The Incredible Adventure of Omalizumab.

The basis of our current understanding of allergies begins with the discovery of IgE in the mid-1960s. The whole theory of the physiology and pathophysiology of allergic diseases, including rhinitis and asthma, dates from that period. Among the key regions of IgE identified were the FAB (fragment antigen binding) portion that has the ability to capture allergens, and the Cε3 domain, through which IgE binds to its membrane receptor. It was then postulated that blocking IgE at the level of the Cε3 domain would prevent it from binding to its receptor and thus set in motion the allergic cascade. This was the beginning of the development of omalizumab, a monoclonal antibody with an anti-IgE effect. In this article, we review the pathophysiology of allergic disease and trace the clinical development of omalizumab. We also review the benefits of omalizumab treatment that are apparently unrelated to allergies, such as its effect on immunity and bronchial remodeling.

Development of a high-throughput platform to measure plasmid transfer frequency.

Antibiotic resistance represents one of the greatest threats to global health. The spread of antibiotic resistance genes among bacteria occurs mostly through horizontal gene transfer via conjugation mediated by plasmids. This process implies a direct contact between a donor and a recipient bacterium which acquires the antibiotic resistance genes encoded by the plasmid and, concomitantly, the capacity to transfer the acquired plasmid to a new recipient. Classical assays for the measurement of plasmid transfer frequency (i.e., conjugation frequency) are often characterized by a high variability and, hence, they require many biological and technical replicates to reduce such variability and the accompanying uncertainty. In addition, classical conjugation assays are commonly tedious and time-consuming because they typically involve counting colonies on a large number of plates for the quantification of donors, recipients, and transconjugants (i.e., the bacteria that have received the genetic material by conjugation). Due to the magnitude of the antibiotic resistance problem, it is critical to develop reliable and rapid methods for the quantification of plasmid transfer frequency that allow the simultaneous analysis of many samples. Here, we present the development of a high-throughput, reliable, quick, easy, and cost-effective method to simultaneously accomplish and measure multiple conjugation events in 96-well plates, in which the quantification of donors, recipients, and transconjugants is estimated from the time required to reach a specific threshold value (OD600 value) in the bacterial growth curves. Our method successfully discriminates different plasmid transfer frequencies, yielding results that are equivalent to those obtained by a classical conjugation assay.

Potential impact of mepolizumab in stepping down anti-osteporotic treatment in corticosteroid-dependent asthma.

Oral corticosteroids (OCS) are commonly used for the acute management of severe asthma exacerbations or as maintenance therapy; however, chronic use is associated with significant toxicities, e.g., osteoporosis. In the REal worlD Effectiveness and Safety (REDES) study of mepolizumab in a multicentric Spanish cohort of asthma patients, mepolizumab effectively reduced clinically severe asthma exacerbations and decreased OCS dependence. This post-hoc analysis further evaluates mepolizumab's de-escalation effect on OCS dose. Patients enrolled in REDES who had OCS consumption data available for 12 months pre- and post-mepolizumab treatment were included in this analysis. Primary outcomes were to determine the change in the proportion of patients eligible for anti-osteoporotic treatment due to the changes in OCS consumption before and after 1 year of mepolizumab treatment. All analyses are descriptive. Approximately one-third (98/318; 30.8%) of patients in REDES were on maintenance OCS at the time of mepolizumab treatment initiation. In REDES, mean cumulative OCS exposure decreased by 54.3% after 1 year of treatment. The proportion of patients on high-dose OCS (≥7.5 mg/day) fell from 57.1% at baseline to 28.9% after 12 months of mepolizumab treatment. Thus, 53.6% of OCS-dependent asthma patients treated with mepolizumab would cease to be candidates for anti-osteoporotic treatment according to guidelines thresholds.

Dual Monoclonal Antibody Therapy for a Severe Asthma Patient.

INTRODUCTION: Omalizumab, the first biological treatment for severe allergic bronchial asthma, has been on the market for more than a decade. Omalizumab was initially considered to be an IgE-blocking agent, and therefore, an inhibitor of the Th2 (allergic or adaptive) cascade. More recently, other monoclonal antibodies for severe eosinophilic asthma have become available, which exert an anti-eosinophilic effect basically by blocking IL5 or its receptor. These agents exert this effect regardless of the origin of the eosinophils (i.e., the adaptive or the innate immune system). CASE STUDY: An oral corticosteroid-dependent allergic asthma patient was treated with omalizumab. After a year of treatment, the improvement remained very limited and the medical team proposed discontinuation. However, the patient felt that her asthma had improved and she refused to give up the therapy, which continued for ten years. The mean accumulated oral corticosteroid dose per month during the last year was around 200 mg; despite this, the FEV1 was low, Since the patient had a high number of eosinophils in peripheral blood, she accepted a switch to mepolizumab when this agent became available. One year later, the clinical improvement was limited and severe symptoms of allergy reappeared, and a combination of monoclonal antiobodies (omalizumab and mepolizumab) was proposed. RESULTS: After 24 months of dual therapy, a marked improvement in the FEV1 was observed, reaching the normal range, and the OC dose was reduced to 2.5 mg per day of prednisolone. No side effects were observed. CONCLUSIONS: In some severe allergic asthma patients with persistently high eosinophil counts in peripheral blood and who are considered non- or mild responders to anti-IgE and anti-IL5 administered individually, a combination of the two antibodies covering the entire T2 spectrum may be effective.

As-needed ICS-LABA in Mild Asthma: What Does the Evidence Say?

For the last three decades, the guidelines for asthma management have supported a stepwise therapeutic approach, based on the administration of controller medications (especially inhaled corticosteroids) complemented by on-demand use of rescue medication. Classically, the rescue medication recommended comprised short-acting ß agonists (SABA). Some years ago, the use of Symbicort Maintenance and Reliever Therapy (SMART) demonstrated the benefits of a combination of budesonide-formoterol, an inhaled corticosteroid, and a long-acting ß agonist (ICS-LABA) as rescue medication in moderate and severe asthma. The results were enthusiastically received, and this therapeutic option was adopted in the guidelines for moderate to severe asthma patients. Recently, four trials (two randomised placebo control trials under the auspices of the SYGMA project and two real-life studies, Novel START, and the PRACTICAL trial) have explored the potential benefits of substituting SABA with budesonide-formoterol as rescue medication in mild asthma patients. The SYGMA 1 and 2 studies showed that the combination with formoterol-budesonide as rescue medication provides better asthma control than short-acting ß-agonists alone in GINA step 2 patients, although the superiority was slight. Compared to budesonide maintenance therapy, the fixed combination of ICS-LABA on demand provides poorer asthma control. Regarding exacerbations, the fixed dose ICS-LABA combination on demand showed the same benefits for the prevention of exacerbations as chronic ICS treatment in mild asthma patients. The Novel START study, which assessed a population with milder symptoms, concluded that the fixed dose ICS-LABA combination used as needed was superior to SABA (albuterol) as needed for the prevention of asthma exacerbations. These results in fact show that, in undertreated GINA step 2 with only SABA as needed, ICS-LABA is more effective than SABA. The authors of PRACTICAL concluded that the study provided modest evidence that the ICS-LABA combination used as-needed for symptom relief reduces the rate of severe exacerbations compared with maintenance low-dose budesonide plus terbutaline as needed, although the study was not limited to mild asthma since according to the treatment consumed, it was evident that they had recruited some moderate asthma patients. Despite this poor evidence, and ignoring the clinical histological benefits of chronic inhaled corticosteroids (especially when administered promptly), GINA 2019 recently recommended daily low dose ICS or ICS-LABA as needed as a first option for step 2 patients. For step 1, symptom-driven or as-needed treatment with ICS-LABA is recommended rather than SABA alone (the preferred option until the last GINA update). Finally, the SIENA study showed that 73% of patients with mild asthma do not have an eosinophilic phenotype and that these patients have a similar clinical response to ICS (mometasone) and antimuscarinic drugs (tiotropium), results that challenge the indication of a drug combination that incorporates ICS as a first option. Overall, we believe there is insufficient evidence for the systematic recommendation of as-needed ICS-LABA instead of SABA on request for GINA step 1 or as a replacement for chronic ICS in GINA step 2.

Correction to: As-needed ICS-LABA in Mild Asthma: What Does the Evidence Say?

Abstract, fourth to last sentence, which currently reads.

A step-down protocol for omalizumab treatment in oral corticosteroid-dependent allergic asthma patients.

AIMS: There are no specific criteria for a step-down or withdrawal dose of omalizumab (OMA). Our purpose was to evaluate the viability of a protocol for OMAlizumab DOse REduction (the OMADORE study) in severe allergic asthma (SAA). METHODS: The study population included 35 SAA patients treated during a minimum period of 1 year with oral corticosteroids (OC) equivalent to a mean daily dose of 4 mg of methyl-prednisolone. To qualify for the protocol, the patients had to have received treatment with OMA for at least one and a half years, OC dose had to have reached the lowest tolerated dose and spirometry had to be greater than or equal to that at entry. The interventions were (a) OMA dose was reduced by half; (b) if patients were clinically stable after 6 months, the dose was halved again; (c) if repeated OC boosters were needed and/or spirometry worsened by more than 10%, OMA dose was raised to the previous figure until stabilization. RESULTS: Mean age was 52.5 (17) years, median monthly OC dose was 120 (IQR: 225) mg. Pulmonary function: FVC: 79.7 (20.2)%; FEV1 : 64.8 (21.7)%; FEV1 / FVC: 61.7(13.8)%. OMA could be withdrawn in 34.3% of the patients; 22.9% tolerated a reduction, and in 42.9% the dose could not be modified. Follow-up time after reduction or withdrawal ranged from 12 to 30 months. There were no severe exacerbations requiring emergency assistance or admission. CONCLUSIONS: The OMADORE study found that in more than 50% of SAA patients on OC, OMA dose can be safely reduced or withdrawn based on a progressive dose reduction protocol.

Omalizumab Is Equally Effective in Persistent Allergic Oral Corticosteroid-Dependent Asthma Caused by Either Seasonal or Perennial Allergens: A Pilot Study.

Omalizumab is marketed for chronic severe asthma patients who are allergic to perennial allergens. Our purpose was to investigate whether omalizumab is also effective in persistent severe asthma due to seasonal allergens. Thirty patients with oral corticosteroid-dependent asthma were treated with Omalizumab according to the dosing table. For each patient with asthma due to seasonal allergens, we recruited the next two consecutive patients with asthma due to perennial allergens. The dose of oral methyl prednisolone was tapered at a rate of 2 mg every two weeks after the start of treatment with omalizumab depending on tolerance. At each monthly visit, a forced spirometry and fractional exhaled nitric oxide (FeNO) measurement were performed and the accumulated monthly methyl prednisolone dose was calculated. At entry, there were no differences between groups in terms of gender, body mass index or obesity, year exacerbation rate, monthly dose of methyl-prednisolone (MP), FeNO and blood immunoglobuline E (IgE) MP, FeNO and IgE values, or spirometry (perennial: FVC: 76%; FEV1: 62%; seasonal: FVC: 79%; FEV1: 70%). The follow-up lasted 76 weeks. One patient in each group was considered a non-responder. Spirometry did not worsen in either group. There was a significant intragroup reduction in annual exacerbation rate and methyl prednisolone consumption but no differences were detected in the intergroup comparison. Omalizumab offered the same clinical benefits in the two cohorts regardless of whether the asthma was caused by a seasonal or a perennial allergen. These results strongly suggest that allergens are the trigger in chronic asthma but that it is the persistent exposure to IgE that causes the chronicity.

Influence of dynamic leaks in volume-targeted pressure support noninvasive ventilation: a bench study.

INTRODUCTION: The effect of leaks on volume-targeted pressure support noninvasive ventilation mode has only been tested with continuous simulated leaks. The objective of the study was to assess the influence of random leaks occurring either during inspiration or expiration. METHODS: Analysis of the volume-targeted pressure support mode in 6 commercial ventilators with single-limb circuits and intentional leak in a bench study (restrictive model). Unintentional leaks were introduced through a mechanical system during inspiration (threshold valve with 2 levels of leaks) or during expiration (active valve). Results of delivered tidal volume (VT) and pressure support were externally recorded. A pre-set VT of 550 mL was programmed, with a wide range of pressure support values. RESULTS: All the ventilators showed a deviation of delivered versus programmed VT below 10% in the period without unintentional leaks. In the model with unintentional inspiratory leaks, a progressive drop in delivered VT and pressure support was observed for all ventilators. The reduction in the delivered VT for the highest inspiratory leak ranged between 21 and 40%, corresponding to a decrease in pressure support between 3.09 and 10.15 cm H2O after 5 min. Conversely, in the expiratory model, increases in delivered VT and pressure support were observed, ranging between 16 and 33% and between 2.7 and 6.5 cm H2O, respectively. CONCLUSIONS: The introduction of random leaks influences the performance of commercial ventilators with single-limb circuits and intentional leak. The decrease in delivered VT with inspiratory leaks reaches a magnitude that may have clinically important impacts.

Effect of dynamic random leaks on the monitoring accuracy of home mechanical ventilators: a bench study.

BACKGROUND: So far, the accuracy of tidal volume (VT) and leak measures provided by the built-in software of commercial home ventilators has only been tested using bench linear models with fixed calibrated and continuous leaks. The objective was to assess the reliability of the estimation of tidal volume (VT) and unintentional leaks in a single tubing bench model which introduces random dynamic leaks during inspiratory or expiratory phases. METHODS: The built-in software of four commercial home ventilators and a fifth ventilator-independent ad hoc designed external software tool were tested with two levels of leaks and two different models with excess leaks (inspiration or expiration). The external software analyzed separately the inspiratory and expiratory unintentional leaks. RESULTS: In basal condition, all ventilators but one underestimated tidal volume with values ranging between -1.5 ± 3.3% to -8.7% ± 3.27%. In the model with excess of inspiratory leaks, VT was overestimated by all four commercial software tools, with values ranging from 18.27 ± 7.05% to 35.92 ± 17.7%, whereas the ventilator independent-software gave a smaller difference (3.03 ± 2.6%). Leaks were underestimated by two applications with values of -11.47 ± 6.32 and -5.9 ± 0.52 L/min. With expiratory leaks, VT was overestimated by the software of one ventilator and the ventilator-independent software and significantly underestimated by the other three, with deviations ranging from +10.94 ± 7.1 to -48 ± 23.08%. The four commercial tools tested overestimated unintentional leaks, with values between 2.19 ± 0.85 to 3.08 ± 0.43 L/min. CONCLUSIONS: In a bench model, the presence of unintentional random leaks may be a source of error in the measurement of VT and leaks provided by the software of home ventilators. Analyzing leaks during inspiration and expiration separately may reduce this source of error.

Effect of leak and breathing pattern on the accuracy of tidal volume estimation by commercial home ventilators: a bench study.

BACKGROUND: New home ventilators are able to provide clinicians data of interest through built-in software. Monitoring of tidal volume (VT) is a key point in the assessment of the efficacy of home mechanical ventilation. OBJECTIVE: To assess the reliability of the VT provided by 5 ventilators in a bench test. METHODS: Five commercial ventilators from 4 different manufacturers were tested in pressure support mode with the help of a breathing simulator under different conditions of mechanical respiratory pattern, inflation pressure, and intentional leakage. Values provided by the built-in software of each ventilator were compared breath to breath with the VT monitored through an external pneumotachograph. Ten breaths for each condition were compared for every tested situation. RESULTS: All tested ventilators underestimated VT (ranges of -21.7 mL to -83.5 mL, which corresponded to -3.6% to -14.7% of the externally measured VT). A direct relationship between leak and underestimation was found in 4 ventilators, with higher underestimations of the VT when the leakage increased, ranging between -2.27% and -5.42% for each 10 L/min increase in the leakage. A ventilator that included an algorithm that computes the pressure loss through the tube as a function of the flow exiting the ventilator had the minimal effect of leaks on the estimation of VT (0.3%). In 3 ventilators the underestimation was also influenced by mechanical pattern (lower underestimation with restrictive, and higher with obstructive). CONCLUSIONS: The inclusion of algorithms that calculate the pressure loss as a function of the flow exiting the ventilator in commercial models may increase the reliability of VT estimation.

Software de monitorización de ventilación mecánica domiciliaria: ¿medir más o medir mejor? / Home Mechanical Ventilation Monitoring Software: Measure More or Measure better?

En los últimos años ha aumentado el interés por conocer las consecuencias de la interacción paciente-ventilador sobre la mecánica pulmonar en ventilación no invasiva. Es por ello que diversas empresas fabricantes de ventiladores han incorporado a los mismos la posibilidad de monitorización de la ventilación on-line y de descarga de los datos almacenados en su memoria interna. Sin embargo, no existe consenso en la forma de presentación de estos datos, y dichos dispositivos aún no están lo suficientemente validados como para ser empleados de forma sistemática en la práctica clínica. El presente trabajo tiene por objetivo efectuar un análisis crítico y argumentado de las características técnicas de la determinación de variables de monitorización en uso en los diferentes software incorporados a ventiladores comerciales y de las formas de presentación de estas mediciones en pantalla, enfatizando los defectos y las virtudes de cada una de ellas y analizando su comportamiento en situaciones comunes en la práctica clínica, como los cambios en la interfase o la presencia de fugas accidentales. Asimismo, se proponen vías de solución para establecer las directrices futuras acerca de los parámetros que pueden resultar de importancia para el clínico y la forma de proporcionar e interpretar dicha información(AU)

In recent years, there has been an increasing interest in knowing the consequences of the patient-ventilator interaction in non-invasive mechanical ventilation. Therefore, several ventilator manufacturers have incorporated into their devices the possibility to monitor ventilation on-line and download the data stored in their internal memories. However, there is not a consensus as to how these data should be presented, and said devices have still not been sufficiently validated to be used systematically in clinical practice. The objective of the present study is to develop a critical, argumentative analysis of the technical characteristics for determining the monitor variables used in the different software programs incorporated in commercial ventilators. Likewise, the study contemplates the presentation of the measurements on the screen display, emphasizing the advantages and defects of each one and analyzing their behavior in common clinical practice situations, such as changes in the interface or the presence of accidental leaks. In addition, solution mechanisms are proposed for establishing future directives for the parameters that are important for clinicians, as well as the manner for providing and interpreting said information(AU)

Home mechanical ventilation monitoring software: measure more or measure better?

In recent years, there has been an increasing interest in knowing the consequences of the patient-ventilator interaction in non-invasive mechanical ventilation. Therefore, several ventilator manufacturers have incorporated into their devices the possibility to monitor ventilation on-line and download the data stored in their internal memories. However, there is not a consensus as to how these data should be presented, and said devices have still not been sufficiently validated to be used systematically in clinical practice. The objective of the present study is to develop a critical, argumentative analysis of the technical characteristics for determining the monitor variables used in the different software programs incorporated in commercial ventilators. Likewise, the study contemplates the presentation of the measurements on the screen display, emphasizing the advantages and defects of each one and analyzing their behavior in common clinical practice situations, such as changes in the interface or the presence of accidental leaks. In addition, solution mechanisms are proposed for establishing future directives for the parameters that are important for clinicians, as well as the manner for providing and interpreting said information.