ESC HEART FAILURE ORIGINAL ARTICLE ESC Heart Failure 2021; 8: 4506–4516 Published online 1 November 2021 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.13660 Lung ultrasound in outpatients with heart failure: the wet-to-dry HF study Mar Domingo1 , Josep Lupón1,2,3, Nicolas Girerd4, Laura Conangla1, Marta de Antonio1,3, Pedro Moliner1, Evelyn Santiago-Vacas1, Pau Codina1, German Cediel1, Giosafat Spitaleri1, Beatriz González1, Violeta Diaz1, Carmen Rivas1, Patricia Velayos1, Julio Núñez3,5,6 and Antoni Bayes-Genís1,2,3* 1 Heart Failure Clinic, Cardiology Service, Germans Trias i Pujol Hospital, Carretera del Canyet s/n, Barcelona, 08916, Spain; 2Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain; 3CIBERCV, Instituto de Salud Carlos III, Madrid, Spain; 4Centre d’Investigations Cliniques Plurithématique 1433, INSERM DCAC, CHRU de Nancy, F-CRIN INI-CRCT, Université de Lorraine, Vandoeuvre-lès-Nancy, France; 5Cardiology Department, Hospital Clínico Universitario, INCLIVA, València, Spain; 6 Department of Medicine, Universitat de València, València, Spain Abstract Aims In ambulatory patients with chronic heart failure (HF), congestion and decongestion assessment may be challenging. The aim of this study is to assess the value of lung ultrasound (LUS) in outpatients with HF in characterizing decompensation and recompensation, and in outcomes prediction. Methods and results Heart failure outpatients attended to establish HF decompensation were included. LUS was blindly performed at baseline (LUS1) and at clinical recompensation (LUS2). B-lines were counted in eight scanned areas. Diagnosis of no HF decompensation vs. right-sided, left-sided, or global HF decompensation, and patients’ management were performed by physicians blinded to LUS1. Outcome was the composite of all-cause death or HF-related hospitalization. Two hundred and thirty-three suspicions of HF decompensation were included in 187 patients (71.4 ± 11.3 years, 66.8% men). Mean B-line (LUS1) was 17.6 ± 11.2 vs. 3.7 ± 4.5 for episodes with and without HF decompensation, respectively (P < 0.001). Global HF decompensation showed the highest number of B-lines (20.6 ± 11), followed by left-sided (19.7 ± 11.6) and right-sided (13.5 ± 9.8). B-lines declined to 6.9 ± 6.7 (LUS2) (P < 0.001 vs. LUS1) after treatment, within a mean time of 24.2 ± 23.7 days [median 13.5 days (interquartile range 6–40)]. B-lines were significantly associated with the composite endpoint at 30 days (hazard ratio [HR] 1.04 [95% confidence interval 1.01–1.07], P = 0.02), but not at 60 (P = 0.22) or 180 days (P = 0.54). In multivariable analysis, B-line number remained as an independent predictor of the composite endpoint at 30 days, [HR 1.04 (1.01–1.07), P = 0.014], with a 4% increase risk per B-line added. B-lines correlated significantly with CA125 (R = 0.30, P = 0.001). Conclusions Lung ultrasound supports the diagnostic work-up of congestion and decongestion in chronic HF outpatients and identifies patients at high risk of short-term events. Keywords Heart failure; Lung ultrasound; Pulmonary congestion; Prognosis Received: 5 April 2021; Revised: 26 August 2021; Accepted: 27 September 2021 *Correspondence to: Antoni Bayes-Genis, Heart Failure Clinic, Cardiology Service, Germans Trias i Pujol Hospital, Carretera del Canyet s/n, 08916 Badalona, Spain. Tel: +34 934978915; Fax: +34 934978939. Email: abayesgenis@gmail.com Introduction based only in clinical assessment and can be reliant on physicians’ skills. In outpatients with chronic heart failure (HF), an unplanned Clinical anamnesis and physical examination are hospitalization is one of the strongest predictors of cornerstones of congestion evaluation, but both have several increased mortality.1 Early detection of systemic congestion limitations, showing high specificity but low sensitivity.2,3 In is key to improving patients’ management, because it this context, several decompensation risk scores to rule out allows adjusting outpatient diuretic treatment and congestion have been developed to improve patient’s fluid therefore avoid hospital admissions, but it might be difficult status evaluation; however, they have built-in subjective, © 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Lung ultrasound in outpatients with heart failure 4507 highly variable measures that may not be applicable at initial fraction (LVEF) < 40%, irrespective of aetiology. Less than stages and which diagnostic performance is at most interme- 5% of patients are admitted to the HF unit for asymptomatic diate. Therefore, diagnosing HF is a challenge, especially reduced LVEF after acute myocardial infarction. Since 2001, when based on clinical examination, as considerable diagnos- all patients have been seen regularly during follow-up ac- tic uncertainty may remain. Even in the absence of clinical cording to a set schedule and their clinical needs [REGI-UNIC findings of congestion, patients with HF may have elevated register (PI-18-037)]. Structured follow-up includes left ventricular filling pressures, and decompensation may quarterly nurse visits and one visit from a physician not be timely recognized; on the other hand, symptoms such (cardiologist, internist, or family physician) every 6 months; as fatigue, dizziness, or shortness of breath may appear in a transthoracic Doppler-echocardiogram is performed scenarios other than HF. routinely by scheduled protocol at 1 year and every 2 years Complementary tests in addition to clinical evaluation can thereafter, and as many times as needed according to the improve the diagnosis approach of patients with congestion, clinical situation by experienced echocardiographers with a but not always are available in the outpatient setting (natri- Philips iE33 system using a 3.5 MHz bandwidth sector uretic peptides & echocardiography) or have limited accuracy transducer. For clinical needs, patients can contact the clinic (chest radiography). spontaneously for an unscheduled visit in case of suspected Beyond clinical acumen, lung ultrasound (LUS) appears to HF decompensation and be reassessed as many times as be a reliable tool for the evaluation of interstitial necessary. The clinic has the infrastructure for short-term syndromes including lung congestion detection and diuretic and other intravenous drug administration. quantification, where the number and distribution of For this study, we included consecutive patients older than B-lines indicate the amount of extravascular fluid in the 18 years evaluated due to suspicion of HF decompensation lung.4 B-lines are a sonographic artefact caused by the from 11 July 2016 to 31 July 2017. Exclusion criteria for the interaction between air and water in the interstitial space.5 analysis were previous diagnosis of pulmonary fibrosis, lung Therefore, LUS may be an alternative method of lung fluid cancer, congenital lung or heart disease, dialysis, or previous retention assessment, even in asymptomatic or mildly major thoracic surgery. We also excluded patients with subclinical patients where lung congestion signs may go radiological pachypleuritis by checking the annual chest unnoticed. Advantages of LUS include bedside availability x-ray performed in our scheduled follow-up protocol. The and feasibility, as its performance takes less than 15 min study was performed in accordance with the Guidelines of in experienced hands. the Helsinki Declaration. Lung ultrasound is already widely used in acute HF diagno- sis and prognosis in the emergency setting,6,7 reaching a sen- sitivity and specificity as high as 0.88 and 0.90, respectively8; Data collection nevertheless, its value has not been described well in outpa- tients with suspected HF decompensation. The wet-to-dry HF Visits were performed by physicians of the HF clinic (MdA, study aimed to characterize LUS in the entire process of am- PM, ES-V, JS, & PC), blinded to LUS results and biomarker bulatory HF decompensation management, including initial values. Clinical evaluation included decompensation evaluation, pulmonary congestion changes, and predictive assessment, using the HF clinical disease severity score value for HF hospitalizations. We hypothesized that LUS, per- (CDSS),11,12 with a decompensated patient defined as having formed during the visit, would add value to the diagnosis, a score ≥ 2. Each of the major criteria counts for 1 point monitoring, and prognosis of congestion in outpatients with (paroxysmal nocturnal dyspnoea, pulmonary crackles, established HF. elevated jugular venous pressure, & third heart sound); each of the minor criteria counts for 0.5 point (orthopnoea, reduced exercise tolerance, resting sinus tachycardia, jugular venous pressure > 4 cm, hepatomegaly, & peripheral Methods oedema). Demographic and clinical data were recorded from the computerized medical record review by one of the Study design and patients researchers (MD). As a part of the study, peripheral venous blood samples This is a prospective single-centre observational cohort were obtained for a biomarker panel performance. study of ambulatory patients examined at a specific HF clinic N-terminal pro-brain natriuretic peptide (NT-proBNP) was that they visited due to suspicion of HF decompensation. measured using Cobas Elecsys kits (Roche Diagnostics), Criteria for referral to the HF unit have been reported cancer antigen 125 (CA125) by use of an Architect CA 125 II elsewhere9,10; briefly, the main criterion is having HF assay (Abbott Diagnostic) and soluble ST2 (sST2) by use of a according to the ESC definition, with at least one human soluble neprilysin/CD10 ELISA kit (Aviscera hospitalization and/or reduced left ventricular ejection Bioscience). ESC Heart Failure 2021; 8: 4506–4516 DOI: 10.1002/ehf2.13660 4508 M. Domingo et al. Lung ultrasound assessment Follow-up Lung ultrasound examination was performed in situ with a Final diagnosis by the physician in charge of the initial clinical pocket portable device (V-scan handheld single-probe device, evaluation included four categories (no HF decompensation, General Electric) by one of the two experienced investigators right-sided HF decompensation, left-sided HF decompensa- (MD& LC), blinded to clinical and visit data. Eight areas, tion, and global HF decompensation), according to the established by a previous expert panel13 and validated HF guidelines of the European Society of Cardiology17 against other approach in an emergency setting, were exam- [left-sided: orthopnoea, paroxysmal nocturnal dyspnoea, ined (two upper and two lower areas of each hemithorax); pulmonary rales (bilateral), peripheral oedema (bilateral); patients were examined while in a semi-supine position dur- right-sided: jugular venous dilatation, peripheral oedema ing the exam (Figure 1). LUS was performed using a (bilateral), congested hepatomegaly, hepatojugular reflux, phased-array transducer, perpendicular to the ribs, with an ascites, symptoms of gut congestion]; global HF decompen- imaging depth of 14 cm, and 2 s clip videos were recorded. sation included symptoms/signs of both left and right HF. LUS images were analysed offline by one of the two trained As LUS data were blinded to treating physicians, comple- investigators (MD & LC), who recorded the number of B-lines mentary test for diagnostic purposes (blood test, chest x- in the sagittal scan of every thoracic area. A B-line was de- ray, and other explorations) and management of HF decom- fined as a discrete laser-like vertical hyperechoic reverbera- pensation was based on the routine workup. Patients with- tion artefact that arises from the pleural line, extends to out HF decompensation were no longer followed for study the bottom of the screen without fading, and moves synchro- purposes; those with diagnosed HF decompensation were nously with lung sliding.13 Pleural effusion was considered visited for clinical assessment, and intravenous treatment equivalent to 10 B-lines. The sum of B-lines across the eight if needed, as many times as necessary. lung zones was used for the main analyses, as previous stud- Blinded LUS follow-up included a first thoracic scan ies have done in HF cohorts.14,15 A simplified 4-lung-zones at the initial visit (Wet-LUS1), and a second study protocol (an upper anterior and a lower lateral area of each (Dry-LUS2) at the time the patient was considered hemithorax) was also performed in a sensitivity analysis16 clinically recompensated. For prognostic purposes, the pri- (Figure 1). mary endpoints were the composite of all-cause death Figure 1 The eight thoracic areas scanned in the wet-to-dry HF study (upper panel): lung areas 1, 4, 5, and 8 (green border) were used for the sim- plified 4-lung-zones protocol; examples of LUS scans showing decreasing lung congestion (lower panel). LUS, lung ultrasound. ESC Heart Failure 2021; 8: 4506–4516 DOI: 10.1002/ehf2.13660 Lung ultrasound in outpatients with heart failure 4509 or HF-related hospitalization at 1, 2, and 6 months. Table 1 Demographic and clinical characteristics of the 187 patients at first decompensation All patients completed 6 months of follow-up or until death. Total, N = 187 N Age 71.4 ± 11.3 187 Male sex, n (%) 125 (66.8) 187 Data analysis and statistics White 183 (97.9) 187 Aetiology 187 Ischaemic heart disease 83 (44.4) Each episode of suspected or confirmed HF decompensation Dilated CM 32 (17.1) was treated as an individual independent data point in the Hypertensive 17 (9.1) Alcohol CM 6 (3.2) analyses, although some of them occurred in the same pa- a Drug-induced CM 5 (2.7) tient. Categorical values are described as absolute numbers Valvular 19 (10.2) (percentages) and continuous variables as means (standard Hypertrophic CM 6 (3.2) Other 19 (10.2) deviation) or medians (interquartile ranges), depending on HF duration (months) 61.0 (26.9–127.5) 187 whether data distribution was normal or non-normal as NYHA class, n (%) 187 assessed by normal Q–Q plots. All episodes of suspicion of I–II 67 (35.8) III–IV 120 (64.2) HF decompensation were included, even if they occurred in CDSS score 1.75 ± 1.04 187 the same patient, for the B-lines group analyses. In contrast, LVEF (%) 42.5 ± 14.3 187 only HF-decompensation episodes were used for the progno- COPD, n (%) 37 (19.8) 187 Hypertension 134 (71.7) 187 sis analysis. Differences in clinical variables among groups Diabetes 102 (54.5) 187 were assessed by χ 2 test, t-test, Mann Whitney U-test, and Atrial fibrillation/flutter, n (%) 78 (41.7) 187 b means comparison (ANOVA) with Scheffe post-hoc analysis, Anaemia 109 (58.3) 182 c Renal insufficiency , n (%) 125 (66.8) 187 as appropriate. Differences in B-lines [per lung area (LA) and 2 BMI (kg/m ) 29.2 ± 6.2 181 total sum] between episodes with and without the diagnosis Systolic pressure (mm) 122.8 ± 20.2 187 of HF decompensation were assessed by mean comparisons Heart rate (bpm) 75.4 ± 15.7 187 Urea (mg/dL) 69 (52–105) 187 for independent data (t-test). Differences in B-lines (per LA Na (mEq/L) 137.8 ± 3.2 186 and total sum) among episodes of the three different catego- K (mEq/L) 4.3 ± 0.5 185 ries of HF were assessed by means comparison (ANOVA) with NT-proBNP (ng/L) 6,792 ± 8,478 183 sST2 (ng/mL) 75.4 ± 56.2 135 Scheffe post-hoc analysis. Differences between LUS1 and CA125 (U/mL) 61.1 ± 81.3 123 LUS2 were assessed by paired t-test. Correlation between Treatments 187 the total B-lines sum and biomarker concentrations was ACEI or ARB 132 (70.6) Sacubitril/Valsartan 33 (17.6) assessed using Pearson correlation. Univariable Cox regres- Beta-blockers 165 (88.2) sion analyses were performed using the composite endpoint MRA 112 (59.9) as the dependent variable and the total sum of B-lines as Loop diuretics 157 (84.0) Digoxin 34 (18.2) the independent variable. In a second step, multivariable Ivabradine 28 (15.0) Cox regression analysis (backward stepwise conditional) was CRT 27 (14.4) performed for the composite endpoint at 30 days, adding ICD 39 (20.9) age, sex, New York Heart Association (NYHA) functional class, ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II LVEF, and NT-proBNP at the decompensation visit as covari- receptor blocker; BMI, body mass index; CA125, cancer antigen 125; CDSS, HF clinical disease severity score; CM, cardiomyopathy; ates given their clinical relevance. In a sensitivity analysis, this COPD, chronic obstructive pulmonary disease; CRT, cardiac multivariable Cox regression was performed by patients and resynchronization therapy; ICD, implantable cardiac defibrillator; not by episodes (only the last episode per patient). HF, heart failure; LVEF, left ventricular ejection fraction; MRA, min- eralocorticoid receptor antagonist; NT-proBNP, N-terminal pro- brain natriuretic peptide; NYHA, New York Heart Association; sST2, soluble interleukin-1 receptor-like 1. Data in mean ± SD, median (Q1–Q3), or n (%). Results a Chemotherapy agents. Haemoglobin < 120 g/L in women and <130 g/L in men. b Estimated glomerular filtration rate (Chronic Kidney Disease Epide- c Baseline demographics miology Collaboration equation) < 60 mL/min per 1.73 m . 2 Two hundred and thirty-three suspected independent decom- pensations in 187 patients were prospectively evaluated (152 hort was 71 years; patients were predominantly male and of patients with one, 27 with two, 5 with three, and 3 with four ischemic aetiology, and they were mainly in NYHA functional episodes of suspicion of HF) (Supporting Information, class III. Last previous LVEF was 42.5% ± 14.3 (the first LVEF Figure S1). Table 1 shows demographic and clinical character- at first clinic visit of the studied cohort was 34% ± 12.7). Pa- istics of the 187 patients at the first episode of suspicion of HF tients were treated according to international guidelines and decompensation. In summary, the mean age of the total co- more than 75% received loop diuretics. ESC Heart Failure 2021; 8: 4506–4516 DOI: 10.1002/ehf2.13660 4510 M. Domingo et al. Mean CDSS of the cohort was 1.75 ± 1.04 points, being in- LUS1 data as well as biomarker profiles of the 233 episodes, trinsically higher in the independent data points classified as according to the final HF diagnosis. Episodes without HF de- a HF decompensation (2.15 ± 0.97) (Table 2). Lung basal compensation had significantly lower total B-line counts crackles, orthopnoea, paroxysmal nocturnal dyspnoea, and (3.7 ± 4.5) than the 176 with HF decompensation jugular ingurgitation were unusual in those episodes without (17.6 ± 11.2) (P < 0.001). Independent data points with the final diagnosis of HF decompensation (Table 2). right-sided decompensation had significantly lower B-lines Acute respiratory infection (19.3%) and anaemia/iron defi- count than left-sided and global HF-decompensation ciency (8.8%) were the most frequent diagnosis in the epi- (13.49 ± 9.81 vs. 19.67 ± 11.58, P = 0.01 and 20.64 ± 11.09, sodes considered non-HF decompensation (N = 57). In 27 P = 0.001 respectively, Table S1). episodes (47.4%), the cause of symptoms was not found, Regarding LA sites, the number of B-lines was significantly and one patient was diagnosed with pulmonary embolism. higher in all LA in episodes with decompensated HF (Table 3). Tiredness (38.6%) and dyspnoea (31.6%), followed by oedema Lower areas, especially lateral zones (LA4 and LA8), were and cough, were the most frequent symptoms in this group. those with the highest number of B-lines (P < 0.001 for both LA4 and LA8 vs. all the other LA; P = 0.61 between LA4 and LA8). This was specifically observed in episodes with the diag- Lung ultrasound association with clinical data nosis of HF decompensation (again P < 0.001 for both LA4 and LA8 vs. all the other LA; P = 0.93 between LA4 and The mean number of B-lines in LUS1 assessment of all the HF LA8). Table S2 shows the number of B-lines by LA according suspicion episodes was 14.2 ± 11.6. Table 2 shows clinical and to the type of HF decompensation. Table 2 Clinical characteristics of patients in 233 episodes studied for possible decompensation No HF diagnosis, N = 57 HF diagnosis, N = 176 P value CDSS score 0.68 ± 0.51 2.15 ± 0.97 0.001 NYHA class III–IV, n (%) 24 (42.1) 129 (73.3) <0.001 Systolic BP (mmHg) 121.7 ± 19.1 122 ± 20 0.92 Heart rate (bpm) 70 ± 12.6 77.0 ± 16.32 0.004 Urea (mg/dL) 55 (43.5–80) 77 (55–122) <0.001 2 eGFR (mL/min/1.73 m ) 59 ± 27.9 44.2 ± 22.4 <0.001 Haemoglobin (g/dL) 12.9 ± 2.1 11.7 ± 1.9 <0.001 Na (mEq/L) 137.6 ± 3.1 137.8 ± 3.3 0.69 K (mEq/L) 4.4 ± 0.5 4.2 ± 0.5 0.04 a NT-proBNP (ng/L) 3145 ± 6425 8388 ± 8775 <0.001 b sST2 (ng/mL) 46 ± 41.4 86.7 ± 53.9 <0.001 c CA125 (U/mL) 15 (10–21.5) 38 (18–38) <0.001 Clinical findings Crackles 1 (1.8) 62 (35.2%) <0.001 Jugular venous distention 4 (7.0) 70 (39.8%) <0.001 Orthopnoea 1 (1.8) 49 (27.8%) <0.001 Paroxysmal nocturnal dyspnoea 1 (1.8) 28 (15.9%) 0.003 ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CA125, cancer antigen 125; CDSS, HF clinical disease severity score; eGFR, estimated glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration equation); LUS, lung ultra- sound; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; sST2, soluble Interleukin-1 receptor-like 1. Data in mean ± SD, median (Q1–Q3), or n (%). N = 225. a N = 171. b N = 159. c Table 3 Total LUS1 data by lung areas and based on the diagnosis of HF decompensation Total suspicions of decompensation, N = 233 No HF diagnosis, N = 57 HF diagnosis, N = 176 P value LA1 1.36 ± 2.02 0.33 ± 1.14 1.70 ± 2.13 <0.001 LA2 1.64 ± 2.07 0.39 ± 0.68 2.05 ± 2.20 <0.001 LA3 1.48 ± 2.21 0.47 ± 1.43 1.81 ± 2.32 <0.001 LA4 2.94 ± 3.26 0.89 ± 1.54 3.60 ± 3.39 <0.001 LA5 1.15 ± 1.53 0.25 ± 0.85 1.44 ± 1.59 <0.001 LA6 0.75 ± 1.20 0.11 ± 0.31 0.96 ± 1.30 <0.001 LA7 1.73 ± 1.92 0.40 ± 0.80 2.15 ± 1.99 <0.001 LA8 3.09 ± 3.14 0.86 ± 1.91 3.81 ± 3.13 <0.001 Total B-lines sum 14.2 ± 11.6 3.7 ± 4.5 17.6 ± 11.2 <0.001 LA, lung area. ESC Heart Failure 2021; 8: 4506–4516 DOI: 10.1002/ehf2.13660 Lung ultrasound in outpatients with heart failure 4511 In HF decompensation episodes, the mean number of Lung ultrasound and outcomes in HF B-lines moderately correlated with CDSS (R = 0.31, decompensation episodes P < 0.001) and NYHA functional class at the moment of the visit (P for trend = 0.01), and inversely with LVEF During the 6 months of follow-up, 66 primary composite end- (R = 0.29, P < 0.001). In contrast, we did not found a corre- points were recorded in 61 decompensation episodes (53 lation with age (R = 0.05, P = 0.54), sex (men 17.4 ± 11.0 vs. HF-related hospitalizations—4 patients had 2 hospitaliza- women 17.9 ± 11.6, P = 0.76), or the presence of atrial fibril- tions—and 26 deaths). Twenty-seven composite endpoints lation/flutter (present 18.9 ± 9 vs. absent 17.3 ± 11.2, occurred during the first month (23 HF hospitalizations in P = 0.78). 23 patients and 7 deaths) and 41 during the first 2 months Relative to biomarkers, NT-proBNP was available in 171 (35 HF hospitalizations in 35 patients and 10 deaths). In the out of the 176 episodes of HF decompensation, sST2 was Cox regression analyses, total B-line sum was significantly as- available in 125, and CA125 in 113. The highest correlation sociated with the composite endpoint at 30 days (Table 5), of B-line count was found with CA 125 (R = 0.30, P = 0.001), but not at 60 days [HR 1.02 (95% CI 0.99–1.04), P = 0.22] followed by NT-proBNP (R = 0.21, P = 0.006), and finally nor at 6 months [HR 1.01 (95% CI 0.99–1.03), P = 0.54]. sST2 (R = 0.22, P = 0.02). Figure 2 shows event-free survival curves up to 30 days based Of the 176 HF decompensation episodes, a second LUS at on the B-line sum, comparing first quartile (0–8 B-lines) vs. the time of recompensation (LUS2) was available in 110, quartiles second to fourth (≥9 B-lines). In the multivariable within a mean time of 24.2 ± 23.7 days [median 13.5 days (in- analysis including age, sex, NYHA functional class, LVEF, and terquartile range 6–40)] (Figure S1). Interestingly, when pa- NT-proBNP, the total B-line sum remained statistically tients were considered clinically compensated in every significantly associated with the composite endpoint at independent data point (LUS2), the total sum of B-lines de- 30 days, carrying an increase of 4% in risk per every creased from 17.3 ± 11.0 to 6.9 ± 6.7 (P < 0.001). This signif- additional B-line [HR 1.04 (1.00–1.07), P < 0.05], together icant decrease in B-lines occurred in all LA (all P < 0.001) with NYHA functional class (Table 5). Of note, NT-proBNP (Table 4). Remarkably, the number of residual B-lines in those was neutrally associated with outcome. recompensated episodes (dry) was still significantly higher Short-term prognostic value of B-lines sum was quite than that observed in the initially considered homogeneous among several subgroups based on non-decompensated (6.9 ± 6.7 vs. 3.7 ± 4.5, P = 0.002). demographic and clinical data (Figure 3). In the sensitivity analysis performed by patients and not by episodes (only last episode per patient), B-lines sum remained significantly associated with the composite endpoint at 30 days (Table 6). Figure S2 shows event-free Table 4 LUS1 (wet) and LUS2 (dry) data of the 110 episodes diagnosed as HF decompensation with LUS2 study available survival curves up to 30 days based on the B-line sum, comparing first quartile vs. quartiles second to fourth based Wet (LUS1) Dry (LUS2) P value on patients and not on episodes (only last episode per Total B-lines sum 17.3 ± 11.0 6.9 ± 6.6 <0001 patient). LA1 1.7 ± 2.0 0.4 ± 0.9 <0.001 LA2 1.9 ± 2.0 0.0 ± 1.5 <0.001 LA3 1.7 ± 2.1 0.7 ± 1.5 <0.001 LA4 3.5 ± 3.30 1.8 ± 2.8 <0.001 Sensitivity analysis of simplified 4-area lung LA5 1.5 ± 1.6 0.5 ± 1.0 <0.001 LA6 1.0 ± 1.3 0.3 ± 0.6 <0.001 ultrasound protocol LA7 2.2 ± 2.0 0.7 ± 1.0 <0.001 LA8 3.8 ± 3.1 1.6 ± 2.2 <0.001 Independent episodes with a clinical final diagnosis of HF de- LA, lung area. compensation had significantly more B-lines than those with- Table 5 Cox regression analyses for the primary composite endpoint at 30 days by decompensation HF episodes Univariable Multivariable HR 95% CI P value HR 95% CI P value Total B-lines sum 1.04 1.01–1.07 0.021 1.04 1.01–1.07 0.014 Age 0.98 0.95–1.02 0.35 — — — Female sex 0.60 0.20–1.73 0.34 — — — NYHA class 2.48 1.09–5.7 0.031 — — — LVEF 1.00 0.98–1.03 0.91 — — — a NT-proBNP 1.00 1.00–1.00 0.57 — — — LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association. a Per 100 ng/L. ESC Heart Failure 2021; 8: 4506–4516 DOI: 10.1002/ehf2.13660 4512 M. Domingo et al. Figure 2 Event-free survival at 30 days for the composite endpoint of all-cause death or HF hospitalization, based on B-lines sum quartiles [Q1 (≤8) vs. Q2–Q4 (9–52)]. Figure 3 Forest plots for B-lines sum for the composite endpoint of all-cause death or HF hospitalization at 30 days according to several subgroups. Circles represent hazard ratio values, while the horizontal lines through the circles illustrate the length of the confidence interval. out (10.5 ± 7.1 vs. 2.3 ± 3.2, P < 0.001) in the 4-zone proto- and right-sided (8.5 ± 6.8); significant differences were only col. Global HF decompensation showed the highest number found between right-sided and global HF decompensation of B-lines (12.8 ± 7.5), followed by left-sided (10.6 ± 6.2) (P = 0.002). ESC Heart Failure 2021; 8: 4506–4516 DOI: 10.1002/ehf2.13660 Lung ultrasound in outpatients with heart failure 4513 Table 6 Cox regression analyses for the primary composite endpoint at 30 days by patient (last HF episode, N = 145) Univariable Multivariable HR 95% CI P value HR 95% CI P value Total B-lines sum 1.04 1.01–1.07 0.025 1.04 1.01–1.08 0.017 Age 0.98 0.94–1.02 0.26 — — — Female sex 0.58 0.20–1.68 0.31 — — — NYHA class 2.44 1.04–5.70 0.04 — — — LVEF 1.01 0.98–1.03 0.71 — — — a NT-proBNP 1.00 1.00–1.00 0.85 — — — CI, confidence interval; HR, hazard ratio; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association. a Per 100 ng/L. In the sensitivity multivariable analysis, the B-line sum did also be useful in the initial evaluation in this setting, al- not remain statistically significantly associated with the com- though 8-zone protocol has been found to be superior in posite endpoint at 30 days [HR 1.06 (1.00–1.12), P = 0.07], al- other studies.20 Although all LA can be affected by pulmo- though a 6% increase in risk per additional B-line was found. nary congestion, the lower zones are classically the first to exhibit extravascular fluid in all profiles of patients with HF.21 As expected, data from our study also show that the highest number of B-lines is found in lower lateral Discussion areas (LA4 and LA8). Lung ultrasound has been widely evaluated in acute dys- Previous data from our group and from other studies pnoea settings, especially in the emergency room and critical performed in stable patients have demonstrated that care wards, showing more diagnostic accuracy for HF than subclinical pulmonary congestion is common in patients with chest radiography or NT-proBNP.18 Nevertheless, few studies chronic HF,22,23 even in the absence of symptoms and clinical have addressed its value in chronic HF ambulatory patients to findings. Therefore, it is not surprising that, in this study, refine (less obvious and less acute) decompensated HF episodes without a clinical final diagnosis of HF diagnosis. In our cohort of HF outpatients with mostly decompensation showed 3.7 ± 4.5 B-lines on LUS, quite mild-to-moderate systolic dysfunction, our results show that comparable with the sum of B-lines we found in HF stable (i) LUS is a useful tool in the diagnosis of HF decompensation patients.22 As expected, episodes classified as having left or and allows the monitoring of pulmonary congestion during global HF decompensation had higher numbers of B-lines, follow-up; (ii) pulmonary congestion by LUS is present in all even taking into consideration the fact that pleural effusion, HF clinical subtypes (i.e. right-sided/left-sided HF) but more which can also be observed in right HF decompensation, importantly so in left-sided and global HF; (iii) LUS accounted for 10 B-lines. significantly predicts short-term outcomes in ambulatory Furthermore, LUS is a reliable tool for monitoring pulmo- patients with decompensated HF whereas NT-proBNP did nary fluid overload changes during outpatient follow-up, be- not; and (iv) the number of B-lines correlates with known cause the B-line profile varies according to the timing of congestion biomarkers (Figure S3). assessment. In this context, we also performed a second LUS to evaluate residual pulmonary congestion after clinical improvement. In our cohort, B-lines decreased significantly Lung ultrasound findings from 17.26 ± 11.0 to 6.85 ± 6.66, the latter number being very similar to that we have previously reported in stable patients This single-centre study shows that in situ LUS can aid the (5.1 ± 6.1),22 but still significantly higher than that in the diagnostic workup of acute congestion in patients with episodes considered as non-decompensation. That fact established HF, becoming a key element in the initial probably reflects that some pulmonary congestion still re- evaluation, because the number of B-lines increases in mains despite the observed clinical improvement. This result the episodes with confirmed HF decompensation, similarly suggests that LUS could be useful for clinicians in tailoring HF to what is reported in other smaller studies.19 Specifically, diuretic therapy during decompensation; in fact, LUS-guided episodes with HF decompensation have a significantly and treatment has been reported to be effective in both chronic markedly higher total count of B-lines (17.6 ± 11.23) than and acute HF post discharge,24,25 because LUS examination those without congestion in our cohort (3.7 ± 4.5). might be more sensitive in detecting congestion than clinical Similarly, in the 4-zone protocol, episodes with a final evaluation in several HF scenarios.16,21,22,26 clinical diagnosis of HF decompensation also had Other technologies are arising for early HF decompensa- significantly more B-lines than those without (10.5 ± 7.1 tion evaluation in outpatients such as impedance measure- vs. 2.3 ± 3.2), suggesting that this simplified protocol could ment, home telemonitoring, and wearable technology and ESC Heart Failure 2021; 8: 4506–4516 DOI: 10.1002/ehf2.13660 4514 M. Domingo et al. devices that measure pulmonary artery or left atrial pressure and cardiac biomarkers other than CA125 in HF patients, wirelessly. Integrating LUS with some of these tools could be- as we have previous reported.36 come a novel approach that have to be investigated. Lung ultrasound prognosis Limitations This was a single-centre study with patients treated at a Assessing pulmonary congestion accurately is critical to pro- specific multidisciplinary HF clinic at a day-hospital in a viding the optimal approach to hospitalized HF patients, be- tertiary-care hospital. Most of our patients had high risk cause the number of B-lines at admission and discharge of unfavourable outcomes because they were referred after predicts short-term outcomes.27–31 Our data further show at least one hospital admission and partially recovered that B-lines assessment in an ambulatory setting also strongly LVEF. We cannot disregard selection bias by disease sever- predicted outcomes; specifically, each B-line added increased ity and management. Each episode of suspected or by 4% the composite endpoint of all-cause death or confirmed HF decompensation was treated as an individual HF-related hospitalization at 30 days. Furthermore, the sum independent data point in the analyses, although some of of B-lines across all LA, together with NYHA functional class, them occurred in the same patient. This should be taken remained as an independent prognostic factor in the multi- into account when analysing our results as they can be in- variable analysis, outperforming natriuretic peptides. Re- fluenced by the existence co-dependence in some variables. markably, patients with ≤8 B-lines (quartile 1) showed The number of B-lines may be impacted by the clip significantly less events at 30 days. This added prognostic duration37; in our study, due to the characteristics of the value was proved only in short-term follow-up, different from device, we recorded 2 s video clips that may have under- what has been observed in acute or stable chronic HF pa- represented the number of B-lines; However, such record- tients. We speculate that it may be due to various reasons. ing strategy is likely to be the one used in routine First, our clinic provides a structured follow-up, including un- proactice. Finally, we did not perform other emerging types scheduled visits. Similar to our results, Rivas-Lasarte et al.,25 of point-of-care ultrasound for assessing venous congestion, with a specified high intensity intervention, did not find sig- such as the Venous Excess Ultrasound Score protocol.38 nificant differences in HF hospitalizations during a 6 month follow-up. Second, we treated decompensated HF episodes with ambulatory IV diuretics within the first 30 days, thus de- creasing the likelihood of HF admissions (and association with Conclusions HF admissions) for longer follow-ups. Because a previous study by Platz et al.16 reported that, in Our data show that LUS is a valuable tool to identify HF patients hospitalized for acute HF, a 4-zone LUS is highly cor- decompensation in chronic HF outpatients. B-lines count related for prognostic purposes with the 8-zone LUS, we also identifies clinical profile of congestion (right-sided, left- evaluated this protocol in our cohort. However, our data sided, or global) and appears to precisely assess pulmonary show that in ambulatory decompensations, the B-line count congestion changes during follow-up. B-line count added was not significantly associated with short-term outcomes prognostic information regarding short-term outcomes in when using this simplified protocol. ambulatory patients with confirmed HF decompensation. CA125 showed the best correlation between the B-line count and several biomarkers. Lung ultrasound and biomarkers In our study, CA125 showed the best correlation between the number of B-lines and established cardiac biomarkers. Conflict of interest CA125 is a glycoprotein synthesized by epithelial serosal N.G. reports honoraria from AstraZeneca, Bayer, Boehringer, cells at sites such as the pericardium, pleura, and perito- Novartis, and Vifor. The rest of the authors have no conflict neum, with proved usefulness for fluid overload assessment of interest regarding the present study. in patients with acute HF.32 Moreover, as a risk stratifica- tion tool, serum CA125 levels have been associated with poor outcomes, and have even been used to guide diuretic treatment.33 Although LUS and CA125 are both congestion Funding and short-term prognostic markers,34,35 there is little evi- dence of their association in acute and chronic HF. Our This research was supported by Fundació La Marató de TV3 finding supports hypothesized correlations between B-lines (PI 201510.10). The Nancy team is supported by the RHU ESC Heart Failure 2021; 8: 4506–4516 DOI: 10.1002/ehf2.13660 Lung ultrasound in outpatients with heart failure 4515 Fight-HF, a public grant overseen by the French National Re- Supporting information search Agency (ANR) as part of the second ‘Investissements d’Avenir’ programme (reference: ANR-15-RHUS-0004), by Additional supporting information may be found online in the the French PIA project ‘Lorraine Université d’Excellence’ (ref- Supporting Information section at the end of the article. erence: ANR-15-IDEX-04-LUE), the ANR FOCUS-MR (refer- ence: ANR-15-CE14-0032-01), ERA-CVD EXPERT (reference: Figure S1. Study flow-chart. ANR-16-ECVD-0002-02), the Contrat de Plan Etat Lorraine Figure S2. Event-free survival at 30 days for the composite IT2MP, and FEDER Lorraine. end-point of all-cause death or HF hospitalization, comparing quartiles (Q1 [≤8] vs. Q2-Q4 [9–52]) based on patients and not on episodes (only last episode per patient). Figure S3. Summary of the study. LUS protocol performed in Consent to participate patients with HF decompensation suspicion (left panel) al- lows to confirm HF diagnosis, classify HF type and assess All participants provided written informed consent. recopensation. B-lines sum significantly difer according to HF situation (right-upper panel) and showed short-term prog- nostic value (right-lower panel). Table S1. Clinical characteristics of patients in the 176 diag- Consent for publication nosed HF decompensations based on type of HF Table S2. LUS1 (Wet) data by lung areas based on the type of the local ethical committee and all participants gave their HF decompensation written consent to publish the study. References 1. Huusko J, Tuominen S, Studer R, Corda meta-analysis. JAMA Netw Open 2019; 11. Troughton RW, Frampton CM, Yandle S, Proudfoot C, Lassenius M, Ukkonen 2: e190703. TG, Espiner EA, Nicholls MG, Richards H. Recurrent hospitalizations are 7. Platz E, Merz AA, Jhund PS, Vazir A, AM. 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