patient categories and in high altitude residents. The 5th and 95th percentile of the tricuspid annular plane systolic excursion to systolic pulmonary artery pressure ratio at rest were 0.7 to 2.0 mm/mm Hg at rest and 0.5 to 1.5 mm/mm Hg at peak exercise, and were decreased at rest and exercise in all disease categories and in high-altitude residents. An increased all-cause mortality was predicted by a resting tricuspid annular plane systolic excursion to systolic pulmonary artery pressure <0.7 mm/mm Hg and mean pulmonary artery pressure-cardiac output >5 mm Hg.min/L. CONCLUSIONS: Exercise echocardiography of the pulmonary circulation and the right ventricle discloses prognostically relevant differences between healthy subjects, athletes, high-altitude residents, and patients with various cardio-respiratory conditions. (Right Heart International NETwork During Exercise in Different Clinical Conditions; NCT03041337).

Combination of acute exacerbation of idiopathic nonspecific interstitial pneumonia and pulmonary embolism after booster anti-COVID-19 vaccination.

Coronavirus disease-2019 (COVID-19) is a systemic disorder with the lung and the vasculature being the preferred targets. Patients with interstitial lung diseases represent a category at high risk of progression in the case of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection, and as such deserve special attention. We first describe the combination of acute exacerbation and pulmonary embolism in an elderly ILD patient after booster anti-COVID-19 mRNA vaccination. Vaccines availability had significantly and safety impacted COVID-19 morbidity and mortality worldwide. Immunization against COVID-19 is indisputable but must not be separated from the awareness of potential adverse effects in fragile patients.