Exercise-induced Laryngeal Obstruction Research Articles

Treatment and Outcome Metrics for Speech-Language Pathology Treatment of Upper Airway Disorders: A Systematic Review.

Clinical treatment strategies and progress metrics for patients with inducible laryngeal obstruction (ILO) and exercise-induced laryngeal obstruction (EILO) have not been systematically applied across clinics. The goals of this review were to identify the intervention strategies used to treat upper airway disorders and determine the clinical metrics by which improvement or resolution of ILO/EILO is determined in clinical studies of speech-language pathology intervention. A systematic review was conducted using the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Systematic Reviews Checklist. English language, full-text publications were identified through MEDLINE (Ovid), APA PsycINFO, and Web of Science for publications that described clinical outcomes following behavioral treatment for ILO provided by a speech-language pathologist (SLP). A total of 238 sources were retrieved, of which 75 were duplicates. Titles and abstracts of 163 were screened, with 22 sources included for full-text review. Citation review yielded nine additional resources. Thirty-one sources were included for data extraction. Most sources described use of respiratory/laryngeal retraining. There was a lack of consistency for clinical and standardized metrics used to evaluate improvement or resolution of upper airway symptoms. Behavioral and standardized outcome metrics for evaluating therapy outcomes from SLP behavioral intervention of ILO/EILO are not consistently applied. Clinical metrics standards for clinicians are needed to provide a means to evaluate graded improvement in treatment and changes in health care utilization as well as for training less-experienced clinicians. https://doi.org/10.23641/asha.27172683.

Application of computational fluid dynamics to investigate pathophysiological mechanisms in exercise-induced laryngeal obstruction.

The underlying pathophysiological mechanisms of exercise-induced laryngeal obstruction (EILO) remain to be fully established. It is hypothesized that high inspiratory flow rates can exert a force on laryngeal airway walls that contribute to its inward collapse causing obstruction. Computational fluid dynamics (CFD) presents an opportunity to explore the distribution of forces in a patient-specific upper airway geometry. The current study combined exercise physiological data and CFD simulation to explore differences in airflow and force distribution between a patient with EILO and a healthy matched control. Participants underwent incremental exercise testing with continuous recording of respiratory airflow and laryngoscopic video, followed by an MRI scan. The respiratory and MRI data were used to generate a subject-specific CFD model of upper respiratory airflow. In patient with EILO, the posterior supraglottis experiences an inwardly directed net force, whose magnitude increases nonlinearly with larger flow rates, with slight changes in the direction toward the center of the airway. The control demonstrated an outwardly directed force at all regions of the wall, with a magnitude that increases linearly with larger flow rates. A comparison is made between the CFD results and endoscopic visualization of supraglottic collapse, and a very good agreement is found. The current study presents the first hybrid physiological and computational approach to investigate the pathophysiological mechanisms of EILO, with preliminary findings showing great potential, but should be used in larger sample sizes to confirm findings.NEW & NOTEWORTHY The current study is the first to use a hybrid combined computational fluid dynamics (CFD) and exercise physiology approach to investigate pathophysiology in exercise-induced laryngeal obstruction (EILO). The hybrid methodology is a promising approach to explore the pathophysiological mechanisms underlying the condition. Notable differences occur in the distribution of airflow and wall forces between the EILO and control participants, which align with symptoms and visual observations.

Oscillatory airflow through the hypopharyngeal and supraglottic airway

Exercise-induced laryngeal obstruction (EILO) is a known cause of exertional dyspnoea, characterised by paradoxical inward collapse of laryngeal tissues. The pathophysiological mechanisms of EILO remain to be fully established, but insufficient mechanical resistance of laryngeal tissues to air-induced loads is hypothesised. It is understood that airflow and anatomic configurations of the airway play a key role in the wall pressure distribution of the larynx. While breathing is a cyclic process with directional changes of airflow, the literature is confined to steady, unidirectional airflow. It is necessary to assess the role of oscillatory airflow on the loads on the laryngeal airway. This study investigates the effect of oscillatory airflow on the laryngeal flow fields and air-induced loads. A computational fluid dynamics model of the upper respiratory tract (URT) is developed using the Reynolds-averaged Navier-Stokes equations. Five oscillatory airflow cases through a single geometry are considered, utilising sinusoidal breathing cycles with different breathing frequencies (24, 32 and 40 breaths per minute) and peak inspiratory flow rates (96, 168 and 240 L/min). Results include the airflow velocity distribution in the URT, and the air-induced pressure and forces. It is demonstrated that inspiratory velocity distribution varies with breathing frequency and intensity. The force acting on the URT walls are in-phase with the airflow rate and therefore exhibit quasi-steady behaviour. These findings are also reflected in the force vectors acting on the aryepiglottic folds and indicate that air-induced closure of the supraglottis in EILO is influenced by the breathing intensity rather than the breathing frequency.

Investigation of exertional dyspnoea by cardiopulmonary exercise testing with continuous laryngoscopy

ObjectivesAbnormal breathlessness at maximal exercise may be caused by a range of conditions, including exercise-induced bronchospasm, breathing pattern disorder, or exercise-induced laryngeal obstruction. These three disorders may not be detected on standard cardiopulmonary exercise testing. The aim of this study was to describe diagnostic outcomes of an expanded protocol during cardiopulmonary exercise testing. DesignRetrospective cohort study. MethodsPatients presenting with abnormal breathlessness on maximal exercise underwent continuous laryngoscopy with cardiopulmonary exercise testing on a stationary cycle ergometer. Breathing pattern disorder was evaluated by video and ventilatory data. Pre- and post-exercise spirometry was performed. Results24 adult patients were evaluated; 10 were professional athletes. Mean age was 40 years (range 18–73). Nine of 24 (38 %) were diagnosed with exercise-induced laryngeal obstruction and referred for speech pathology. Six of these had supraglottic exercise-induced laryngeal obstruction; all were aged <30 years; 5/6 were professional athletes. One patient had breathing pattern disorder and was referred for physiotherapy; one had exercise-induced bronchospasm, requiring escalation of asthma medication; one had muscle tension dysphonia resulting in referral to an otolaryngologist who administered a laryngeal injection of botulinum toxin. A further four patients had unexplained lower maximal oxygen consumption with cardiac limitation and were referred for further cardiac investigation. ConclusionsIn patients reporting abnormal breathlessness at maximal exercise, this expanded exercise protocol provided diagnostic information in 66.7 % cases which contributed to further personalised management.

Epiglottic retraction is useful in diagnosis of exercise-induced laryngeal obstruction

Background Exercise-induced laryngeal obstruction (EILO) is distinguished as upper airway obstruction accompanied by inspiratory dyspnoea and stridor during highly intensive exercises. Epiglottic retraction in the diagnosis of EILO has not been sufficiently explored. Aims/objectives We highlight the importance of epiglottic retraction in patients with EILO by evaluation by several diagnostic methods for EILO. Consideration of epiglottic retraction may be important for accurate diagnosis of EILO. Results Epiglottic retraction could be observed in three patients by laryngoscopy during heavy breathing and in two patients by continuous laryngoscopy during exercise. Stridor occurred by the forward prolapse of the arytenoids, but not by epiglottic retraction. In comparison with three athletes from other sports, lung volume was significantly greater in four swimmers although it was not different related to depending on the existence of epiglottic retraction. Conclusions and significance Laryngoscopy during heavy breathing is suggested to be useful to detect the epiglottic retraction, which might be overlooked if only continuous laryngoscopy during exercise is used. Epiglottic retraction was not rare in Japanese swimmers’ exercise-induced laryngeal obstruction in our cohort and it might be related to the greater lung volume.

Exercise-Induced Bronchoconstriction in Children: State of the Art from Diagnosis to Treatment.

Exercise-induced bronchoconstriction (EIB) is a common clinical entity in people with asthma. EIB is characterized by postexercise airway obstruction that results in symptoms such as coughing, dyspnea, wheezing, chest tightness, and increased fatigue. The underlying mechanism of EIB is not completely understood. "Osmotic theory" and "thermal or vascular theory" have been proposed. Initial assessment must include a specific work-up to exclude alternative diagnoses like exercise-induced laryngeal obstruction (EILO), cardiac disease, or physical deconditioning. Detailed medical history and clinical examination must be followed by basal spirometry and exercise challenge test. The standardized treadmill running (TR) test, a controlled and standardized method to assess bronchial response to exercise, is the most adopted exercise challenge test for children aged at least 8 years. In the TR test, the goal is to reach the target heart rate in a short period and maintain it for at least 6 min. The test is then followed by spirometry at specific time points (5, 10, 15, and 30 min after exercise). In addition, bronchoprovocation tests like dry air hyperpnea (exercise and eucapnic voluntary hyperpnea) or osmotic aerosols (inhaled mannitol) can be considered when the diagnosis is uncertain. Treatment options include both pharmacological and behavioral approaches. Considering medications, the use of short-acting beta-agonists (SABA) just before exercise is the commonest option strategy, but daily inhaled corticosteroids (ICS) can also be considered, especially when EIB is not controlled with SABA only or when the patients practice physical activity very often. Among the behavioral approaches, warm-up before exercise, breathing through the nose or face mask, and avoiding polluted environments are all recommended strategies to reduce EIB risk. This review summarizes the latest evidence published over the last 10 years on the pathogenesis, diagnosis using spirometry and indirect bronchoprovocation tests, and treatment strategies, including SABA and ICS, of EIB. A specific focus has been placed on EIB management in young athletes, since this condition can not only prevent them from practicing regular physical activity but also competitive sports.

Long-Term Outcomes of Respiratory Retraining Therapy for Exercise-Induced Laryngeal Obstruction

ObjectiveTo assess the long-term outcomes and efficacy of respiratory retraining therapy in patients with exercise-induced laryngeal obstruction (EILO). MethodsA retrospective chart review and prospective questionnaire-based survey was conducted on 88 patients who received respiratory retraining therapy for EILO at our institution over the past 5 years Results34 patients were included in the final analysis, with a mean age at symptom onset and age at initial evaluation of 13.67 ± 2.96 and 15.12 ± 3.48, respectively. We found a statistically significant difference in the pre-treatment and post-treatment Dyspnea Indices following respiratory retraining therapy, with a mean difference of 12.03 ± 7.18 (p < 0.001). When asked about the effectiveness of respiratory retraining therapy, the majority of patients (n = 28) reported improvement (13.3% “a little”, 13.3% “somewhat better”, 53.3% (“a lot better”, and 13.3% complete resolution of symptoms. Only 2 patients (6.7%) responded that their breathing “did not get better.” The most effective therapy techniques cited by patients were abdominal breathing (n = 10), ratio breathing (n = 5), and pursed lip or “straw” breathing (n = 5). ConclusionRespiratory retraining therapy represents an effective technique in both the short-term and long-term management of EILO. This therapy remains the first line in management of EILO due to its ease of administration, non-invasive nature, and durable effect on breathing function.

Exercise-induced Laryngeal Obstruction

Exercise-induced Laryngeal Obstruction

Diagnostics of Exercise-Induced Laryngeal Obstruction Using Machine Learning: A Narrative Review

Objective: This paper explores machine learning methods for exercise-induced laryngeal obstruction (EILO) diagnostics. Traditional diagnostic approaches like CLE scoring face subjectivity, limiting precise objective assessments. Machine learning is introduced as a theoretical solution to potentially overcome these limitations and improve diagnostic precision. Methods: A narrative review was conducted to explore the integration of machine learning techniques in the diagnostics of EILO. Result: Three machine learning methods for the segmentation of laryngeal images were discovered: fully convolutional network, Mask R-CNN, and 3D VOSNet. Our findings reveal that the integration of machine learning with EILO diagnostics remains a largely untapped research domain, providing significant room for further exploration. Conclusions: The integration of ML techniques for EILO diagnostics has the potential to be a helpful tool for clinicians. The application of computer vision ML methods, such as image segmentation, to delineate laryngeal structures paves the way for a more objective assessment. While challenges persist, especially in differences in patients’ laryngeal anatomy, the synergy of ML and medical expertise is an important field to explore in the years to come.

Effects of Exercise-Induced Laryngeal Obstruction in Adolescents: A Qualitative Study.

The purpose of this study was to examine the influence of exercise-induced laryngeal obstruction (EILO) on adolescents. Twenty patients (< 17 years) diagnosed with EILO participated in this study. Patients completed semistructured interviews examining their experience with the health care system, treatment, and the effects of EILO symptoms on quality of life. Interviews were analyzed using a combination of directed and conventional content analyses. Researchers identified seven overarching themes either prior to or during analysis, and 24 subthemes were inductively identified from patient interviews using open, axial, and selective coding. On average, patients went 1.9 years between symptom onset and EILO diagnosis. Patients described symptom onset as frightening and confusing. Even after initially reporting symptoms to a medical provider, patients went an average of 10.5 months before diagnosis. Patients perceived that delays in diagnosis prevented efficient management and allowed symptoms to escalate. Patients reported that EILO detrimentally influenced athletic performance, forcing them to pace themselves or cease participation altogether. Social and academic effects of EILO included missed classes, difficulty in physical education courses, and resentment from teammates if athletic performance declined. Both athletes and nonathletes indicated that EILO elicited feelings of fear, frustration, dread, guilt, and embarrassment. Patients reported that therapy with a speech-language pathologist (SLP) effectively addressed symptoms; however, employing rescue breathing techniques was often more difficult than anticipated. Physical and emotional sequelae associated with EILO may have widespread influence on patient quality of life. Therapy with an SLP reportedly ameliorated EILO symptoms; however, patients indicated that delayed diagnosis allowed negative effects to intensify prior to treatment.

Exercise – induced laryngeal obstruction (EILO) – challenge of sports medicine

Exercise induced laryngeal obstruction (EILO) is a paroxysmal paradoxical obstruction of the larynx during inspiration. This condition manifests as attacks of inspiratory dyspnea with stridor at the peak of physical exertion, when the respiratory rate is close to maximum. EILO primarily affects young athletes. This dysfunction requires differentiation from bronchial asthma, which also manifests itself as paroxysmal dyspnea. Endoscopic visualization of the larynx during a seizure provoked by intense exercise is necessary for EILO diagnosis. This condition may have a detrimental effect on the of professional athletes’ careers. Numerous therapeutic methods have been proposed for the treatment of EILO, from pulmonary rehabilitation, through injection of botulinum toxin into the muscles of the larynx, to surgical procedures widening the lumen of this organ. There is no evidence that inhalation is effective in the traatmant of this condition. A rational protocol for the management of a patient diagnosed with EILO is essential. Effective differentiation with bronchial asthma will help reduce the overuse of inhaled drugs by athletes.

Are Questionnaires Helpful To Predict Exercise-Induced Bronchoconstriction (EIB) And Exercise-Induced Laryngeal Obstruction (EILO)?

Exercise induced laryngeal obstruction (EILO) is an important differential diagnosis to exercise induced bronchoconstriction (EIB) and diagnosed via continuous laryngoscopy while exercising (CLE). However, availability of CLE is limited to specialized centres. And without CLE EILO is often misdiagnosed as EIB. Therefore it is essential to carefully preselect potential EILO candidates. Aim of this study was to investigate whether two short questionnaires -Asthma Control Test (ACT) and Dyspnea Index (DI) evaluating upper airway-related dyspnea- can differentiate between EIB and EILO. Patients with dyspnea while exercising were analysed with an exercise challenge in the cold chamber (ECC) to diagnose EIB in visit 1 (V1), as appropriate a CLE in visit 2 (V2, 4-6 weeks after V1) and ACT and DI in V1 and V2. EIB patients were treated with asthma medication after V1. Complete dataset of 36 subjects were gathered. The ACT showed lower values in V2 in EILO compared to EIB patients. A lack of improvement in ACT in V2 after asthma medication of EIB patients is suspicious for additional EILO diagnosis. The DI showed higher values in V1 in EILO compared to EIB patients. A score≥30 can predict a positive CLE reaction. ACT and DI are valuable tools in preselecting CLE candidates to assure timely diagnostic despite limited diagnostic capabilities.

A multidimensional strategy to managing dysfunctional breathing and exercise-induced laryngeal obstruction in adolescent athletes

BackgroundExercise induced laryngeal obstruction (EILO) causes inspiratory distress in the upper airway in many adolescent athletes. The nature of EILO is not fully understood, and effective management strategies are lacking. This study aimed to assess the effectiveness of a multidimensional individually tailored intervention, including Norwegian Psychomotor Physiotherapy (NPMP), elements of cognitive behavioural therapy and a rehabilitation plan, in reducing inspiratory distress and dysfunctional breathing in adolescent athletes with EILO.MethodsA mixed methods design, which combined qualitative and quantitative research, was used. Data, including subjective experiences of respiratory distress, findings from body examinations and objective measurements of lung function and aerobic capacity were gathered before and after a five month intervention involving 18 participants.ResultsFollowing the intervention, the participants showed a reduction in respiratory distress and anxiousness associated with their breathing difficulties. Furthermore, the participants reported to be more in control of their breathing. The body assessments revealed a more functional breathing motion and improved posture, which imply that the breathing was less thoracic and more diaphragmatic in rest and exercise in all participants after the intervention.ConclusionsOur results suggest that a multidimensional individually tailored intervention, including NPMP based physiotherapy, cognitive behavioural therapy elements, and a rehabilitation plan may reduce inspiratory distress and dysfunctional breathing in athletes with EILO.Trial registrationClinicalTrials.gov Protocol Registration and Results system NCT06033755, date of registration: September12, 2023. Retrospectively registered.

Exercise-induced laryngeal obstruction : diagnosis and management

Exercise-induced laryngeal obstruction (EILO) is a condition characterized by temporary narrowing or closure of the larynx during physical activity, in particular during intense physical exertion. It generally affects teenagers and young adults and is often misdiagnosed as exercise-induced asthma. Symptoms include dyspnea, wheezing and a feeling of throat tightness during exercise. The aim of this article is to review this often underrecognized condition, its diagnosis and its management.

Exercise-induced Laryngeal Obstruction

Exercise-induced Laryngeal Obstruction

Hypopharyngeal geometry impact on air-induced loads on the supraglottis

Exercise-induced laryngeal obstruction (EILO) describes paradoxical laryngeal closure during inspiration at high-intensity exercise. It is hypothesised that during intense activity, the air-induced loads on supraglottic walls overcome their internal stiffness, leading to the obstruction. Recent investigations have revealed that the air-induced loads on the supraglottic walls vary nonlinearly with increasing flow rate. It is, however, unclear whether certain geometric configurations of the hypopharynx and larynx may contribute to the predisposition to EILO. This study investigates the influence of hypopharyngeal and laryngeal geometry on upper respiratory tract airflow and air-induced forces. A computational fluid dynamics model is developed to study airflow through larynx. Four real, adult upper respiratory tracts with variable configurations are considered. Two steady, uniform inspiratory flow rates of 60 L/min and 180 L/min are considered. The analysis shows that geometries with a space lateral to the epiglottis (EpiS) and piriform fossae (PF) directs the hypopharyngeal and supraglottic pressure field to remain positive and increase with the flow rate. In geometries with EpiS and PF, pressure differential occurs around the aryepiglottic fold producing a net inward force over the region. The three-fold increase in flow rate induces near ten-fold increases in force over the region which may facilitate the closure. It is concluded that hypopharyngeal anatomy, particularly the piriform fossae, play a significant role in the obstruction of the supraglottic airway and should be considered in research and clinical assessment of EILO.

Feasibility of Constant Work Rate Testing to Detect Exercise-Induced Laryngeal Obstruction.

Exercise-induced laryngeal obstruction (EILO) is a condition in which laryngeal structures inappropriately obstruct the upper airway during exercise. The standard diagnostic test for EILO is the continuous laryngoscopy during exercise (CLE) test, usually performed with an incremental work rate protocol regardless of the nature of the triggering event. Typically, laryngeal obstruction occurs only briefly at the end of an incremental test, near peak work capacity. We aimed to investigate constant work rate (CWR) protocols for CLE testing to expand diagnostic test modalities and improve the understanding of EILO. In this prospective, self-controlled feasibility study, 10 patients with EILO performed both an incremental and a CWR CLE test at 70%, 80%, and 90% of maximal exercise capacity. Laryngoscopic video data were recorded and compared, and we evaluated the ability of CWR to reproduce the symptoms and laryngeal obstruction seen in incremental testing. In 70%-90% of cases, CWR testing induced at least the same severity of obstruction as incremental testing and CLE scores remained comparable across test modalities. CWR at 70% allowed observation of laryngeal obstruction for a significantly longer duration than in incremental testing (158 s; 95% confidence interval, 25-291 s; P = 0.027). Dyspnea intensity appeared higher during CWR testing compared with incremental testing. Submaximal CWR CLE testing is feasible and able to induce EILO equivalent to the standard incremental CLE test. This is the first step toward tailored CLE exercise protocols, and further studies are now needed to establish the utility of CWR in clinical and research settings.

Prevalence and characterisation of exercise-induced laryngeal obstruction in patients with exercise-induced dyspnoea.

The prevalence of exercise-induced laryngeal obstruction is largely unknown. This study aimed to evaluate the prevalence of this condition in a selected study population of patients with exercise-induced dyspnoea. A retrospective analysis was conducted of demographic data, co-morbidities, medication, symptoms, performance level of sporting activities, continuous laryngoscopy exercise test results and subsequent treatment. Data from 184 patients were analysed. The overall prevalence of exercise-induced laryngeal obstruction in the study population was 40 per cent, and the highest prevalence was among females aged under 18 years (61 per cent). However, a high prevalence among males aged under 18 years (50 per cent) and among adults regardless of gender (34 per cent) was also found. The prevalence of exercise-induced laryngeal obstruction is clinically relevant regardless of age and gender. Clinicians are encouraged to consider exercise-induced laryngeal obstruction as a possible diagnosis in patients suffering from exercise-induced respiratory symptoms. No single characteristic that can distinguish exercise-induced laryngeal obstruction from other similar conditions was identified.

Computational fluid dynamics of upper airway aerodynamics for exercise-induced laryngeal obstruction: A feasibility study.

Use of computational fluid dynamic (CFD) simulations to measure the changes in upper airway geometry and aerodynamics during (a) an episode of Exercise-Induced Laryngeal Obstruction (EILO) and (b) speech therapy exercises commonly employed for patients with EILO. Magnetic resonance imaging stills of the upper airway including the nasal and oral cavities from an adult female were used to re-construct three-dimensional geometries of the upper airway. The CFD simulations were used to compute the maximum volume flow rate (l/s), pressure (Pa), airflow velocity (m/s) and area of cross-section opening in eight planes along the vocal tract, separately for inhalation and exhalation. Numerical predictions from three-dimensional geometrical modeling of the upper airway suggest that the technique of nose breathing for inhalation and pursed lip breathing for exhalation show most promising pressure conditions and cross-sectional diameters for rescue breathing exercises. Also, if EILO is due to the constriction at the vocal fold level, then a quick sniff may also be a proper rescue inhalation exercise. EILO affects both the inspiratory and the expiratory phases of breathing. A prior knowledge of the supraglottal aerodynamics and the corresponding upper airway geometry from CFD analysis has the potential to assist the clinician in choosing the most effective rescue breathing technique for optimal functional outcome of speech therapy intervention in patients with EILO and in understanding the pathophysiology of EILO on a case-by-case basis with future studies. 4.

Clinical Profiles of Children and Adolescents With Induced Laryngeal Obstruction (ILO) and Exercise Induced Laryngeal Obstruction (EILO).

To compare clinical profiles of pediatric patients with Induced Laryngeal Obstruction (ILO), Exercise Induced Laryngeal Obstruction (EILO), and EILO with non-exertion related secondary triggers (EILO+). A retrospective observational cohort design was employed. Four-hundred and twenty-three patients <18 years of age were identified from the electronic medical record of a large children's hospital. All patients underwent evaluations with a laryngologist and speech-language pathologist and were diagnosed with EILO/ILO. Patients were divided into 3 groups based on dyspnea triggers reported in initial evaluations. Groups consisted of patients with EILO (N = 281), ILO (N = 30), and EILO+ (N = 112). Patient demographics, EILO/ILO symptoms, endoscopy findings, medical comorbidities, medical history, and EILO/ILO treatment information were extracted and compared across EILO/ILO subtypes. Patients with EILO experienced higher rates of hyperventilation (P < .001), sore throat (P = .023), and chest pain (P = .003). Patients with ILO were significantly younger in age (P = .017) and presented with increased rates of nighttime symptoms (P < .001), globus sensation (P = .008), self-reported reflux symptoms (P = .023), and history of gastrointestinal conditions (P = .034). Patients with EILO+ were more likely to be female (P = .037) and presented with higher prevalence of anxiety (P = .003), ADHD (P = .004), chest tightness (P = .030), and cough (P < .001). Patients with EILO, ILO, and EILO+ present with overlapping but unique clinical profiles. A prospective study is warranted to determine the etiology of these differences and clarify how the efficacy of EILO, ILO, and EILO+ treatment can be maximized. 4.