The contemporary management of early-stage Hodgkin lymphoma (ES-HL) involves balancing the risk of late adverse effects of radiotherapy against the increased risk of relapse if radiotherapy is omitted. This study provides information on the risk of radiation-related cardiovascular disease to help personalize the delivery of radiotherapy in ES-HL.We predicted 30-year absolute cardiovascular risk from chemotherapy and involved field radiotherapy in patients who were positron emission tomography (PET)–negative following three cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy within a UK randomized trial of PET-directed therapy for ES-HL. Cardiac and carotid radiation doses and chemotherapy exposure were combined with established dose-response relationships and population-based mortality and incidence rates.Average mean heart dose was 4.0 Gy (range 0.1-24.0 Gy) and average bilateral common carotid artery dose was 21.5 Gy (range 0.6-38.1 Gy), based on individualized cardiovascular dosimetry for 144 PET-negative patients receiving involved field radiotherapy. The average predicted 30-year radiation-related absolute excess overall cardiovascular mortality was 0.56% , whereas average predicted 30-year excess incidence was 6.24% . For cardiac disease, the average predicted 30-year radiation-related absolute excess mortality was 0.42%  and for stroke, it was 0.14%.Predicted excess cardiovascular risk is small for most patients, so radiotherapy may provide net benefit. However, for a minority of patients receiving high doses of radiation to cardiovascular structures, it may be preferable to consider advanced radiotherapy techniques to reduce doses or to omit radiotherapy and accept the increased relapse risk. Individual assessment of cardiovascular and other risks before treatment would allow personalized decision making about radiotherapy in ES-HL. In the past, extended-field radiotherapy and higher radiation doses provided good disease control but incurred substantial risks of second cancers and cardiovascular disease (CVD).3 More recently, randomized controlled trials (RCTs) have combined clinical risk factors and positron emission tomography (PET)—a radiologic biomarker of response—to identify patients for whom initial treatment can be less intensive, hopefully reducing long-term toxicity without compromising cure.6Over recent decades, the standard management of early-stage Hodgkin lymphoma (ES-HL) has been combined modality treatment including chemotherapy and radiotherapy. For favorable ES-HL, this is currently two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy and 20 Gy involved field radiotherapy (IFRT), giving excellent 5-year survival .Key ObjectiveTo predict 30-year absolute excess risks of radiation-related cardiovascular disease for positron emission tomography–negative patients given radiotherapy in the UK RAPID trial of early-stage Hodgkin lymphoma using novel methodology that combines individual radiation dosimetry and epidemiologic data.Knowledge GeneratedMean heart dose was < 1 Gy for more than half the patients and < 5 Gy for more than two thirds, whereas mean bilateral common carotid dose was 21 Gy. If radiotherapy were given selectively to the 50% of patients with the lowest predicted risks, then their average predicted 30-year absolute excess risks of radiation-related cardiovascular disease would be 0.11% for mortality and 1.79% for incidence.RelevanceFor the majority of positron emission tomography–negative patients in the RAPID trial, the predicted cardiovascular risks are small. These risks should be even lower with the most modern radiotherapy techniques. The decision to give radiotherapy for early-stage Hodgkin lymphoma should be patient-specific, based on individualized risk predictions of dose to critical structures and of all the late effects of these exposures.7 1-2 were randomly assigned either to no further treatment (NFT) or to IFRT. Considering all randomly assigned patients, 3-year progression-free survival (PFS) did not differ between the two groups . However, considering only the patients who received their allocated treatment, the benefit of radiotherapy was significant .5 Further evidence for radiotherapy benefit was reported for the EORTC/LYSA/FIL H10 and GHSG H16 Trials.6 While PFS is appropriate for assessing the efficacy of Hodgkin lymphoma (HL) treatment over 3-5 years, an overall assessment of the effect of radiotherapy needs to take late toxicity into account, balancing a proven improvement in initial disease control versus radiotherapy toxicities that may occur beyond 5-10 years and compromise long-term health and survival.2The UK National Cancer Research Institute Lymphoma Study Group RAPID trial was an RCT in ES-HL designed to test the omission of radiotherapy following a complete metabolic response on fluorodeoxyglucose-PET scans after three cycles of ABVD. Patients achieving Deauville score8 While cardiac doses are lower with IFRT than extended-field radiotherapy,10 no detailed description of doses received by individual cardiac substructures with IFRT has been published, nor have any predictions been made of the resulting cardiovascular risks for an RCT cohort.Among HL survivors, cardiac death was, historically, the leading cause of mortality associated with radiotherapy exposure of a single organ.The aim of this study is to quantify the cardiovascular radiation doses received by ES-HL patients given IFRT within a recent RCT and to use them to predict the absolute risk of radiation-related CVD. Greater understanding of these risks would improve a personalized approach to the contemporary use of radiotherapy.Six hundred two patients were enrolled into the trial during 2003-2010 . Five hundred seventy-one received three cycles of ABVD followed by fluorodeoxyglucose-PET. Among PET-negative individuals , 209 were randomly assigned to IFRT and 183 received it. Among PET-positive individuals , 129 received IFRT .11 The dose specified was 30 Gy in 1.8-2.0 Gy fractions, treated in the supine position, by opposed anterior and posterior 5-8 MV beams, both delivered daily.IFRT comprised treating the extent of disease detected by computed tomography (CT) before chemotherapy. There was no intention to treat uninvolved contiguous nodal areas, or entire nodal regions. The recommended field-edge margins were 5 cm up-and-down involved nodal chains with 1.5-2.0 cm lateral margins around the postchemotherapy volume of disease within the mediastinum.Radiotherapy departments supplied details of the IFRT administered to the National Radiotherapy Trials Quality Assurance team. Where CT planning was used (72%), the original data sets were requested. If the CT did not cover the entire heart, regression was used to estimate the volume missing to calculate heart dose and to estimate doses to cardiac substructures. Where x-ray simulation was used (28%), copies of films were requested and substitute CTs were used to estimate dosimetry. Further details are in the Data Supplement. Treatment data collection and subsequent analysis were approved by the appropriate Research Ethics Committee.14 and stroke15 following HL treatment, combined with 5-year age- and sex-specific death rates from CVD in the general UK population. Deaths from all causes other than CVD in the general population were competing risks. The 30-year risk of incident CVD was estimated in a similar fashion, using age- and sex-specific first CVD incidence rates from a representative UK cohort16 (details are in the Data Supplement).Predictions of 30-year cardiovascular mortality were based on individual radiation doses to the whole heart, left ventricle, heart valves, and common carotid arteries, and the administered anthracycline dose. They were derived using the estimated percentage increases in mortality rate per unit dose obtained from long-term studies of cardiac diseaseOf the 183 PET-negative patients who received IFRT, data sufficient to complete dosimetry were available for 144 . Of the 129 PET-positive patients who received IFRT, data sufficient to complete dosimetry were available for 103 (79.8%). The baseline characteristics of patients for whom dosimetry was and was not completed were similar (Data Supplement).For PET-negative patients, the average MHD was 4.0 Gy: 0.3 Gy for those without and 7.8 Gy for those with mediastinal involvement Table . For almThe average predicted 30-year cardiovascular mortality risk for PET-negative patients who received IFRT after ABVD was 5.02% , and comprised 3.52% expected risk from general population rates plus 0.94% absolute excess risk because of anthracycline chemotherapy and a further 0.56% because of IFRT  because of a higher proportion with mediastinal involvement (59% v 41%) and, on average, a lower inferior border to the mediastinal radiation field . Consequently, the predicted proportional increase in mortality from heart disease was on average higher for females. However, as men have higher cardiac mortality rates in the general population, the estimated 30-year absolute excess mortality risk from treatment-related heart disease (chemotherapy and radiotherapy combined) was actually lower for females .When the PET-negative patients were subdivided into five categories of MHD, the average predicted 30-year absolute excess risk of radiation-related mortality from heart disease ranged from 0.03% for those receiving < 0.5 Gy MHD to 2.20% for those receiving 10+ Gy . This comprised 22.9% expected risk from general population rates plus 6.7% absolute excess risk because of anthracycline chemotherapy and a further 6.2% because of IFRT Fig A. The abWhen individuals were grouped into five categories of MHD, the average predicted 30-year absolute excess risk of developing radiation-related heart disease ranged from 0.21% for those receiving < 0.5 Gy MHD to 16.33% for those receiving 10+ Gy Fig C. For inWhen individuals were grouped into four categories of mean bilateral carotid artery dose, the predicted 30-year absolute excess risk of incident stroke ranged from 0.66% in those receiving < 10 Gy to 3.42% in those receiving ≥ 30 Gy , and comparison of baseline characteristics suggests that this sample is representative of the entire cohort. The study includes patients from 42 radiotherapy centers across the United Kingdom . It is therefore a representative sample of UK practice at the time.A strength of this study is the number of individuals  for whom dosimetry was completed, which is considerably greater than in the largest previous study reporting cardiac doses from IFRT (n = 41).28 Second, the method used to predict radiation-related CVD has not been prospectively validated, as 20 additional years of follow-up would be required to assess the accuracy of the predictions. Our method is, however, based on the best available epidemiologic evidence regarding the magnitude of the long-term risks of radiation and anthracycline chemotherapy in HL survivors, together with current mortality and incidence rates in the general population. Third, we cannot provide separate risks for patients with pre-existing cardiovascular risk factors such as smoking and diabetes. In the future, adjustments to the model could use individual data on cardiovascular risk factors, but such information was not available for this study. Fourth, we did not attempt to model the possible impact of HL relapse in a small proportion of patients or the cardiotoxicity of subsequent treatments, so it is likely that we are underestimating the net benefit of initial radiotherapy. Finally, although we used the dose metrics from the best epidemiologic evidence currently available15 as the basis for our methods, we recognize the ongoing uncertainty over the radiation dose metric that may best predict the risks of radiation-related cardiac disease and stroke.30There are, however, some limitations to this study. First, not all dosimetry was based on individual anatomy, as substitute CT data sets and data interpolation were used to calculate doses for a minority of patients (28%). This is unlikely to affect the average cardiovascular doses and predicted risks substantially, as demonstrated in a recent study.31) may also help to identify patients who would benefit most from combined modality treatment.The challenge of a personalized approach in ES-HL is to balance the risk of late adverse effects from radiotherapy against the omission of radiotherapy, which in turn increases risk of relapse and necessitates further therapy, perhaps including autologous stem-cell transplantation. If, rather than giving radiotherapy to all patients (or to none) regardless of their individual risk of late effects, radiotherapy were given just to patients predicted to be at lower risk of radiation-related CVD, then a substantial proportion of the benefit in terms of recurrence reduction would remain while fewer radiation-related cardiovascular complications would occur. For example, if the 50% of PET-negative patients at lowest risk of cardiovascular complications received radiotherapy, around 50% of the recurrences that would occur by withholding radiotherapy would be prevented, but only one fifth of the excess cardiovascular mortality from irradiating the whole cohort would be incurred (0.11%, Figs 32 the use of deep-inspiration breath-hold techniques,33 optimized intensity-modulated radiotherapy,34 and proton beam therapy,18 have reduced irradiated volumes and radiation doses to normal tissues, especially when combined with a 20 Gy prescribed dose for favorable ES-HL.35 Radiation-related CVD is not the only late side effect that may be reduced by the omission of radiotherapy. Risks of second cancers and other radiation-related late toxicities such as xerostomia and hypothyroidism, which would also be reduced by a chemotherapy-only approach, are also likely to be lower with contemporary radiotherapy, but a comprehensive assessment of late toxicities goes beyond the scope of this study. Consideration of all the important toxicities of alternative treatment strategies including the toxicity of treating possible HL relapse would likely suggest that an optimal approach will involve irradiating those ES-HL patients who are at lower risk of RT-related toxicity, rather than a strategy advising radiotherapy for all or none, based only on PET response.It should be noted that developments in radiotherapy techniques since the RAPID trial, including smaller target volumes,35 would result in even lower predicted risks than those seen for the RAPID cohort. As the sites of disease and degree of mediastinal involvement are known at diagnosis, the radiation doses to cardiovascular organs, and hence the risk of radiation-related CVD, can be estimated when the initial treatment strategy is decided. Such an approach could identify high-risk patients who, because of their predicted radiation-related cardiovascular risk, should be considered for treatment with chemotherapy alone as well as for novel radiation techniques, such as deep-inspiration breath-hold techniques and proton beam therapy, that can minimize cardiac exposure.33 As knowledge increases, a personalized assessment including all relevant risks would be helpful in determining the optimal strategy for individual patients.In conclusion, IFRT for ES-HL as given in RAPID is likely to produce a small increase in the long-term risk of CVD. However, the magnitude of the risk varies widely and, for a majority of patients, the benefit of reduced HL relapse substantially outweighs the risk of CVD. With more modern radiotherapy techniques, the cardiovascular radiation doses achieved


Although promising results have been reported for Magnetic Resonance image-guided High-Intensity Focused Ultrasound (MR-HIFU) treatment of uterine fibroids, this treatment is not yet widely implemented in clinical practice. During the implementation of a new technology, lessons are learned and an institutional learning-curve often has to be completed. The primary aim of our prospective cohort study was to characterize our learning-curve based on our clinical outcomes. Secondary aims included identifying our lessons learned during implementation of MR-HIFU on a technical, patient selection, patient counseling, medical specialists and organizational level.Our first seventy patients showed significant symptom reduction and improvement of quality of life at 3, 6 and 12 months after MR-HIFU treatment compared to baseline. After the first 25 cases, a clear plateau phase was reached in terms of failed treatments. The median non-perfused volume percentage of these first 25 treatments was 44.6% (range: 0–99.7), compared to a median of 74.7% (range: 0–120.6) for the subsequent treatments.Our findings describe the learning-curve during the implementation of MR-HIFU and include straightforward suggestions to shorten learning-curves for future users. Moreover, the lessons we learned on technique, patient selection, patient counseling, medical specialists and organization, together with the provided supplements, may be of benefit to other institutions aiming to implement MR-HIFU treatment of uterine fibroids.Trial registration ISRCTN14634593. Registered January 12, 2021—Retrospectively registered, https://www.isrctn.com/ISRCTN14634593.The online version contains supplementary material available at 10.1186/s13244-021-01128-w. Our learning-curve flattened after 25 uterine fibroid MR-HIFU treatments.A completed institutional learning-curve is a requirement for MR-HIFU adoption.Implementation barriers include technique, patient selection, patient counseling, specialists and organization.Early involvement of all relevant parties is essential for adequate implementation.Uterine fibroids are benign tumors and clinically apparent in 25% of women during their reproductive age. They cause symptoms such as heavy menstrual bleeding, abdominal pain or pressure and subfertility . In receClinical and technical aspects of the MR-HIFU treatment have already been reported in detail , 8, 9. LWe designed a single-arm prospective cohort study . This study consisted of two parts; both parts were approved by our medical ethical board and participants needed to sign informed consent before participating. The implementation of the MR-HIFU treatment described in this article concerns participants of the second part, the MaSSII study.In the first part  we aimed to get an overview of the uterine fibroid tissue type distribution using multiparametric magnetic resonance imaging (MRI) parameters  likely to cause the clinical symptoms and no calcified fibroids. The Funaki classification, which classifies fibroids into Funaki type 1, 2 or 3 fibroids based on signal intensity on T2-weighted MRI images, was also used as a screening tool  was to explore whether biomarkers found by the multiparametric MaSSI MRI scan could predict MR-HIFU treatment outcome. Women participating in the MaSSI study between June 2016 and January 2019 and eligible for MR-HIFU, were offered the MR-HIFU treatment option. Inclusion criteria were women with uterine fibroid-related symptoms, aged between 18 and 59 years and pre- or perimenopausal status. Women were excluded when post-menopausal, pregnant, not willing or able to sign informed consent, had a wish to conceive, a BMI > 40 kg/mWhen women were considered eligible for MR-HIFU treatment and willing to participate, they were screened at the anesthesiology department and received information about the conscious sedation during the MR-HIFU procedure. The evening before the treatment, women had to shave their lower abdomen and had to fast overnight. In the morning at admission to day care, women received a bladder catheter, an enema, an intravenous line and pre-medication  was administered to assess the NPV%.After the procedure, patients stayed at day care for a few hours. Before discharge, the radiologist visited the patient to check for vital parameters, adverse events like (radiating) pain and possible signs of skin burn of the abdomen. If no irregularities were found, patients could leave the hospital the same day. Follow-up by the gynecologist was planned one week after treatment, and 3 and 6 months post-treatment at the outpatient clinic  were collected in a standardized form, and an MRI report was added to the electronic patient file  by our medical ethical board, manually electronic patient file search was performed to screen for possible reinterventions and pregnancy outcomes of all included patients. Second MR-HIFU treatments for different fibroids were not considered as reinterventions, nor were (re)start of medication or an intra-uterine device. Women were requested not to fill out the follow-up UFS-QoL questionnaire after a reintervention.During MaSSII inclusions, all failed treatments were logged and analyses to determine the most probable cause of failure took place immediately by the involved treatment team. When solutions were available, they were directly implemented in upcoming treatments and date of implementation was recorded. After finishing MaSSII inclusions, all causes of treatment failure were categorized and their occurrence in time, revealed an expected learning-curve per type of failure. We then evaluated our expected learning-curve by comparing reached NPV%, symptom and QoL improvement and reintervention rates between those women treated during and those women treated after completing our learning-curve.While implementing MR-HIFU in our hospital, different process steps were taken Table  19]. Th. Th19]. Statistical analyses were performed using IBM SPSS version 26. Categorical data were presented as numbers and percentages. Continuous variables were presented as mean (SD ±) in case of normal distribution or median (range) in case of skewed distribution. Distribution was assessed by the Shapiro–Wilk test and complemented by plots.U test. A p value of < 0.05 was considered significant. Multiple testing correction was performed using the Holm–Bonferroni method. To estimate confounding by loss-to-follow-up, we compared NPV% between patients who completed the questionnaires during follow-up and patients who were lost to follow-up.Differences between symptom severity , QoL , NPV% and fibroid volume at baseline/directly post-treatment and follow-up were tested by means of the Wilcoxon signed rank test. Differences between age, BMI, fibroid diameter, tSSS, tHRQL, NPV% and fibroid volume of women that were treated during the learning-curve phase and women that were treated after this phase were assessed by the Mann–Whitney In total 168 women were included in the MaSSI study. Seventy women (41.7%) with 102 fibroids were treated as part of the MaSSII study. Demographic characteristics and fibroid characteristics are described in Table p = 0.13). tSSS was significantly reduced at all follow-up points when compared to baseline, tHRQL score was significantly increased compared to baseline . A total of nineteen women (27.1%) needed a reintervention. One woman needed two reinterventions. The median NPV% post-treatment of women that underwent a reintervention was 4.5% (range: 0–98.3). Fifteen of twenty reinterventions (75%) took place in the first 12 months and nineteen of twenty reinterventions (95%) in the first 24 months after the initial MR-HIFU treatment.A total of 25% (19/76) of the treatments could be classified as treatment failures due to different reasons , and the NPV% immediately post-treatment was significantly lower . The percentage of women with a reintervention after the first 25 treatments was 45.5%, compared to 18.8% after the remaining treatments  is increasingly used during uncomfortable radiological interventions and is also suitable for the MR-HIFU treatment of fibroids , 23. SedThe six remaining failures during treatment, in which the fibroid could not be adequately heated, occurred when we extended our inclusion criteria. In retrospect, we had become overconfident after being able to manage the previous described treatment failures, and started including fibroid types not suitable for MR-HIFU treatment.When analyzing all failures in time, it became clear that most treatment failures occurred within the first 25 treatments and therefore we considered this our learning-curve. Earlier studies reported the existence of a learning-curve during implementation of the MR-HIFU treatment of uterine fibroids , 25. OkaWhen our initial inclusion and exclusion criteria were applied to the women participating in our MaSSI study, 47.6% (80/168) of women would have been eligible for MR-HIFU treatment. We found that the risk on failure was particularly high in case of deep sonications (10–12 cm from skin to fibroid) and/or a thick abdominal fat layer (3–4 cm) in combination with high signal intensity on the T2-weighted MRI scan (Funaki 2 or 3). When this combination of factors is present, restraints should be exercised in the decision to treat this patient.As we gained experience, we adjusted our inclusion and exclusion criteria to increase eligibility, particularly fibroids classified as Funaki 3 fibroids. We experienced that several Funaki 3 fibroids could successfully be treated, although including high signal intensity fibroids also led to treatment failures. Therefore at this point, we are reluctant to include Funaki 3 fibroids.Initially, we intended to treat only women with one fibroid. However, if more than one but less than five fibroids seemed to cause symptoms, more fibroids were treated from June 2017 (after 22 treatments) onward. In October 2017 (after 26 treatments) we implemented our new manipulation protocol , and froIn 26% (18/70) of patients, an adverse event on treatment day occurred Table  and in 4Counseling of patients about the different fibroid treatment options, including MR-HIFU, was performed by the gynecologist. However, since MR-HIFU is performed by radiologists, additional counseling by radiologists is recommended for those patients who opt for MR-HIFU. At the beginning of our study, we experienced very high expectations of the effect of MR-HIFU, particularly concerning the time women could expect improvement. Later, more emphasis was put on realistic expectations and the timeline.In order to successfully implement MR-HIFU treatment of uterine fibroids, collaboration between radiologists and gynecologists is essential . Since MSince the MR-HIFU treatment was performed by the radiologist and the follow-up was handled by the gynecologist, clear agreements needed to be made on who had which responsibilities at what stage with regard to the patient. We decided in our institution that the radiologist was responsible during treatment and the following 24 h, the gynecologist was responsible from 24 h after treatment onward.Implementation of a new treatment can be challenging, and publications on process evaluation or implementation strategy are scarce in general . We appoBefore we started with the implementation of MR-HIFU, we could not find formats such as template reports of screening MRI scans, multidisciplinary meetings and Standard Operating Procedure (SOP’s). We expected that these documents would reduce logistic barriers, would improve efficiency and effectiveness and would facilitate implementation. Since the radiology department did not have a nursing ward, nurses needed to be trained to take care of our MR-HIFU patients at the gynecology department. A standardized nursing protocol was implemented in June 2017. Additionally, we implemented preparations at the gynecology ward, such as the blather catheter, pre-medication and IV-line to increase efficiency and save valuable MRI time. All these procedures were described in an SOP that included counseling, screening, treatment and follow-up to improve the efficiency of all different stages of the MR-HIFU treatment  from the start of implementation of this new technique, in order to facilitate dissemination and further adoption after proven (cost)effectiveness .MR-HIFU itself and the implementation of this multidisciplinary uterine fibroid treatment are complex, especially with the current lack of standard guidelines, and this might discourage new sites to start offering this non-invasive treatment option. In this article we reported all lessons learned, while we implemented the MR-HIFU treatment of uterine fibroids in our hospital and we provided straightforward ready-to-use protocols on how to perform sedation, suggestions for MRI examination and SOP’s on logistics in our supplements. On different levels of implementation, Table The primary goal of our MaSS study, and this article, was not to evaluate all clinical outcomes in detail. Therefore, multiple limitations can be reported concerning the clinical outcome data collection. A high lost-to-follow-up number was seen, partly due to reinterventions, which might have led to an overestimation of clinical symptom and QoL improvement, although outcomes are in line with current literature. Baseline characteristics of our first 25 patients differed from the remaining patients, probably leading to favorable and unfavorable situations, and the follow-up duration varies between the first 25 and the subsequent group, although follow-up was at least one year and most reinterventions of the learning-curve took place within the first year. Moreover, the use of oral contraceptives or intra-uterine devices after MR-HIFU treatment could have interfered with symptom improvement. Nevertheless, we believe this does not curtail the usefulness of our lessons learned.Since the improvement of our counseling, screening and treatment protocols took place continuously during inclusion , identifying which of them contributed to the change in clinical outcome is challenging. The cutoff point used for the analysis of our clinical outcomes was somewhat arbitrary. However, despite we broadened eligibility and included more complicated cases, after completing our learning-curve, failure rate decreased and relevant outcomes like NPV% and reintervention rate improved.We used an adjusted process evaluation model when retrospectively evaluating our implementation process. For future analyses we recommend to prospectively evaluate the implementation processes, since this ease the process and can be used for quality improvements .Some hurdles still have to be overcome in order to reach complete adoption of the MR-HIFU treatment of uterine fibroids. When it comes to clinical outcomes, improvement can be reached by further optimizing screening. On a technical level, tools to sonicate fibroids with high signal intensity and techniques to measure NPV% during treatment are necessary to further increase eligibility and shorten treatment time. Randomized controlled trials comparing long-term (cost)effectiveness of MR-HIFU with standard fibroid care, from both clinical and societal perspective, are needed.In this article we identified our learning-curve by analyzing our clinical results, and we presented the implementation of uterine fibroid MR-HIFU treatment in our non-academic teaching hospital. Our lessons learned on a technical, patient selection, patient counseling, medical specialists and organizational level, are described in detail, and the provided supplements are likely to be of benefit to other hospitals willing to commence with offering MR-HIFU as novel treatment option to women with symptomatic uterine fibroids.Additional file 1. Supplement 1: MRI protocol. Supplement 2: Standard Operating Procedure (SOP). Supplement 3: Sedation protocol.


Control of the COVID-19 pandemic has been impeded by the slow global uptake of targeted vaccines, emergence of more transmissible variants, and resistance to continuation of nonpharmaceutical interventions. Commonly used vaccines can have nonspecific immune effects, and several have been shown to have beneficial heterologous effects against SARS-CoV-2 infection. However, there is no science-based guidance on effective implementation of such heterologous vaccine interventions (HVIs) to counter the current or future pandemics. We modeled the effect of different HVI strategies on the winter 2020 COVID-19 wave in the United States, finding that targeting both elderly and nonelderly populations and intervening during pandemic growth phases  led to the greatest reduction in morbidity and mortality. Bacillus Calmette–Guérin, inactivated influenza vaccine, oral polio vaccine, and other vaccines have been associated with some protection from SARS-CoV-2 infection and amelioration of COVID-19 disease. If heterologous vaccine interventions (HVIs) are to be seriously considered by policy makers as bridging or boosting interventions in pandemic settings to augment nonpharmaceutical interventions and specific vaccination efforts, evidence is needed to determine their optimal implementation. Using the COVID-19 International Modeling Consortium mathematical model, we show that logistically realistic HVIs with low (5 to 15%) effectiveness could have reduced COVID-19 cases, hospitalization, and mortality in the United States fall/winter 2020 wave. Similar to other mass drug administration campaigns , HVI impact is highly dependent on both age targeting and intervention timing in relation to incidence, with maximal benefit accruing from implementation across the widest age cohort when the pandemic reproduction number is >1.0. Optimal HVI logistics therefore differ from optimal rollout parameters for specific COVID-19 immunizations. These results may be generalizable beyond COVID-19 and the US to indicate how even minimally effective heterologous immunization campaigns could reduce the burden of future viral pandemics.COVID-19 remains a stark health threat worldwide, in part because of minimal levels of targeted vaccination outside high-income countries and highly transmissible variants causing infection in vaccinated individuals. Decades of theoretical and experimental data suggest that nonspecific effects of non–COVID-19 vaccines may help bolster population immunological resilience to new pathogens. These routine vaccinations can stimulate heterologous cross-protective effects, which modulate nontargeted infections. For example, immunization with  On March 16th, 2020, Imperial College London released a landmark report advocating the suppression of SARS-CoV-2 to avoid a pandemic catastrophe . In the The rollout of specific COVID-19 vaccines in 2021 led to a temporary reduction of pandemic caseloads in countries with effective vaccine campaigns and ample stocks, but even this has not proven to be the sought-for panacea for epidemiological, logistical, and political reasons. The emergence of virus variants—now dominated by the Omicron and Delta strains—that are more transmissible and pathogenic have reversed many gains achieved to date and have raised questions about the durability of current vaccine efficacy . AlthougOne as-yet unutilized intervention to potentially prevent SARS-CoV-2 infection and reduce COVID-19 disease is based upon heterologous or nonspecific effects (NSEs) induced by available non–SARS-CoV-2 vaccines . The het815Bacillus Calmette–Guérin (BCG) vaccine , measles-containing vaccines (MCVs), and several other common immunizations. OPV has been associated with beneficial NSE , 36–38 a3639Hemophilus influenza type-B, measles mumps rubella (MMR), varicella, hepatitis A/B, pneumococcal conjugate, and inactivated influenza vaccines are associated with decreased SARS-CoV-2 infection rates , an open-source, age-structured, country-specific, dynamic compartmental model of SARS-CoV-2 transmission and COVID-19 illness, treatment, and mortality, to illustrate how the logistics of implementing a heterologous vaccine intervention (HVI)—in particular, the timing of initiation of such a vaccination campaign in relation to trends in disease incidence and also the age-related population targeting of such a campaign—largely determine the magnitude of their impact. In particular, we instituted an explicitly defined HVI in one of three distinct time frames during the large fall/winter wave of SARS-CoV-2 in the United States  and across the same total number of individuals in one of three distinct age-targeted population groups .We used the COVID-19 International Modeling (CoMo) Consortium Model , or as a solitary “bridging” intervention to reduce or delay COVID-19-related morbidity and mortality until a specific vaccine is available. Here, we explore the last use: that of a solo heterologous vaccination used as a temporizing “bridging” intervention that has only a low level of heterologous effectiveness at reducing viral transmission  and clinical severity . Given the high levels of targeted vaccination now attained in many high-income countries, our results with respect to the prevaccinated US outbreak should be seen as general, model-informed operational guidance that could maximize the beneficial effect of efforts to use common vaccination programs to mitigate and temporize the impact of COVID-19, and possibly future viral pandemics, in the majority of countries worldwide that have not yet received sufficient quantities of COVID-19–specific vaccines to ensure population protection.Through March 7th, 2021, there were 29,034,160 reported SARS-CoV-2 infections and 524,652 COVID-19 deaths in the US. From March 17th, 2020 (when reporting started), through March 7th, 2021, the US saw an average of 56,405 daily COVID-19 non-intensive care unit (ICU) hospitalizations. *Materials and Methods). In contrast, later interventions lead to a larger reduction in both reported and unreported cases, with the greatest effect seen in interventions targeting the broadest targeted age group (20+ y old) starting in December and January  that target three different age-defined populations  at different timepoints in during the US Fall 2020 COVID-19 wave led to different simulated epidemiological and clinical outcomes A–D. Acro January B. Simila January C, signal January . This reCumulative A–F and dThese effects are further illustrated in SI Appendix, Experimental Parameters and Baseline Results; full model outputs for the baseline and December 1st, 2020, HVI campaign targeting 20+ y olds is available at https://github.com/ocelhay/como.https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html), we find that targeting HVI campaigns to both elderly and nonelderly populations  and initiating those campaigns during pandemic growth phases  leads to the greatest reduction in COVID-19 morbidity and mortality.Using the US experience of COVID-19 through Spring 2021 as a modeling “test bed,” we show that the addition of even minimally efficacious HVIs to ongoing NPIs may reduce pandemic caseloads, hospitalization, and mortality. However, our simulations reveal that the effectiveness of such heterologous interventions depends heavily on several key operational parameters, including the timing of HVI implementation in relation to pandemic disease activity and also the age targeting of the HVI campaigns. Contrary to guidance for the phased rollout of COVID-19–specific vaccines  undertaken during the upswing of this surge. Furthermore, even low-effectiveness HVIs undertaken prior to such surges (whose timing may be highly unpredictable) may delay peak hospitalizations and mortality sufficiently to give time for specific vaccination campaigns to gain traction and prevent these delayed cases from presenting. In the specific US COVID-19 scenario modeled here, such interventions delay peak mortality from early January (at which point <10 million people had received at least one dose of specific COVID-19 vaccines) to mid-February (by which time >40 million had received at least one dose), creating a “bridging intervention” that potentially could have preserved hospital capacity, saved lives, and also prevented nonhospitalized cases that risk evolution into “Long COVID,” with its attendant health risks.Our model realistically differentiates the likelihood of case finding on the basis of symptomaticity. Since younger individuals are less likely to be symptomatic when infected with SARS-CoV-2, changes in their infection status can be obscured with looking solely at reported cases. The greater decline in combined reported and unreported cases B compareOur finding of improved overall outcomes when targeting vaccination to include these younger populations, even for a disease whose prime morbidity and mortality falls on older populations, has been found in modeling-based studies of both COVID-19 and other viral illnesses such as influenza , 67. AddModel-based epidemiological studies such as ours are subject to many caveats, not least that models that are fitted to past data may not give accurate projections of future trends. To avoid predictive errors of this sort, we deliberately chose to perform retrospective “what if”-type simulations of different HVIs in a well-fitted modeling environment that could accommodate a realistic suite of NPIs in combination with experimental interventions and could recreate in silico the course of the US pandemic experience through the start of widespread specific COVID-19 vaccination. This is typically called “scenario” or “intervention modeling” as opposed to forecasting. Although this framework is amenable to modeling the use of heterologous vaccination as an adjunct or extender of such specific vaccination campaigns , there is little evidence available to parameterize such an effect. Even with the HVI modeled here, the choice of the 5 to 15% range of clinical protection and transmission reduction is admittedly based on limited and largely indirect evidence . For thiA concluding thought is that HVIs may be useful for "flattening the curve" of the current pandemic in at least two ways: by delaying and reducing peak COVID-19 transmission in the majority of low- and middle-income countries that, because of lack of vaccine availability or other factors have yet to fully mount COVID-19–specific vaccine campaigns; and by lowering infection rates and consequent hospitalizations and deaths in both minimally and highly vaccinated nations during surges of vaccine-escaping SARS-CoV-2 variants such as Omicron . Since they would be limited to the use of already fully licensed vaccines, HVIs should not carry increased risks for targeted populations beyond those of standard vaccination campaigns, and therefore may help circumvent delays and outright resistance related to concerns about the safety of novel pandemic-targeting vaccines. Because typically they would involve the use of widely used vaccines, to which a large portion of the population has been antigenically sensitized, HVIs may provide rapid immune boosting for immediate viral threats . For these reasons, we believe that HVIs should take their place alongside NPIs in the “early pandemic intervention toolkit” of public health emergency response planners, forming part of the public health armamentarium against both inevitable future pandemics and breakthrough infection risk from more transmissible or immune-escaping variants of current pathogens. In addition to their solely health-related impact, these interventions could also help to mitigate the severe social and economic effects of lockdown policies through earlier pandemic control. If increased uptake of nonspecific vaccination, alone or in combination with other routinely recommended vaccine interventions, could partially attenuate the COVID-19 pandemic, it may provide public health and political leaders with sufficient gains around which to leverage increased social and economic activity to reverse some of the devastating toll this infection has taken on daily life worldwide.https://comomodel.net) to carry out the simulations reported here. The CoMo Model, developed to support policy-related analyses of potential COVID-19 management strategies by Consortium members (https://como.bmj.com), is an open-source, spreadsheet template–based, age-structured, compartmental susceptible-exposed-infectious-recovered-susceptible model to estimate the trajectory of COVID-19 based on different scenarios and assess the potential impact of various nonpharmaceutical/behavioral change strategies as well as treatment and vaccines. Details of the modeling framework, including all NPI settings and other parameter values used in the current simulations, are available in the SI Appendix; an overview of the model structure, including all mathematical equations governing progression through clinical and health care utilization compartments, has been published elsewhere ; it can be parameterized to cases, mortality, hospitalizations, or any combination of these three for a defined region; and it can implement one or more of nine NPIs , one medical intervention (dexamethasone), and logistically realistic vaccination campaigns . Because the model is freely available on the Web and is template based, anyone can both recreate and extend the experiments reported here using the information supplied in the SI Appendix.The CoMo Model is distinguished from standard age-structured compartmental models by several attributes: It is country specific (in terms of both population structure and age-based mixing); it incorporates detailed disease severity–specific treatment compartments as well as explicit health care facility utilization based on the Cornell COVID Caseload Calculator (https://www.google.com/covid19/mobility/)], and treatment . Data on total US COVID-19 cases and mortality were obtained from the New York Times GitHub site (https://raw.githubusercontent.com/nytimes/covid-19-data/master/us.csv), and hospitalization data were obtained from The COVID Tracking Project  through March 7th, 2021.Model calibration was achieved by adjusting parameters relating to viral activity , hospitalization and mortality , six start dates (vaccination campaigns starting the first day of each month from September 2020 through February 2021), and three levels of heterologous vaccine efficacy both for reducing SARS-CoV-2 transmission and for subsequent risk of COVID-19 hospitalization and mortality if infected . Due to the brief (∼1 y) time frame of interest, there was no temporal waning of heterologous effects.https://www.cdc.gov/flu/fluvaxview/nursinghome/report1718/reporti/index.html), we anchored HVI coverage in the 65+ age cohort at 50%, representing ∼27.4 million people. To ensure that the number of individuals vaccinated in each of the three targeted populations was identical , we adjusted the vaccination campaigns to target 11% of those 20 older, 17% of those 40 and older, and 50% of those 65 and older in the US population. This eliminated the possibility of bias resulting from relatively more or fewer resultant heterologous vaccinees in the three age-targeted population cohorts. The timing of interventions coincided with typical annual influenza vaccination , which in 2020 also coincided with the presurge, intrasurge, and postsurge period of the nationwide fall/winter US COVID-19 wave.Based on reported rates of seasonal influenza vaccination coverage among the general population across US states ranging from 37.8 to 63.4%  The mean incubation period was 3.5 d, and the mean duration of the infectious period was 4.5 d, each with a range of 1 to 7 d). Mean hospital lengths of stay were modeled as 6 d for regular medical ward, 10 d for ICU stay without mechanical ventilation, and 12 d for duration of mechanical ventilation, consistent with both published literature and the US-based Epic Health Research Network (https://epicresearch.org/articles/inpatient-lengths-of-stay-and-number-of-icu-days-among-covid-19-patients-differ-from-common-model-assumptions/). Total modeled US hospital, ICU, and mechanical ventilatory capacity  was never exceeded during any simulation run. We assumed that 75% of all symptomatic and 2% of all asymptomatic SARS-CoV-2 infections would be reported, 15% of all infected individuals would develop severe enough symptoms to warrant hospitalization, 25% of hospitalized patients required ICU admission, 60% of those admitted to the ICU required mechanical ventilation, and 50% of all hospitalized patients require supplemental oxygen (see SI Appendix for details). Targeted COVID-19 vaccination commenced in the US on December 14th, 2020, and increased from that time onwards to the end of the modeled period . To account for the effect of COVID-19 vaccination, we relaxed modeled NPI controls after this point to appropriately fit mortality and hospitalizations. In this way, although COVID-19 vaccination was not explicitly modeled, its effect on population outcomes is incorporated into all results.The baseline model was calibrated to US COVID-19 case, mortality, and hospitalization data through March 7th, 2021, with inflation of predicted cases to match hospitalization and death rates prior to July 2020 when the US testing first reached sufficient coverage to achieve a national positivity rate <5% (ref. SI Appendix for complete parameterization information). The model was run from February 16th, 2020, through June 30th, 2021. Each of the 162 experimental model outputs were generated from 50 iterations for each distinct parameter and intervention set subjected to 0.01 SD “noise” to generate 95% credible intervals. Statistical analysis was performed with the R statistical package (version 3.6.3) and Microsoft Excel 2016 .The baseline model was calibrated to the data by ensuring the data falls within the 95% model credible intervals generated from 100 model iterations applying 0.03 SD Gaussian “noise” to the 24 most sensitive model parameters (see Supplementary File


Biomarkers are essential tools in the practice of cardiology. They assist with diagnosis, prognosis, and guiding therapy in many different cardiovascular diseases. Numerous biomarkers have become strongly associated with different cardiovascular conditions, such as troponin with acute coronary syndrome and natriuretic peptides with heart failure. Even though these biomarkers have been in practice for almost two decades, their uses continue to expand beyond their original roles. Additionally, many new biomarkers have been discovered with increasing utility in cardiovascular disease, including soluble suppression of tumorigenicity 2, galectin 3, and biomarkers of fibrosis, metabolism, and inflammation. How these old and new biomarkers are being expanded into clinical practice is constantly in evolution. This review will highlight some of the recent major advancements in the rapidly evolving field of biomarkers. Recently, there has been a surge of studies reporting potential uses of biomarkers, both new and old. Thus, it is important for clinicians to remain up to date on the evolving uses of different biomarkers. Although many advances with biomarkers have been made throughout cardiology, such as in valvular heart disease and atrial fibrillation, this review will focus on recent advances in HF, acute coronary syndrome (ACS), and prevention. A common theme in these conditions is the substantial prognostic utility of both natriuretic peptides (NPs), BNP and its N-terminal fragment (NT-proBNP), and high-sensitivity cardiac troponin (hs-cTn). Additionally, the biomarkers soluble suppression of tumorigenicity 2 (sST2) and galectin 3  are emerging with different roles in many cardiovascular conditions. Lastly, there have been many novel biomarkers for diagnosis and prognosis or to supplement current biomarkers in these areas of cardiology.Biomarkers have become a backbone of risk prediction, diagnosis, and therapeutic monitoring throughout cardiology. Ever since the publication of the Breathing Not Properly trial that established B-type natriuretic peptide (BNP) as a crucial biomarker in the management of heart failure (HF), a variety of biomarkers have found increasing use in cardiology2. The development of hs-cTn brought a new era to the diagnosis and risk stratification of patients with ACS, coronary artery disease (CAD), or other conditions. In a patient presenting with chest pain or symptoms concerning for cardiac ischemia and possible non-ST elevation (NSTE)-ACS, troponin is critical for determining the presence of myocardial infarction (MI). Although hs-cTn was rapidly adopted, questions were raised about its optimal use in NSTE-ACS. Fortunately, recent studies have reaffirmed prior findings and assured the safety of its current implementation in clinical practice. Additionally, other biomarkers have been explored in ACS that can improve the risk stratification of patients with ACS for future events.One of the most impactful biomarker advancements in the past decade has been the development of hs-cTn. Troponin is a complex with three subunits in myocytes and is involved in contraction and relaxation. Two isoforms (T and I) in cardiomyocytes are cardiac-specific and this has been exploited clinically to help identify cardiomyocyte injury with greater specificity than prior biomarkers like CK-MB. Further refinement in clinical assays has improved the sensitivity of troponin detection, and the newest generation of hs-cTn assays are able to detect troponin in at least 50% of healthy individuals; ideally, the goal is to detect troponin in more than 95% of healthy individuals3. In 2020, these guidelines were updated to include important advances for using hs-cTn in the field of NSTE-ACS4. These include the incorporation of 0/2h-algorithms and recognition of vendor-specific assay cut-offs for the different hs-cTnI assay used for ruling in and ruling out acute MI  of more than 99.5% and patients who were ruled out for MI had very low rates of death and major adverse cardiovascular events (death and MI) at 30 days 6. It is worth noting that the positive predictive value of the 0/1-h algorithm was only fair, but the power of the algorithm lies in its ability to rapidly and safely rule out an MI usually within 3 hours of presentation.In 2015, the European Society of Cardiology (ESC) adopted a rapid rule-out algorithm  using either hs-cTnI or hs-cTnT assessed at presentation and 1 hour later for patients presenting with suspected NSTE-ACSacute MI 4. InitiaSTAT assay had an NPV of 99.5% for excluding an MI and there were no cardiac deaths at 30 days in this population, further validating the rapid rule out of the 0/1-h algorithm7. Similarly, a multi-center cohort study in the US examined outcomes of patients on the basis of their initial hs-cTnI measurement using the Siemens Atellica IM and ADVIA Centaur assays and found that a level of less than 5 ng/L had a high NPV for NSTE-ACS and low risk for death8. Importantly, the authors also found that a cut-off of hs-cTnI of at least 120 ng/L identified patients who are at high risk for adverse cardiac events and who should strongly be considered for treatment of ACS on the basis of this single troponin measurement8. Recognizing the variability in assays by vendor and cut-offs proposed in prior algorithms, Neumann et al. went beyond prior studies and evaluated patient outcomes based on different cut-offs and time frames for repeat hs-cTn measurement9. In doing this, the authors developed a nomogram for risk and the NPV based on initial measurements and follow-up values9. This chart can be readily applied in clinical practice, helping a provider determine a patient’s risk based on their institutions cut-offs and timing of hs-cTn assessment.Although these studies validated the use of the 0/1h-algorithm, other important questions about the clinical use of hs-cTn in NSTE-ACS remained. The 0/1h-algorithm allows MI to be ruled out if the first hs-cTn value is below the level of detection in a patient presenting three or more hours from symptom onset. A meta-analysis demonstrated that an hs-cTnI of less than 5 ng/L using the Abbott ARCHITECT11. An important caveat, though, is that far fewer patients with renal dysfunction will meet rule-out criteria since they are more frequently found to have an elevated troponin11. Additionally, the specificity of hs-cTn is lower in this population, as might be expected. Even though MI may not be subsequently diagnosed, clinicians should remember that patients with renal dysfunction have an increased risk for cardiovascular disease (CVD) and these studies found that patients with an elevated hs-cTn had a two-fold greater risk of major adverse cardiovascular events, highlighting the role of hs-cTn in risk stratification10.A recognized analytical confounder of hs-cTn in ACS is renal impairment. Patients with renal dysfunction frequently have elevated cTn levels even if they are not presenting with ACS. This made the use of hs-cTn assays in patients with renal dysfunction a concern. However, many studies have confirmed that a low hs-cTn and the 0/1h-algorithm are still valid in patients with renal dysfunction and can safely rule out an MI12. At least one study has shown that age-specific cut-offs can influence the diagnostic accuracy of the hs-cTnT assay, and age-specific cut-offs should be considered13. However, further studies are needed to validate these findings with the hs-cTnT assay and with the different hs-cTnI assays. In regard to sex, troponin values are typically lower in women than men and some hs-cTn manufacturers have recommended sex-specific cut-offs14. However, many studies have not shown a substantial difference in diagnostic accuracy of the hs-cTnT assay using sex-specific cut-offs16. Results with hs-cTnI assays have varied; some studies show differences in diagnostic accuracy when using sex-based cut-offs, and others show no difference17. Although the ESC Guidelines have not adopted age- or sex-specific cut-offs, this is still an area of active research; with further study, age- and sex-specific cut-offs may be incorporated into algorithms14. The key is for the clinician to recognize the influence of confounders such as age, sex, and renal dysfunction on diagnostic accuracy of hs-cTn. In total, though, these studies and others have solidified the safety and utility of hs-cTn to rule out MI. In the appropriate clinical setting, they provide reassurance that a patient can be discharged for further outpatient evaluation with a low likelihood of adverse outcomes.Although studies have confirmed the utility the use of hs-cTn in renal dysfunction, there is still debate about how to account for other confounders of hs-cTn interpretation, including age and sex. Troponin values are known to increase as an individual grows older19. Notably in one of the studies, patients with elevated NT-proBNP had more cardiovascular risk factors and more frequently had left ventricular systolic dysfunction18. Thus, this persistent elevation in NT-proBNP may be a reflection of adverse cardiac remodeling following ischemia from increased wall tension, persistent neurohormonal elevation, or potentially even other conditions known to cause an elevation in NPs like atrial fibrillation. Thus, assessment of NT-proBNP at time of ACS and in the post-ACS period may help identify high-risk patients who might benefit from more-aggressive medical therapy and surveillance. This potentially includes aggressive up-titration of medical therapies that inhibit the sympathetic nervous system (SNS) and renin–angiotensin–aldosterone system (RAAS), control of comorbidities such as diabetes mellitus and hypertension, selection of more-aggressive lipid-lowering therapies, use of more-potent antithrombotic agents, early repeat echocardiography to assess for adverse cardiac remodeling, prolonged electrocardiographic monitoring for arrhythmias, and potentially referral for advanced therapies such as cardiac transplantation. Beyond NPs, other novel biomarkers are also showing promise for risk stratification after an ACS event.As valuable as hs-cTn has become in ACS, it alone cannot fully risk-stratify a patient, and other biomarkers are showing promise in this area. The NPs have found an increasingly important prognostic role in ACS. NPs are released from the heart in the setting of increased wall stress and myocardial stretch most frequently associated with pressure or volume overload. NPs are frequently elevated with myocardial ischemia from increased myocardial stress and neurohormonal activation. Two recent studies have shown that patients with persistently elevated NT-proBNP following an ACS event have a substantially increased risk of cardiac death, MI, and urgent revascularization20. These risk estimates were in addition to the highest value of cTnT entered into a multivariable model demonstrating that Gal-3 was prognostic beyond cTn. Whether serial assessment enhances utility still needs to be determined. More recently, serial assessment of growth differentiation factor 15 (GDF-15), a stress-induced cytokine, in patients who present with ACS was shown to be associated with an increased risk of cardiac death, MI, and urgent revascularization in patients with persistently elevated levels21. In total, serial assessment of biomarkers appears to provide a powerful tool for risk stratification and potentially directing intensity of medical therapy in patients with ACS.Gal-3 is a beta-galactoside–binding lectin that is secreted by activated macrophages and reflects myocardial fibrosis and remodeling in injured myocardium. Thus, Gal-3 may add further pathophysiologic insight by reflecting cellular recruitment for repair from injury and fibrosis beyond hs-cTn which reflects cardiomyocyte injury and NPs which reflect cardiomyocyte stretch and stress. When Gal-3 was measured at the time of MI, elevated levels were associated with an increased risk of subsequent HF  and death (2.4-fold increased risk for tertile 3 compared with tertile 1)22. Other biomarkers are showing promise to improve risk stratification. NT-proBNP, Gal-3, and GDF-15 show substantial promise to further risk-stratify patients who may benefit from more-aggressive medical therapy, such as more-potent anti-platelet agents, lipid-lowering therapies, RAAS and SNS blockade, and potentially inflammation modification and surveillance. In the future, a clinician might measure Gal-3 at the time of an MI to risk-stratify patients beyond hs-cTn for risk of death and development of HF. After the ACS event, NT-proBNP and GDF-15 could be measured to further identify heightened risk for death and recurrent ACS. Whether a combination of these biomarkers could further improve risk stratification is yet to be studied, and further studies are needed to determine whether a panel of biomarkers may provide the best risk stratification of patients with ACS and which therapies to apply in high-risk patients to reduce risk of death and recurrent ACS.The field of ACS has seen many recent biomarker advancements . The uti23. Since the adoption of NPs into clinical practice in HF, HF has remained one of the major areas of continued growth and utilization of biomarkers. Recently, the field of chronic HF has seen some exciting advancements while acute HF has also had a few major developments.One of the first areas in which biomarkers made a substantial impact in cardiology was HF. This is where BNP and NT-proBNP first demonstrated their utility for assisting with diagnosing HF, specifically with high sensitivities to exclude a diagnosis of HF. These prior findings resulted in a class I recommendation in the American College of Cardiology/American Heart Association (ACC/AHA) Heart Failure Guidelines for measuring BNP or NT-proBNP in any patient presenting with a suspected diagnosis of HF24. Patients with a left ventricular ejection fraction of not more than 40% and a prior HF event within 12 months were enrolled with the goal of reducing NT-proBNP levels to less than 1000 pg/mL by up-titration of medical therapy in those assigned to the intervention arm. The trial was stopped prior to completion because of futility. After 894 patients were enrolled, 164 patients (37%) in the biomarker-guided group and 164 patients (37%) in the usual-care arm experienced the primary composite outcome of first HF hospitalization or cardiovascular mortality  over a median follow-up of 15 months24. These findings were thought to be the end of biomarker-guided therapy. However, there are important caveats to these findings and further analyses have shown the potential usefulness of biomarkers during titration of medical therapy.Prior studies of NP-guided therapy have had variable outcomes; some showed improved outcomes and others did not. Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) attempted to resolve this question with a large multi-center randomized trial comparing NT-proBNP–guided treatment versus usual care in high-risk patients with HF25. Additionally, a hypothetical experiment using the BIOlogy Study to Tailored Treatment in Chronic Heart Failure (BIOSTAT-CHF) examined outcomes in patients if they underwent three different scenarios: (1) all patients up-titrated to more than 50% of recommended doses, (2) up-titration according to a biomarker-based treatment selection model, and (3) no patient is up-titrated to more than 50% of recommended doses26. In these hypothetical scenarios, patients with a biomarker approach had a substantially reduced rate of death and HF hospitalization compared with other scenarios, again demonstrating the potential benefits of a biomarker-guided approach. Although these latter two analyses do suggest some potential role of biomarker-guided therapy, neither was a randomized controlled trial and it should be remembered that the only large randomized trial, GUIDE-IT, did not show benefit from a biomarker-guided strategy. With this caveat in mind, there may still be a potential role for biomarker-guided therapy. A proposed use of biomarker-guided therapy in HF is to aggressively up-titrate medical therapy in HF, checking NT-proBNP while adjusting therapy, and the most important NT-proBNP measurement is the last one measured when medical therapy is felt to be optimized. If the last NT-proBNP is more than 1000 pg/mL, then a potentially high-risk patient with HF has been identified and further means of optimization or potentially advanced therapies should be considered  and all-cause mortality  and improved quality-of-life scoresnsidered . Althoug27. In the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, ARNI therapy led to a reduction in NT-proBNP levels but did not substantially change BNP levels28. This finding prompted investigators to suggest that NT-proBNP should be the preferred biomarker measured in the setting of ARNI therapy. However, subsequent studies have questioned this. In a study that evaluated many assays of NT-proBNP and BNP in the setting of ANRI therapy, levels of BNP inconsistently changed depending on which assay was used, while NT-proBNP generally decreased regardless of assay used, and atrial natriuretic peptide (ANP) levels consistently increased29. This study highlights that BNP changes with ARNI may be more dependent on the assay used for measurement than actual neprilysin inhibition. Furthermore, an analysis of the prognostic utility of BNP with concurrent ARNI therapy from PARADIGM-HF demonstrated that BNP remained prognostic for the outcome of cardiovascular death or HF hospitalization30. This highlights that BNP remains a prognostic biomarker in the setting of ARNI therapy and maintains that one of BNP’s most important uses in chronic HF is for determining prognosis. Although these studies provide some evidence that the measurement of BNP with ARNI therapy is still useful, the consistent change of NT-proBNP with ARNI therapy, regardless of the assay used, makes it the preferred NP measured with ARNI therapy until further studies can better understand BNP changes with neprilysin inhibition.Another consideration is the use of NPs in the setting of angiotensin receptor neprilysin inhibitor (ARNI) therapy. Neprilysin is an enzyme that breaks down many vasoactive peptides, including the various NPs such as BNP. Theoretically, inhibition of neprilysin will reduce the breakdown of BNP, causing levels to elevate in the setting of ARNI therapy while NT-proBNP levels will change independent of neprilysin inhibition as their clearance is not dependent on neprilysin, although there is debate as to whether BNP is substantially broken down by neprilysin in humans31. Mounting evidence, though, suggests a role for hs-cTn in the risk stratification of patients with chronic HF. Aimo et al. performed a comprehensive individual patient-level data meta-analysis of hs-cTn in patients with chronic HF32. It is worth noting that the majority of patients had hs-cTnT assessed given differences in assay characteristics between hs-cTnT and hs-cTnI depending on the vendor assay used (as discussed earlier). In adjusted models, hs-cTnT retained substantial risk prediction for all-cause mortality , cardiovascular death , and cardiovascular hospitalization 32. Risk began to increase at values of more than 18 ng/L and increased further at higher levels, reinforcing the importance of checking and potentially monitoring hs-cTnT for patient risk.Beyond NPs, hs-cTn and sST2 have affirmed their utility as important biomarkers for risk-stratifying patients with HF. Current ACC/AHA Guidelines give a class I recommendation for measuring hs-cTn in patients presenting with acute HF to evaluate for MI as a possible cause of decompensation and for risk stratification purposes; however, guidelines give only a class IIb recommendation for assessment of hs-cTn in chronic HF31. Prior studies have shown adverse cardiovascular outcomes in chronic HF when levels are more than 35 ng/mL. Recently, Emdin et al. evaluated sST2 in one of the largest patient cohorts and showed that risk of all-cause death, cardiovascular death, and HF hospitalization started to rise at sST2 levels of more than 28 ng/mL33. Additionally, sST2 remained associated with the outcomes after adjusting for NT-proBNP and hs-cTnT levels with an HR of 1.25 to 1.3 per doubling of sST2.ST2 is a member of the interleukin 1 (IL-1) receptor superfamily. The soluble form (sST2) is thought to be a decoy receptor for IL-33 and prevents binding of IL-33 to the ligand form of ST2. This leads to adverse cardiac remodeling, including fibrosis, hypertrophy, and apoptosis. Thus, elevated sST2 levels are associated with myocardial fibrosis and adverse cardiac remodeling. Currently, ACC/AHA HF Guidelines give measurement of sST2 a class IIb recommendation in patients with chronic HF34. Patients with high sST2 at baseline (defined as more than 35 ng/mL) and on low dose of beta-blocker during follow-up  were at the greatest risk for cardiovascular events34. These findings suggest that beta-blocker dose should be aggressively up-titrated in patients with high sST2 levels. A study of 99 patients with HFrEF examined the association between sST2 levels and sudden cardiac death35. The authors found that patients with higher sST2 levels were at a greater risk for sudden cardiac death, a finding that remained significant when adjusting for NT-proBNP35. These findings are hypothesis-generating given the small study sizes but suggest that sST2 may be able to help risk-stratify patients for risk of sudden cardiac death and identify those most likely to benefit from implantable cardiac defibrillator therapy.Some studies also suggest that sST2 might be helpful in selecting therapies for patients with HF. In a study of 151 patients with HF with reduced ejection fraction (HFrEF), the association between beta-blocker therapy and sST2 was examined for a composite outcome of cardiovascular eventset al. evaluated NT-proBNP–guided therapy in acute HF similar to GUIDE-IT36. Patients were randomly assigned to either NT-proBNP–guided therapy defined as trying to obtain a decrease in NT-proBNP of at least 30% from admission by time of discharge or usual care. In the principal analysis, no difference in all-cause mortality or HF hospitalization at 6 months was found36. However, most patients had already achieved at least a 30% reduction in NT-proBNP at the time of randomization, leaving only a small population to actually try to use medical therapy to guide to lower levels. A post-hoc analysis showed that patients with a 30% reduction in NT-proBNP at time of randomization had the lowest prevalence of HF readmission or death (28%) at 6 months whereas those patients who did not have a 30% reduction but subsequently achieved it with guided therapy had a higher prevalence of HF readmission or death (49%) at 6 months, but this was still lower than patients who were unable to obtain a 30% reduction in NT-proBNP who had the highest prevalence of HF readmission or death (59%) at 6 months. The authors highlighted the need to design future studies focusing on the high-risk patients who do not have a 30% reduction in NT-proBNP at the time of stability and to determine whether guided therapy can improve outcomes in this population. Thus, the utility of NP-guided therapy in acute HF is still unanswered.Building on studies from chronic HF, recent studies in acute HF have applied the same biomarkers and other novel biomarkers to further improve acute HF care. Stienen et al.37. They found that admission and discharge sST2 values were highly prognostic for all-cause mortality and cardiovascular death, HRs ranged from 2.06 to 2.46 per doubling of sST2 for these outcomes, and discharge sST2 was predictive of HF readmission with an HR of 1.54 per doubling of sST2. van Vark et al. have shown that serial sST2 monitoring during and after hospitalization for acute HF can improve risk stratification38. They identified two patterns for sST2: a U- and a J-shaped course. J-shaped patients had high sST2 on admission for acute HF but decreased by discharge and remained low after discharge with good outcomes. U-shaped patients had a decline in sST2 that increased after discharge and was associated with an elevated risk of all-cause mortality and HF hospitalization. What drives the J- versus U-shaped trajectory in patients was not clearly defined. However, as sST2 reflects fibrosis, inflammation, and remodeling, the initial triggers leading to an HF decompensation potentially persist in those patients with a U-shaped trajectory after discharge leading to progressive HF. Thus, the trajectory of sST2 may reflect the natural trajectory of HF in each patient and it is not known whether therapeutic interventions can change this trajectory; this is an area of needed research. Similar findings might be seen with other biomarkers such as hs-cTn or NPs if serially measured, but notably the prognostic utility of sST2 measurements remained independently significant when including measurements of serial NT-proBNP in multivariate models38. This study ties together using sST2 in both acute and chronic HF settings and suggests that serial monitoring can enhance risk stratification. The 2017 ACC/AHA HF Guidelines have yet to make a recommendation for assessment of sST2 in the setting of acute HF.The usefulness of sST2 in acute HF, as in chronic HF, was confirmed in a meta-analysis by Aimo et al. recently explored whether IL-1β, an inflammatory cytokine, modulated the prognostic utility of sST239. They examined sST2 and IL-1β in over 300 patients with acute HF. IL-1β levels were correlated with sST2 levels and further risk-stratified patients with an sST2 of at least 35 ng/mL by showing that only those with a concomitant elevation in IL-1β (≥49.1 pg/mL) had an increased risk of death. Further studies are needed to see whether IL-1β should always be measured with sST2 to further discriminate risk in HF.Since ST2 is part of the IL-1 superfamily, Pascual-Figal 40. The prognostic utility of adrenomedullin in HF has been previously described but this was assessed with a stable inactive form40. Recently, an assay has been developed that can measure the biologically active form (bio-ADM) allowing for rapid assessment of congestion in acute HF. Two studies have evaluated bio-ADM for this role in acute HF. In the first study, bio-ADM was measured in over 2000 patients at admission for acute HF in the BIOSTAT-CHF study and separately validated in a cohort of over 1700 patients with acute HF41. bio-ADM was the strongest correlate with a clinical congestion score assessed at admission. Elevated bio-ADM levels were independently associated with an increased risk of all-cause mortality and HF hospitalization with an HR of 1.16 (95% CI 1.06–1.27) per log increase. In the second study, bio-ADM was measured at day 7 or discharge in over 1200 patients from PROTECT 42. bio-ADM was the strongest predictor of residual congestion at discharge, and when patients were discharged with elevated bio-ADM levels and high loop diuretic doses, they had a substantially increased risk of HF readmission with an HR of 4.02 (95% CI 2.23–7.26). bio-ADM appears to be a promising biomarker for assessing congestion and risk in patients with acute HF, but further studies are still needed to see whether risk assessment can turn into action and improved outcomes. In total, these studies demonstrate how impactful biomarkers are in the care of patients with HF  for CVD (defined as coronary heart disease or stroke), 1.67 (95% CI 1.50–1.86) for cardiovascular death, 1.59 (95% CI 1.38–1.83) for coronary heart disease, and 1.35 (95% CI 1.23–1.48) for stroke43. Similarly, in the Atherosclerosis Risk in Communities (ARIC) study, Jia et al. showed that participants with no known CVD who had an hs-cTnI in the highest quintile had an increased risk of incident coronary heart disease , ischemic stroke , atherosclerotic CVD , HF hospitalization , and all-cause mortality  compared with the lowest quintile44. Similar findings were recently reported with hs-cTnT, though in a smaller cohort of patients45. These studies demonstrate a clear potential for using hs-cTn to identify high-risk patients who may benefit from more-aggressive risk factor modification with lipid control, blood pressure control, and potentially antiplatelet agents analogous to checking a high-sensitivity C-reactive peptide for deciding intensity of lipid-lowering therapy.One of the most exciting potentials for biomarkers is to detect patients at high risk for CVD who may be able to receive disease-modifying therapies such as lipid-lowering therapy, aggressive blood pressure control, and use of novel agents such as sodium-glucose co-transport 2 inhibitors to reduce their risk for CVD. In this area, hs-cTn has shown incredible promise. Willeit 46. Thus, compared with hs-cTn studies that have looked predominately at a single time point, serial Gal-3 assessment may help identify high-risk patients for incident CVD. Of note, although this study suggests that Gal-3 may help identify high-risk patients for incident HF, the use of Gal-3 in patients with symptomatic HF is limited since many previous studies have reported a lack of prognostic utility with measuring Gal-3 and medical therapy does not appear to change Gal-3 levels. Further studies are needed to determine how best to integrate these multiple biomarkers. Indeed, some studies have shown that measuring multiple biomarkers can improve risk prediction beyond current models and thus biomarker panels may be most useful in improving risk stratification47.While hs-cTn has demonstrated clear utility, Gal-3 has promise as a screening biomarker. Gal-3 was measured in 2477 participants in the Framingham Heart Study Offspring cohort at two time points. Changes in Gal-3 between assessments were associated with incident HF , CVD , and all-cause mortality Biomarkers have become an essential part of clinical practice in cardiology. The field is moving at a rapid pace, and the goal of this review is to make clinicians aware of some of the major recent advancements. A common theme is the utility of NPs, hs-cTn, sST2, and Gal-3 for risk stratification in CVD and monitoring of disease. Although many studies support the use of NPs and hs-cTn, leading to their incorporation as class I and IIa recommendations in ACC/AHA HF Guidelines for both diagnosis and prognosis, the roles of sST2 and Gal-3 are still evolving for use in risk prediction and prognosis. Furthermore, none of these biomarkers has a defined role in guiding medical therapy, although many studies have been performed with NPs and suggest potential benefit with NP guided therapy in select populations. Other novel biomarkers such as IL-1b and bio-ADM still require further study to determine a clinical role in HF, but initial study results are promising for a potential role in HF management. In the future, a multimarker approach for diagnosis and risk stratification likely will be developed to assess the complex and diverse pathophysiology of HF.48. Other promising novel biomarkers have been mentioned and may become more widely used clinically in the years to come but lack enough evidence for current incorporation into practice. Clinicians should maintain vigilance for future developments with these biomarkers and others.The integration of these various biomarkers into clinical practice can be challenging. A proposed algorithm for using these biomarkers in the disease course of a patient is presented . Cut-off


Background: Interstitial lung sequelae are increasingly being reported in survivors of COVID-19 pneumonia. An early detection of these lesions may help prevent the development of irreversible lung fibrosis. Lung ultrasound (LUS) has shown high diagnostic accuracy in interstitial lung disease (ILD) and could likely be used as a first-line test for post-COVID-19 lung sequelae.Methods: Single-center observational prospective study. Follow-up assessments of consecutive patients hospitalized for COVID-19 pneumonia were conducted 2–5 months after the hospitalization. All patients underwent pulmonary function tests (PFTs), high-resolution computed tomography (HRCT), and LUS. Radiological alterations in HRCT were quantified using the Warrick score. The LUS score was obtained by evaluating the presence of pathological B-lines in 12 thoracic areas . The correlation between the LUS and Warrick scores was analyzed.Results: Three hundred and fifty-two patients who recovered from COVID-19 pneumonia were recruited between July and September 2020. At follow-up, dyspnea was the most frequent symptom (69.3%). FVC and DLCO alterations were present in 79 (22.4%) and 234 (66.5%) patients, respectively. HRCT showed relevant interstitial lung sequelae (RILS) in 154 (43.8%) patients (Warrick score ≥ 7). The LUS score was strongly correlated with the HRCT Warrick score (r = 0.77) and showed a moderate inverse correlation with DLCO (r = −0.55). The ROC curve analysis revealed that a LUS score ≥ 3 indicated an excellent ability to discriminate patients with RILS .Conclusions: LUS could be implemented as a first-line procedure in the evaluation of Post-COVID-19 interstitial lung sequelae. A normal LUS examination rules out the presence of these sequelae in COVID-19 survivors, avoiding the need for additional diagnostic tests such as HRCT. The global coronavirus disease 2019 (COVID-19) pandemic has reached unprecedented dimensions, with more than 246 million cases and 5 million deaths worldwide ; howeverIn previous viral epidemics such as those caused by MERS-CoV and SARS-CoV, a variable percentage of survivors developed interstitial lung disease (ILD), including pulmonary fibrosis (PF) –9. On a In the last decades, LUS has proven to be a suitable alternative to conventional radiological methods in multiple kinds of lung diseases –27. DuriLUS has been previously validated for the detection of ILD secondary to other causes. Several studies, mostly those involving connective tissue disease-associated ILD, have shown significant superiority of LUS over CXR and, most importantly, similar sensitivity and negative predictive value in comparison with CT –37. In aThus, the aim of this study was to describe the diagnostic accuracy of LUS in the assessment of early interstitial sequelae after COVID-19 pneumonia in comparison with CT.Ethics approval was obtained prior to the start of the study by the Medical Ethics Committee of Vall d'Hebron Barcelona University Hospital [PR(AG)461/2020]. Written informed consent was obtained from all the patients before their inclusion.This single-center observational prospective study evaluated 362 survivors hospitalized for COVID-19 pneumonia between March 3, 2020 and April 29, 2020 at Vall d'Hebron University Hospital, Barcelona, Spain. Patients were included consecutively if they visited the dedicated post-COVID-19 outpatient clinic at our respiratory department between July 20, 2020, and September 21, 2020.Patients visited the clinic at least 2 months after their hospital discharge. Patients recovered from severe pneumonia were visited first for medical reasons. We excluded patients with previously diagnosed ILD, congestive heart failure and those who declined to participate. Baseline information was retrieved from medical records. All patients were interviewed face-to-face by experienced pulmonologists and underwent pulmonary function tests (PFTs), including spirometry and measurement of the carbon monoxide diffusing capacity (DLCO) and high-resolution CT (HRCT) and LUS. HRCT and LUS were performed no more than 15 days apart.1), FEV1/FVC ratio, and lung diffusing capacity for carbon monoxide (DLCO). Lung volumes and post-bronchodilation tests were not performed.Lung-function tests were performed at our dedicated laboratory by using Master-Lab equipment  in accordance with international protocols and GLI reference values –40. PulmHRCT examinations were performed by a standard protocol using Siemens Somatom Force Dual Source CT and Siemens Somatom Definition AS+ scanners. Scans were obtained at full inspiration from the apex to the lung base in the supine position. All chest CT scans were reconstructed with a 1.5-mm slice thickness. Iodine contrast agents were not used.HRCT images were evaluated according to the Fleischner Society glossary , and thePulmonary involvement was quantified according to the Warrick score, which has been previously validated in scleroderma-related ILD , 43 and Each HRCT image was evaluated by two blinded, independent thoracic radiologists who calculated the Warrick score. The final Warrick score was the average of the two independent reads if the difference was 4 points or less (variability < 13.3%). In cases with a greater difference, both radiologists met and performed a third consensual assessment.LUS examinations were performed using a Sonosite M-Turbo system equipped with a 2–5-MHz convex transducer. A team of four pulmonologist with expertise in LUS conducted all the examinations. Every patient underwent LUS at the follow-up visit by one of the four examiners mentioned, who was always in a separate consultation, blinded to the clinical and other exploration findings.The scan protocol consisted of a complete examination of all intercostal spaces, which were divided into 12 thoracic areas  . AbnormaPrimary endpoint was to establish the accuracy of LUS in the detection of relevant interstitial lung sequelae (RILS) in COVID-19 survivors in comparison with HRCT.Stata statistical software: Release 15 College Station, TX, StataCorp LLC, USA). Descriptive analysis was performed according to the pneumonia severity groups and the presence of RILS at follow-up. For the qualitative variables, frequencies and percentages were compared using the chi-square test or Fisher's exact test. For the quantitative variables, means (SD) and medians (IQR) were calculated and compared using the Mann-Whitney U-test. The normality of the distribution was analyzed using the Shapiro–Wilk test. The p-value was computed from the Spearman rank correlation coefficient when the variable was continuous and from the χ2 test if the variable was categorical. Statistical significance was set at p < 0.05.All data were analyzed using Stata software  curves were plotted to analyze area under the curves (AUC). A cut-off point in the LUS score was obtained according to Youden index as the value corresponding to a HRCT Warrick score of ≥7.n = 3), congestive heart failure (n = 2) and those who declined to participate (n = 5) were excluded. Consequently, 352 patients were included in our study. Their demographic and clinical characteristics are presented in Three-hundred and sixty-two patients who had recovered from COVID-19 pneumonia after hospitalization were evaluated. Patients with previously diagnosed ILD . The B-line score was strongly correlated with the HRCT Warrick score (r = 0.77) and showed a moderate inverse correlation with DLCO (r = −0.55) (The median (IQR) B-line score was significantly higher in patients in the RILS group  .The ROC curve analysis showed that a B-line score of 3 or more was the best cut-off point to discriminate patients with RILS (Warrick score ≥ 7) . This vaThe B-line score showed excellent inter-observer agreement with a kappa value of 0.90 (95% CI 0.86–0.94). Detection of pleural-line abnormalities showed a poor inter-observer agreement, with a kappa index of 0.48 (95% CI 0.41–0.56).To our knowledge, this is the first large study focusing on the role of LUS for the evaluation of early interstitial sequelae in COVID-19 survivors. The presence of pathological B-lines showed excellent ability to discriminate these persistent abnormalities in comparison with HRCT, supporting the use of LUS as a first-line procedure to rule out post-COVID-19 lung sequelae.We report the follow-up findings for 352 patients evaluated 2–5 months after hospitalization for COVID-19 pneumonia. A high prevalence of functional and radiological sequelae was observed in our population, likely due to the high proportion of severe pneumonia cases. Indeed, data from larger series support the same prevalence rates of persistent radiological abnormalities –15, inclThe natural history of COVID-19 lung sequelae is still unknown, and it is unclear whether full recovery can be expected in all cases. In addition, long COVID is another clinical entity that adds complexity to these uncertainties, as affected patients can manifest persistent respiratory symptoms without evidence of radiological or functional abnormalities on usual explorations , 46. As Therefore, effective diagnostic tests are required for a correct identification and monitoring of patients with post-COVID-19 interstitial lung sequelae. Considering the immensely large population affected, an easy, low-cost, and reproducible diagnostic procedure is crucial to manage this clinical challenge. The belief that LUS could be useful for this purpose motivated the present study.To date, only one report of 38 patients has described the use of LUS for detection of COVID-19 lung sequelae compared to HRCT . In thisIn our study, 352 patients underwent complete LUS exploration of all intercostal spaces, and the findings were quantified in a 12-area score. We searched for the presence of a “lung interstitial syndrome” pattern, which was defined by the presence of multiple B-lines . These aIn our report, we implemented a simplified method since our goal was to discriminate patients with potential interstitial lung sequelae after COVID-19 and not to evaluate the grade or type of abnormalities. Based on the definition of the ICC-LUS , we consPleural line abnormalities such as thickening and fragmentation have also been described as useful sonographic signs for the diagnosis of ILD. Various studies in the last decade have shown that pleural line measurements could be particularly accurate in ruling out pulmonary fibrosis , 35, 53.Early identification of persistent post-COVID-19 interstitial sequelae seems to be crucial, particularly since it may facilitate prompt initiation of treatments to prevent permanent fibrotic changes. Furthermore, given the increasing number of cases worldwide, a diagnostic test available for large populations is essential. The technical characteristics of LUS seem suitable for this purpose since sonography is low-cost, non-ionizing, repeatable, and reproducible in outpatient clinics. Moreover, expertise and skills in LUS can be obtained with a short training trajectory , and theThe present study has some remarkable strengths. First, it is the largest prospective cohort published for this objective. Patients were recruited consecutively, and the same complete protocol was performed in a short time period. HRCT images, considered as the gold-standard, were evaluated by two independent thoracic radiologists, and in cases with significant differences, both radiologists met and performed a third consensual assessment. In addition, LUS operators were blinded to the clinical and radiological data and achieved excellent interobserver agreement. Finally, this was a reproducible and real-life study, since LUS was performed in the outpatient clinic by pulmonologists.Yet, as in any study, there are some limitations. The order of follow-up visits was based on disease severity, potentially causing a relevant bias in the descriptive analysis. Consequently, the study population included a low percentage of mild cases, since many patients in this group had still not visited for follow-up assessments when we stopped study recruitment. However, none of these limitations, which are typical of a real-life study, influenced the primary objective. Another limitation is that we used the Warrick score, which has been validated in scleroderma-related ILD, to grade HRCT abnormalities because of the absence of any other specific score. Moreover, a Warrick cut-off point of ≥7 could lead to the underdiagnosis of milder forms of ILD. In our favor, it is likely that minor abnormalities are not clinically relevant in COVID-19 sequelae, since they could represent an intermediate step toward full recovery. In addition, this score has been widely applied in previous LUS reports of other ILDs and includes the main interstitial abnormalities found in COVID-19 survivors. Nevertheless, more studies are needed to describe how these lesions will evolve over time and whether LUS will continue to play a role in their detection.LUS could be implemented as a first-line procedure in the evaluation of interstitial lung sequelae after COVID-19 pneumonia. The identification of pathological B-lines in a twelve-area score showed a high negative predictive value for the detection of these abnormalities. Consequently, a normal LUS examination could rule out the presence of ILD in COVID-19 survivors, avoiding the need for additional diagnostic tests such as HRCT.dclofent@vhebron.net.The datasets presented in this article are not readily available because approval from the relevant authorities is required. Requests to access the datasets should be directed to The studies involving human participants were reviewed and approved by Medical Ethics Committee of Vall d'Hebron Barcelona University Hospital [PR(AG)461/2020]. The patients/participants provided their written informed consent to participate in this study.DC is the guarantor of the paper and takes full responsibility for the content of the manuscript, including data and analysis. DC, MC, and EP conceived and designed the study, analyzed the data, and drafted the manuscript. Statistical analysis was performed by Santiago Pérez-Hoyos. DC, AF, GG, and MA performed lung ultrasound examinations in all patients. JA, AS, DV, LC, and JE conducted the chest HRCT examinations in all patients. XM, AA, and KL critically reviewed the manuscript for relevant intellectual content. All authors approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.