Determining What Represents Value in the Treatment of Refractory or Unexplained Chronic Cough from the Perspective of Key Stakeholders in Spain Using Multi-Criteria Decision Analysis.

BACKGROUND AND OBJECTIVE: Chronic cough is defined as cough lasting for more than 8 weeks. It can be described as refractory when persisting despite thorough clinical assessment and treatment of any cough-related underlying condition, or unexplained when no underlying cough-related condition can be identified. Refractory or unexplained chronic cough (RCC|UCC) greatly affects patient health-related quality of life (HRQoL). Although around 10% of the population suffer from chronic cough (with 40-60% of these patients suffering from RCC|UCC), there is limited information available in the literature about the condition and the assessment of treatment success. This study aimed to determine what represents value in the treatment of RCC|UCC from the perspective of key stakeholders in Spain using Multi-Criteria Decision Analysis (MCDA) methodology. METHODS: A literature review was conducted to adapt the MCDA framework to the specific context of RCC|UCC. A total of 24 participants were involved, representing three key stakeholder groups (7 patients, 9 physicians and 8 hospital pharmacists). The study was structured in two phases. In Phase 1, participants validated the adapted MCDA framework and assigned relative weights (100-point allocation) to the framework's value criteria/sub-criteria during three individual stakeholder meetings, one per each stakeholder group. In Phase 2, participants were brought together in a multi-stakeholder meeting to review findings of each stakeholder group, after which stakeholders repeated the weighting exercise as a collective group. All meetings included reflective discussion by participants of each value criteria/sub-criteria included within the adapted MCDA framework, where stakeholders shared their perspectives and opinions on what represents value in RCC|UCC. RESULTS: Refractory or unexplained chronic cough is regarded as a chronic medical condition, with variable severity across patients and the potential to heavily impact their HRQoL (including physical, psychological and social/work productivity domains). Current treatments used by healthcare professionals, which have not been specifically developed and are not approved for RCC|UCC, show limited clinical effectiveness and associated safety and tolerability issues, which result in frequent treatment discontinuations. The reduction of the average cough frequency over a 24-h period is regarded as the primary goal of treatment by stakeholders, with the aim of improving HRQoL. Improvement of other cough symptoms, such as intensity, is also considered important. Minor adverse events and a slower onset of treatment effect would be acceptable to stakeholders if accompanied by strong efficacy and improvement in HRQoL. Given the inability to measure cough frequency in clinical practice, Patient-Reported Outcomes (PROs) could be considered a proxy of treatment effectiveness. A multidisciplinary approach to the condition is regarded as key for treatment success. CONCLUSIONS: Refractory or unexplained chronic cough is a medical condition that seriously impacts patients' HRQoL. The primary goal of treatment is to improve patients' HRQoL by reducing the frequency and intensity of cough.

La tos crónica refractaria en la encrucijada / Refractory Chronic Cough at the Crossroads

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Tos crónica. La necesidad de optimizar su tratamiento / Chronic cough. The need to optimize its management

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Tos crónica / Chronic Cough

La tos crónica (TC), o tos que perdura más de 8 semanas, ha merecido un interés creciente en los últimos años debido a los avances producidos que han motivado un cambio de visión respecto a la clásica tríada diagnóstica y terapéutica en vigor desde la década de los setenta. Unos resultados no óptimos en el tratamiento que alcanza los dos tercios de casos, junto a una nueva concepción de la TC como síndrome de hipersensibilidad con 2 polos, periférico y central, similares al dolor crónico, ocasionan que se contemple este problema tan frecuente en la práctica clínica de una nueva manera. Los receptores periféricos de la TC siguen teniendo vigencia bajo la tríada diagnóstica; sin embargo, tanto la convergencia de estímulos como la hipersensibilidad adquirida a nivel del sistema nervioso central son hechos que tienen una repercusión clave en el éxito del tratamiento

Chronic cough (CC), or cough lasting more than 8 weeks, has attracted increased attention in recent years following advances that have changed opinions on the prevailing diagnostic and therapeutic triad in place since the 1970s. Suboptimal treatment results in two thirds of all cases, together with a new notion of CC as a peripheral and central hypersensitivity syndrome similar to chronic pain, have changed the approach to this common complaint in routine clinical practice. The peripheral receptors involved in CC are still a part of the diagnostic triad. However, both convergence of stimuli and central nervous system hypersensitivity are key factors in treatment success

Chronic Cough.

Chronic cough (CC), or cough lasting more than 8 weeks, has attracted increased attention in recent years following advances that have changed opinions on the prevailing diagnostic and therapeutic triad in place since the 1970s. Suboptimal treatment results in two thirds of all cases, together with a new notion of CC as a peripheral and central hypersensitivity syndrome similar to chronic pain, have changed the approach to this common complaint in routine clinical practice. The peripheral receptors involved in CC are still a part of the diagnostic triad. However, both convergence of stimuli and central nervous system hypersensitivity are key factors in treatment success.

Gastroesophageal reflux as a cause of chronic cough, severe asthma, and migratory pulmonary infiltrates.

Gastroesophageal reflux (GER), asthma-type cough and upper airway disease are the most common causes of chronic cough syndrome. We present a case in which impedance-pH monitoring indicated severe mixed acid-nonacid esophageal reflux reaching the upper third of the esophagus in 75% of nonacid events. GER and the associated aspiration episodes were shown to be the cause of severe asthma attacks and migratory pulmonary infiltrates. GER was caused by a sleeve gastrectomy, which seriously disabled the mechanisms preventing reflux from reaching the airways. Respiratory symptoms improved notably after abdominal surgery to correct the GER, suggesting a close causal relationship between GER and all the symptoms, including asthma. However, this issue remains unresolved in the literature.

Expert opinion on the cough hypersensitivity syndrome in respiratory medicine.

In 2011, a European Respiratory Society Task Force embarked on a process to determine the position and clinical relevance of the cough hypersensitivity syndrome, a disorder characterised by troublesome coughing often triggered by low levels of thermal, mechanical or chemical exposure, in the management of patients with chronic cough. A 21-component questionnaire was developed by an iterative process supported by a literature review. 44 key opinion leaders in respiratory medicine were selected and interviewed as to their opinions. There was a high degree of unanimity in the responses obtained, with all opinion leaders supporting the concept of cough hypersensitivity as a clinically useful paradigm. The classic stratification of cough into asthmatic, rhinitic and reflux-related phenotypes was supported. Significant disparity of opinion was seen in the response to two questions concerning the therapy of chronic cough. First, the role of acid suppression in reflux cough was questioned. Secondly, the opinion leaders were split as to whether a trial of oral steroids was indicated to establish a diagnosis of eosinophilic cough. The cough hypersensitivity syndrome was clearly endorsed by the opinion leaders as a valid and useful concept. They considered that support of patients with chronic cough was inadequate and the Task Force recommends that further work is urgently required in this neglected area.

Chronic cough: from a complex dysfunction of the neurological circuit to the production of persistent cough.

Chronic cough or cough that lasts more than 8 weeks, once a chest x-ray and spirometry are confirmed normal, is caused by an alteration in a section of the route between peripheral receptors, mainly in the upper and lower airway and oesophagus, spinal cord and the cough centre in the brain stem involving the cortex. These mechanisms of cough have their homology in the circuit of chronic pain, and on that basis, should expand future research of chronic cough. Clinically chronic cough is easy to diagnose by an excessive response or hypertussia to low-intensity stimuli or banal stimuli, which we now call hypersensitivity cough syndrome, quantified by a positive reflex cough with capsaicin or citric acid. However, hypersensitivity cough syndrome can be impossible to quantify in the laboratory when the hyper-responsiveness originates in the central nervous system. This is normally caused by excessive peripheral input or convergence of stimuli from different sources. Once central hypersensitivity is acquired, peripheral input is not as important for activation of the cough.

Participación laríngea en la tos crónica / The role of the larynx in chronic cough

La tos crónica es la que dura más de 8 semanas. Una vez descartadas las causas clásicas de tos crónica, actualmente se considera que la etiología más probable está constituida por los trastornos sensoriales del nervio vago. Los pacientes con tos crónica de origen laríngeo presentan síntomas asociados como globo, disfagia, disfonía, disnea y/o estridor. Estos pacientes tienen mayor tendencia a sufrir movimiento vocal paradójico. Existe una sensibilización al reflejo de la tos y una respuesta neuropática laríngea causada principalmente por infección viral o por reflujo. La tos asociada a reflujo tiene 2 mecanismos: exposición al ácido en el esófago distal (reflujo gastroesofágico) y microaspiración del contenido esofágico en la laringe y en el árbol traqueobronquial (reflujo faringolaríngeo). La neuropatía laríngea crea hipersensibilidad que respondería bien a la readaptación (rehabilitación) logopédica como forma de tratamiento a tos crónica refractaria. Por ser la tos crónica un signo de neuropatía sensorial de la laringe puede mejorar con medicamentos neurolépticos como amitriptilina y gabapentina (AU)

Cough lasting more than 8 weeks is considered chronic. If the classic causes of chronic cough have been discarded, vagus nerve sensory disturbances are currently considered the most important etiological cause. Patients with chronic cough of laryngeal origin have associated symptoms such as globus, dysphagia, dysphonia, dyspnoea and/or stridor. These patients are more likely to have paradoxical vocal fold movement. There is a higher cough reflex sensibility and neuropathic laryngeal response, mainly caused by viral infection or reflux. The cough associated with reflux has 2 mechanisms: Exposure to acid in the distal oesophagus (gastroesophageal reflux) and microaspiration of oesophageal contents into the larynx and tracheo-bronchial tree (pharyngo-laryngeal reflux). Laryngeal neuropathy hypersensitivity responds well to speech therapy as a treatment for refractory chronic cough. Because chronic cough is a sign of laryngeal sensory, neuropathy can improve with neuroleptic drugs such as amitriptyline and gabapentin (AU)

Refractory chronic cough, or the need to focus on the relationship between the larynx and the esophagus.

In this review we question the current way of handling tackle a problem of chronic cough, especially by the excessive number of patients who can not find complete relief from your cough by anatomical diagnosis of universal use. From the field of Otolaryngology new perspectives arise now considering the larynx as a preferential afferent stimuli cough reflex arc. Also the constitution laryngopharyngeal reflux gas and new approaches to non-acid reflux and the local action of pepsin in laryngeal deserving of a joint review, which can illuminate new ways to handle the problem of chronic refractory cough. We believe that the chronic cough syndrome hpersensitivity as more precise label for chronic cough, should place particular emphasis on laryngeal sensory neuropathy as cough and reflux the influence that may have on their maintenance, and thereby causes definitely wide related to the syndrome if the larynx is incorporated, place greater number of afferent nerves of chronic cough, which are sure to cover much of the case of refractory cough remain without a satisfactory solution. The close collaboration between Otolaryngology, Gastroenterology and Pneumology in a patient with refractory chronic cough seems now an unavoidable necessity.

Tos crónica refractaria. Nuevas perspectivas en diagnóstico y tratamiento / Refractory Chronic Cough: New Perspectives in Diagnosis and Treatment

En los pacientes con tos crónica todavía existe una población cercana al 40% que no mejora definitivamente su tos a pesar de aplicar correctamente el diagnóstico anatómico al uso. En muchos de esos pacientes con tos refractaria los síntomas laríngeos son frecuentes. La zona de la laringe-faringe se configura como el puente entre el esófago y el tracto respiratorio superior e inferior. La asociación de reflujo en pacientes con tos crónica y síntomas como globo laríngeo, picor o la necesidad de aclarar la garganta han merecido atención recientemente por la posibilidad de intervención terapéutica conjunta sobre el reflujo gastroesofágico y la laringe, tanto con nuevas medicaciones como con terapias de rehabilitación laríngea, con beneficios objetivables en la desaparición de la tos crónica en casos que habían sido etiquetados previamente como refractarios(AU)

In patients with chronic cough, nearly 40% of the population does not experience definitive improvement of their cough despite correctly applying the anatomic diagnosis. In many of these patients with refractory cough, laryngeal symptoms are frequent. The region of the larynx/pharynx is configured as a bridge between the esophagus and the upper and lower respiratory tract. The association of reflux in patients with chronic cough and symptoms such as globus pharyngis, itchiness or the need to clear one's throat have recently been given attention due to the possibility of joint therapeutic intervention of the gastroesophageal reflux and larynx, both with new medications as well as with laryngeal rehabilitation therapies, with observed benefits in the disappearance of chronic cough in cases that had been previously labeled as refractory(AU)

The role of the larynx in chronic cough.

Cough lasting more than 8 weeks is considered chronic. If the classic causes of chronic cough have been discarded, vagus nerve sensory disturbances are currently considered the most important etiological cause. Patients with chronic cough of laryngeal origin have associated symptoms such as globus, dysphagia, dysphonia, dyspnoea and/or stridor. These patients are more likely to have paradoxical vocal fold movement. There is a higher cough reflex sensibility and neuropathic laryngeal response, mainly caused by viral infection or reflux. The cough associated with reflux has 2 mechanisms: Exposure to acid in the distal oesophagus (gastroesophageal reflux) and microaspiration of oesophageal contents into the larynx and tracheo-bronchial tree (pharyngo-laryngeal reflux). Laryngeal neuropathy hypersensitivity responds well to speech therapy as a treatment for refractory chronic cough. Because chronic cough is a sign of laryngeal sensory, neuropathy can improve with neuroleptic drugs such as amitriptyline and gabapentin.

Refractory chronic cough: new perspectives in diagnosis and treatment.

In patients with chronic cough, nearly 40% of the population does not experience definitive improvement of their cough despite correctly applying the anatomic diagnosis. In many of these patients with refractory cough, laryngeal symptoms are frequent. The region of the larynx/pharynx is configured as a bridge between the esophagus and the upper and lower respiratory tract. The association of reflux in patients with chronic cough and symptoms such as globus pharyngis, itchiness or the need to clear one's throat have recently been given attention due to the possibility of joint therapeutic intervention of the gastroesophageal reflux and larynx, both with new medications as well as with laryngeal rehabilitation therapies, with observed benefits in the disappearance of chronic cough in cases that had been previously labeled as refractory.

Paraparesia espástica tropical y anestesia: reporte de caso y revisión temática / Tropical Spastic Paraparesis and Anesthesia: Case Report and Topic Review

Introducción: La paraparesia espástica tropical es una infección endémica en Colombia, causada por el retrovirus HTLV-1. Se caracteriza por una mielopatía de lenta instauración que compromete principalmente los miembros inferiores. Las complicaciones como escaras por decúbito prolongado, retención urinaria por disfunción esfinteriana, fracturas, etc. hacen de estos pacientes candidatos quirúrgicos potenciales. Objetivo: Reporte de caso y revisión temática de la fisiopatología, la epidemiología, la clínica y el tratamiento, y de los aspectos anestésicos básicos de la enfermedad. Metodología: Reporte de caso y revisión temática. Se incluyeron en la búsqueda ensayos clínicos, metaanálisis, guías para la práctica, ensayos controlados aleatorizados, revisiones, reportes de casos, artículos clásicos, estudios comparativos, conferencias de consenso, clases magistrales y libros de texto, de artículos publicados sobre paraparesia espástica tropical/mielopatía asociada al HTLV-1 (PET/MAH) e implicaciones anestésicas. Se incluyeron las publicaciones cuyo tema central fuese etiología, fisiopatología, epidemiología, manifestaciones clínicas, tratamiento y repercusiones anestésicas de PET/MAH. Se realizó una búsqueda en PubMed, MdConsult, EBSCOhost, OvidSP y Scielo de artículos en inglés y español. Se utilizaron los términos MeSH: paraparesis, tropical spastic, anesthesia y los términos DeCS: paraparesia espástica tropical, anestesia. Se estudiaron de forma independiente los títulos y resúmenes de los artículos identificados en las bases de datos. Resultados: Se describe el caso de un adulto masculino quien fue llevado a cirugía para reconexión uretral, después de presentar una de las complicaciones características de la paraparesia espástica tropical. La búsqueda arrojó 1.829 estudios. Veinte escritos cumplieron con los criterios de inclusión. Se hace una presentación de implicaciones anestésicas y de la enfermedad.

Introduction: Tropical spastic paraparesis is an endemic infection in Colombia caused by the HTLV-1 retrovirus. It is characterized by a slow and progressive myelopathy that initially targets lower limbs. Complications such as eschars due to a prolonged decubitus, urinary retention to sphincter dysfunction, fractures, etc. make these patients potential surgery candidates. Objective: To report a case and to review the physiopathology, epidemiology, clinical manifestations, treatment and basic anesthetic considerations of this disease. Methods: Case report and topic review. The research included clinical trials, meta-analysis, practice guides, randomized controlled assays, revisions, case reports, classic articles, comparative studies, consensus conferences, magisterial classes and textbooks regarding published articles on tropicalsSpastic paraparesis/HTLV-1 (TSP/HAM) Associated myelopathy and anesthetic implications. Publications focused on etiology, physiopatology, epidemiology, clinical manifestations, treatment and anesthetic repercussions of TSP/ HAM were included in this article. Research was carried out through PubMed, MdConsult, EBSCOhost, OvidSP, and Scielo, of articles in English and Spanish. The MeSH terms used were: paraparesis, tropical spastic, anesthesia and the DeCS terms were: paraparesia espástica tropical, anestesia. Titles and abstracts of articles identified in the database were studied independently. Results: We describe the case of a male adult patient who was admitted to surgery for urethral reconnection after presenting a classic complication of tropical spastic paraparesis. Research on the topic yielded 1829 studies. A total 20 writings met the inclusion criteria. We present implications regarding anesthesia and the disease.

Tos crónica de escasa respuesta al tratamiento e incidencia de reflujo gastroesofágico / Chronic Cough With Limited Response to Treatment and Incidence of Gastroesophageal Reflux

Nuestro objetivo fue evaluar la asociación entre tos crónica y las variables que pudieran incidir en el curso de la tos, con objeto de extraer un perfil del tosedor de peor respuesta. En nuestra unidad de tos crónica 192 pacientes fueron seguidos prospectivamente durante 3 meses, durante los que se valoraron y trataron todas las variables que pudieran influir en el reflejo de la tos. La mejoría de la tos se evaluó por la respuesta del paciente ante una escala visual analógica con puntuaciones de 0 a 4, considerándose el valor 0 como «sin cambios», y como mejoría una puntuación en la escala de 3 o 4. Se consideró tos de escasa respuesta si persistía sin mejoría más allá de los 3 meses. Mediante un modelo de regresión logística multivariante se introdujeron variables candidatas a estar asociadas a la mejoría de la tos a los 3 meses. En el modelo final del perfil del tosedor de mal pronóstico permanecen 3 variables: sexo, reflujo gastroesofágico típico y trastorno psicosocial. Ser hombre está asociado con una mejoría de la tos a los 3 meses (OR=2,10, IC95%: 1,00-4,38). Sin embargo, presentar reflujo gastroesofágico está asociado con una reducción de la mejoría a los 3 meses en un 55% (OR=0,45, IC95%: 0,24-0,84), y padecer un trastorno psicosocial disminuye la probabilidad de mejoría de la tos a los 3 meses en un 70% (OR=0,30, IC95%: 0,09-1,03)(AU)

Our objective was to evaluate the association between chronic cough and the variables that could influence the course of the cough in order to develop a profile for coughers with poor response to treatment. In our Chronic Cough Unit, 192 patients were prospectively followed up for 3 months, during which time all the variables that could influence the cough reflex were evaluated and treated. The improvement in cough was evaluated by the response of the patients to a visual analogical scale with scores from 0 to 4, considering 0 as «no changes» and an improvement as a score of 3 or 4. The cough was considered to have little response to treatment if it persisted without any improvement for more than 3 months. Using a multivariate logistic regression model, we input variables that were candidates for being associated with the improvement in cough 3 months later. In the final profile model of the cougher with poor prognosis, three variables remained: sex, typical gastroesophageal reflux and psychosocial disorder. Being male is associated with an improvement in cough 3 months later (OR=2.10, 95%CI 1.00-4.38). However, having gastroesophageal reflux is associated with a reduction in the improvement three months later in 55% (OR=0.45, 95%CI 0.24-0.84), and having a psychosocial disorder reduces the probability for improvement of the cough 3 months later in 70% (OR=0.30, 95%CI 0.09-1.03)(AU)

Chronic cough with limited response to treatment and incidence of gastroesophageal reflux.

Our objective was to evaluate the association between chronic cough and the variables that could influence the course of the cough in order to develop a profile for coughers with poor response to treatment. In our Chronic Cough Unit, 192 patients were prospectively followed up for 3 months, during which time all the variables that could influence the cough reflex were evaluated and treated. The improvement in cough was evaluated by the response of the patients to a visual analogical scale with scores from 0 to 4, considering 0 as «no changes¼ and an improvement as a score of 3 or 4. The cough was considered to have little response to treatment if it persisted without any improvement for more than 3 months. Using a multivariate logistic regression model, we input variables that were candidates for being associated with the improvement in cough 3 months later. In the final profile model of the cougher with poor prognosis, three variables remained: sex, typical gastroesophageal reflux and psychosocial disorder. Being male is associated with an improvement in cough 3 months later (OR=2.10, 95%CI 1.00-4.38). However, having gastroesophageal reflux is associated with a reduction in the improvement three months later in 55% (OR=0.45, 95%CI 0.24-0.84), and having a psychosocial disorder reduces the probability for improvement of the cough 3 months later in 70% (OR=0.30, 95%CI 0.09-1.03).