Role of Thymic Stromal Lymphopoietin in the Pathophysiology of Asthma and Clinical and Biological Effects of Blockade With Tezepelumab.

BACKGROUND: The airway epithelium is the first line of defense of the respiratory system against the external environment. It plays an active role in the initiation of immune and allergic responses against potential hazards. Among the various specialized cells and cytokines that participate in epithelium-induced responses, alarmins are particularly interesting, given their ample role in mediating T2 and non-T2 inflammatory mechanisms involved in the pathogenesis of asthma. Thymic stromal lymphopoietin (TSLP) is an alarmin with broad effects in asthma that result from its widespread action on multiple cell types, including eosinophils, mast cells, dendritic cells, and group-2 innate lymphoid cells. Its role in allergy-mediated responses, eosinophilic inflammation, airway hyperresponsiveness, mucus hyperproduction, viral tolerance, and airway remodeling is of the utmost importance, as more comprehensive asthma assessments have been developed to explore these pathogenic features. Therefore, blockade with targeting molecules, such as monoclonal antibodies, has emerged as a promising therapeutic option, particularly in patients with multiple pathogenic pathways. In this review, we examine the roles of alarmins (mainly TSLP) in the pathogenesis of asthma and clinical expression and discuss the effects of inhibiting TSLP on several inflammatory and clinical outcomes. We also review the literature supporting treatment with anti-TSLP biologics and the unanswered questions and unmet needs associated with targeting alarmins in asthma.

Response to Monoclonal Antibodies in Asthma: Definitions, Potential Reasons for Failure, and Therapeutic Options for Suboptimal Response.

Real-life data reveal that more than half of severe asthma patients treated with monoclonal antibodies (mAbs) do not achieve a complete response. Response to mAbs must be assessed holistically, considering all the clinically meaningful therapeutic goals, not only reduction of exacerbations and oral corticosteroids. There are 2 different ways of measuring the response to mAbs. One, qualitative, classifies patients according to the degree of disease control they have achieved, without explaining how much a given patient improves relative to the baseline (pre-mAb) clinical situation; the other, quantitative, scores the changes occurring after treatment. Both methods are complementary and essential to making clinical decisions on whether to continue treatment. The various potential causes of suboptimal response to mAbs include incorrect identification of the specific T2 pathways, comorbidities that reduce the room for improvement, insufficient dose, autoimmune phenomena, infections, change in the initial inflammatory endotype, and adverse events. Once a suboptimal response has been confirmed, a well-structured and multifaceted assessment of the potential causes of failure should be performed, with emphasis on the resulting inflammatory process of the airway after mAb therapy and the presence of chronic or recurrent infection. This investigation should guide the decision on the best therapeutic approach. The present review aims to help clinicians gain insights into how to measure response to mAbs and proceed in cases of suboptimal response.

Exacerbations of Severe Asthma While on Anti-IL-5 Biologics.

Anti-interleukin 5 (IL-5) and anti-IL-5 receptor α monoclonal antibodies markedly decrease airway and peripheral blood eosinophil numbers and are thus highly effective in reducing asthma exacerbations. Nonetheless, these biologics do not completely resolve exacerbations. There is very little information on the cellular nature of exacerbations during treatment with biologics. Using illustrative clinical case scenarios, we highlight the importance of carefully characterizing asthmatics at the time of exacerbation and recognizing neutrophilic causes of exacerbations to ensure optimal management. While an eosinophilic exacerbation may improve with more corticosteroids or by switching to another anti-IL-5 monoclonal antibody, a noneosinophilic exacerbation will likely not. An infective exacerbation needs to be recognized, and the pathogen must be identified and treated with the appropriate antimicrobial agent.

Quality indicators in the rational management of severe asthma: A Spanish multidisciplinary consensus.

AIM: Severe asthma is a complex, heterogeneous condition that can be difficult to control despite currently available treatments. Multidisciplinary severe asthma units (SAU) improve control in these patients and are cost-effective in our setting; however, their implementation and development can represent an organizational challenge. The aim of this study was to validate a set of quality care indicators in severe asthma for SAU in Spain. METHODS: The Carabela initiative, sponsored by SEPAR, SEAIC, SECA and SEDISA and implemented by leading specialists, analyzed the care processes followed in 6 pilot centers in Spain to describe the ideal care pathway for severe asthma. This analysis, together with clinical guidelines and SEPAR and SEAIC accreditation criteria for asthma units, were used to draw up a set of 11 quality of care indicators, which were validated by a panel of 60 experts (pulmonologists, allergologists, and health-policy decision-makers) using a modified Delphi method. RESULTS: All 11 indicators achieved a high level of consensus after just one Delphi round. CONCLUSIONS: Experts in severe asthma agree on a series of minimum requirements for the future optimization, standardization, and excellence of current SAUs in Spain. This proposal is well grounded on evidence and professional experience, but the validity of these consensus indicators must be evaluated in clinical practice.

[Troponin-I in hemodynamically-stable pulmonary embolism: correlation with echocardiography and computed tomography angiography]. / Troponina-I en el tromboembolismo pulmonar hemodinámicamente estable: correlación con la ecocardiografía y la angiografía por tomografía computarizada.

BACKGROUND: Troponin-I (TnI) is a marker of severe pulmonary thromboembolism (PTE) in unselected patients. There are few articles that assess its usefulness in hemodynamically-stable patients. OBJECTIVES: To assess the correlation between TnI levels and both echocardiographic/radiologic signs of right ventricle (RV) dysfunction or pulmonary hypertension (PH), and the severity of the pulmonary vascular obstruction. METHODS: We selected patients from a prospective cohort of 103 consecutive patients with PTE and systolic arterial pressure ≥ 90 mmHg. Computed tomography pulmonary angiography (CTPA) and echocardiography were performed in all patients. We performed a post hoc study, analyzing the 68 cases in which TnI was measured, at the discretion of the emergency room physician. RESULTS: Patients included had a median age of 74 years and 50% were male. The patients with elevated TnI had a differentiated clinical profile, suggestive of more severe PTE. There was a significant correlation between TnI levels and systolic pulmonary artery pressure (r=0.46, P<.001), the CTPA-measured pulmonary artery diameter (r=0.48, P<.001), the CTPA-measured RV diameter (r=0.47, P=.001) and the pulmonary vascular obstruction index (r=0.39, P=.001). CONCLUSION: The higher levels of TnI in patients with hemodynamically stable PTE predicts the existence of more severe PE in hemodynamically-stable patients. This biomarker could be used in the clinical practice to select those patients who might require more intensive monitoring or additional complementary studies.

[Intra-articular fracture of the calcaneus associated with injury to lateral collateral ligaments of the ankle]. / Fractura intraarticular de calcáneo asociada a lesión de ligamentos colaterales laterales del tobillo.

Calcaneal fractures are the most frequent of the tarsus (3.5% of all fractures). Young adults are mainly affected, being more frequent in men (5.9:1). On the other hand, ligament injuries associated with fracture of the calcaneus are very infrequent. We describe a case of a 39 year old patient who suffered ankle trauma. He presented instability in plantar flexion and inversion. A fracture of the calcaneus was diagnosed. During surgery, a complete lesion of the lateral ligament complex was found. The reduction and osteosynthesis associated with ligament reconstruction was performed. We consider important to confirm the stability of the ankle after a calcaneus fracture. Lack of diagnosis in this type of injuries can evolve into chronic instability.

Las fracturas de calcáneo son las más frecuentes del tarso (3.5% de todas las fracturas). Afectan a adultos jóvenes, siendo más frecuentes en hombres (5.9:1). Por otro lado, las lesiones ligamentarias asociadas a fractura de calcáneo no son muy frecuentes. Presentamos un caso de un paciente de 39 años que sufrió entorsis de tobillo. Mostraba inestabilidad en flexión plantar e inversión. Radiografías mostraron una fractura de calcáneo. Durante la cirugía se evidenció una lesión completa del complejo ligamentario lateral. Se realizó la reducción y osteosíntesis asociada a la reconstrucción ligamentaria. Ante fracturas de calcáneo es importante corroborar la estabilidad del tobillo. La falta de diagnóstico en este tipo de lesiones puede generar inestabilidades crónicas.

Exhaled nitric oxide predicts control in patients with difficult-to-treat asthma.

We aimed to evaluate the accuracy of baseline exhaled nitric oxide fraction (F(eNO)) to recognise individuals with difficult-to-treat asthma who have the potential to achieve control with a guideline-based stepwise strategy. 102 consecutive patients with suboptimal asthma control underwent stepwise increase in the treatment with maximal fluticasone/salmeterol combination dose for 1 month. Then, those who remained uncontrolled received oral corticosteroids for an additional month. With this approach, 53 patients (52%) gained control. Those who achieved control were more likely to have positive skin results (60.4% versus 34%; p = 0.01), positive bronchodilator test (57.1% versus 35.8%; p = 0.02) and peak expiratory flow variability > or =20% (71.1% versus 49.1%; p = 0.04). Conversely, depression was more frequent in those who remained uncontrolled (18.4 % versus 43.4 %; p = 0.01). An F(eNO) value > or =30 ppb demonstrated a sensitivity of 87.5% (95% CI 73.9-94.5%) and a specificity of 90.6% (95% CI 79.7-95.9%) for the identification of responsive asthmatics. The current results suggest that F(eNO) can identify patients with difficult-to-treat asthma and the potential to respond to high doses of inhaled corticosteroids or systemic steroids.

Response to Monoclonal Antibodies in Asthma: Definitions, Potential Reasons for Failure, and Therapeutic Options for Suboptimal Response

Real-life data reveal that more than half of severe asthma patients treated with monoclonal antibodies (mAbs) do not achieve a complete response. Response to mAbs must be assessed holistically, considering all the clinically meaningful therapeutic goals, not only reduction of exacerbations and oral corticosteroids. There are 2 different ways of measuring the response to mAbs. One, qualitative, classifies patients according to the degree of disease control they have achieved, without explaining how much a given patient improves relative to the baseline (pre-mAb) clinical situation; the other, quantitative, scores the changes occurring after treatment. Both methods are complementary and essential to making clinical decisions on whether to continue treatment. The various potential causes of suboptimal response to mAbs include incorrect identification of the specific T2 pathways, comorbidities that reduce the room for improvement, insufficient dose, autoimmune phenomena, infections, change in the initial inflammatory endotype, and adverse events. Once a suboptimal response has been confirmed, a well-structured and multifaceted assessment of the potential causes of failure should be performed, with emphasis on the resulting inflammatory process of the airway after mAb therapy and the presence of chronic or recurrent infection. This investigation should guide the decision on the best therapeutic approach. The present review aims to help clinicians gain insights into how to measure response to mAbs and proceed in cases of suboptimal response (AU)

Los estudios clínicos en vida real revelan que más de la mitad de los pacientes con asma grave, tratados con anticuerpos monoclonales (mAb), no logran una respuesta completa. La respuesta a los mAbs debe evaluarse de manera integral, considerando todos los objetivos terapéuticos clínicamente significativos y no solo las exacerbaciones o la reducción de corticosteroides orales. Existen dos formas diferentes de medir la respuesta a los mAbs: una, cualitativa, que clasifica a los pacientes según el grado de control de la enfermedad que han logrado, sin explicar cuánto mejora un determinado paciente con respecto a su situación clínica basal (pre-mAb); y la otra, cuantitativa, la cual puntúa los cambios ocurridos después del tratamiento. Ambos métodos son complementarios y claramente esenciales a la hora de tomar decisiones clínicas sobre la continuación del tratamiento con estos fármacos biológicos. Se han descrito varias causas posibles de respuesta subóptima a los mAbs que son: la identificación incorrecta de las vías T2 específicas, las comorbilidades que reducen el margen de mejora, una dosis insuficiente, fenómenos autoinmunes, infecciones, cambio del endotipo inflamatorio inicial y la aparición de efectos adversos. na vez que se ha confirmado una respuesta subóptima, se debe realizar una evaluación bien estructurada y polifacética de estas posibles causas del fracaso, considerando, en particular, el proceso inflamatorio residual de las vías respiratorias tras la terapia con mAb y la presencia de infecciones crónicas o recurrentes. Esta evaluación es la que debe guiar las decisiones sobre el mejor enfoque terapéutico. Esta revisión tiene como objetivo ayudar a los clínicos a obtener un conocimiento más profundo sobre cómo medir la respuesta a los mAbs y cómo proceder con los pacientes que presenten una respuesta subóptima (AU)

Multidisciplinary expert discussion. Uncontrolled asthma: causes, consequences and possible solutions / Debate multidisciplinar de expertos. Asma no controlada: causas, consecuencias y posibles soluciones.

Background. Numerous studies conclude that about half of the asthmatic population is not well controlled. The aim of this study was to discuss causes, consequences and possible solutions of uncontrolled asthma (UCA). Methods. Discussion amongst asthma experts from the fields of Pneumology, Allergy and Primary Care, structured in three phases: 1) survey to get the opinion of participants involved in different areas of UCA; 2) expert meeting, in which the results of the survey were discussed, and the diagnosis, treatment and monitoring of UCA were presented and discussed; and, 3) with the main findings, 83 items were formulated and subjected to consensus among all participants through the Delphi method. Results. There was consensus on 86.7% of the items in the Delphi questionnaire, mostly in terms of agreement. Conclusions. The UCA analysis results show the need for future improvement in the following areas: to incorporate clinical performance protocols into asthma CPG to identify aggravating factors and comorbidities; to develop an inexpensive and easy-to-use tool to identify adherence; to establish patient phenotype; to analyse treatment side effects and to provide personalized treatment, especially assessing its efficacy and safety (symptom control and future risks). It is necessary to generate new evidence to determine additional tests to be used to monitor these patients.

Fractura intraarticular de calcáneo asociada a lesión de ligamentos colaterales laterales del tobillo / Intra-articular fracture of the calcaneus associated with injury to lateral collateral ligaments of the ankle

Resumen: Las fracturas de calcáneo son las más frecuentes del tarso (3.5% de todas las fracturas). Afectan a adultos jóvenes, siendo más frecuentes en hombres (5.9:1). Por otro lado, las lesiones ligamentarias asociadas a fractura de calcáneo no son muy frecuentes. Presentamos un caso de un paciente de 39 años que sufrió entorsis de tobillo. Mostraba inestabilidad en flexión plantar e inversión. Radiografías mostraron una fractura de calcáneo. Durante la cirugía se evidenció una lesión completa del complejo ligamentario lateral. Se realizó la reducción y osteosíntesis asociada a la reconstrucción ligamentaria. Ante fracturas de calcáneo es importante corroborar la estabilidad del tobillo. La falta de diagnóstico en este tipo de lesiones puede generar inestabilidades crónicas.

Abstract: Calcaneal fractures are the most frequent of the tarsus (3.5% of all fractures). Young adults are mainly affected, being more frequent in men (5.9:1). On the other hand, ligament injuries associated with fracture of the calcaneus are very infrequent. We describe a case of a 39 year old patient who suffered ankle trauma. He presented instability in plantar flexion and inversion. A fracture of the calcaneus was diagnosed. During surgery, a complete lesion of the lateral ligament complex was found. The reduction and osteosynthesis associated with ligament reconstruction was performed. We consider important to confirm the stability of the ankle after a calcaneus fracture. Lack of diagnosis in this type of injuries can evolve into chronic instability.

Exacerbations of severe asthma while on anti-IL-5 biologics

Anti-interleukin 5 (IL-5) and anti-IL-5 receptor alfa monoclonal antibodies markedly decrease airway and peripheral blood eosinophil numbers and are thus highly effective in reducing asthma exacerbations. Nonetheless, these biologics do not completely resolve exacerbations. There is very little information on the cellular nature of exacerbations during treatment with biologics. Using illustrative clinical case scenarios, we highlight the importance of carefully characterizing asthmatics at the time of exacerbation and recognizing neutrophilic causes of exacerbations to ensure optimal management. While an eosinophilic exacerbation may improve with more corticosteroids or by switching to another anti-IL-5 monoclonal antibody, a noneosinophilic exacerbation will likely not. An infective exacerbation needs to be recognized, and the pathogen must be identified and treated with the appropriate antimicrobial agent

Los anticuerpos monoclonales anti-interleucina 5 (IL5) y anti-receptor de IL5 son altamente efectivos en reducir las exacerbaciones del asma al disminuir notablemente el número de eosinófilos en las vías respiratorias y en sangre periférica. Sin embargo, aun estando bajo el tratamiento con estos biológicos, las descompensaciones asmáticas no desaparecen por completo. Disponemos de una modesta evidencia que señala la naturaleza de estas exacerbaciones, y los pacientes afectos de asma grave en estas terapias podrían tener exacerbaciones graves no eosinofílicas. Utilizando como escenarios ilustrativos varios casos clínicos, destacamos la importancia de caracterizar cuidadosamente al paciente asmático en el momento de la exacerbación y reconocer las causas neutrofílicas de las exacerbaciones, lo cual es de importancia a la hora de manejar estas exacerbaciones. Si bien una exacerbación eosinofílica puede beneficiarse con más glucocorticosteroides o al cambiar a otro mAb anti-IL5, una exacerbación no eosinofílica probablemente no lo hará. Es necesario reconocer una exacerbación infecciosa, identificar el patógeno y tratarlo con el agente antimicrobiano más apropiado

Henoch-Schönlein purpura as a clinical presentation of small cell lung cancer.

Although exceptionally, Henoch-Schönlein purpura (HSP) may appear as a paraneoplastic syndrome. We report a patient presenting with HSP. A chest X-ray showed a pulmonary nodule, while biopsy of a transthoracic needle aspiration revealed small cell lung cancer. To the best of our knowledge, HSP as a clinical presentation of small cell lung cancer has not been previously reported.