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Macrolides
Macrolides have been shown, in addition to their antibacterial effect, to reduce
the number of neutrophils in induced sputum, reduce cytokine production in
respiratory epithelium and reduce the bronchial hyper-reactivity in patients
with asthma. This, along with knowledge that patients with severe asthma can
be infected with atypical bacteria, has led to macrolides being put forward as a
treatment option. Clinical results of adult trials are not conclusive. However, in
some studies the treatment with azithromycin has been shown to significantly
reduce the number of exacerbations and improve quality of life, in particular in
adult patients with non-allergic asthma [103,104]. A contributing factor to the
effectiveness of macrolides is its ability to reduce the rate of metabolism of
steroids. Current recommendations do not advocate macrolide treatment for
children and adolescents with severe asthma [34], however, it may play a role
in the treatment in those with suspected or proven neutrophil-mediated
inflammation [103,104]. Treatment is then in the form of azithromycin 10
mg/kg, maximum dose 500 mg three times per week. Treatment benefits
should be weighed against development of resistant bacteria, hepatotoxicity,
ototoxicity and the effect on QT interval.
Los macrlidos
Los macrlidos han demostrado que, adems de su efecto antibacteriano,
reducen el nmero de neutrfilos en el esputo inducido, reducen la produccin
de citoquinas en el epitelio respiratorio y reducen la hiperreactividad bronquial
en pacientes con asma. Esto, junto con el conocimiento de que los pacientes
con asma grave pueden infectarse con bacterias atpicas, ha llevado a los
macrlidos a ser una opcin de tratamiento. Los resultados clnicos de los
ensayos en adultos no son concluyentes. Sin embargo, en algunos estudios se
ha demostrado que el tratamiento con azitromicina para reducir
significativamente el nmero de exacerbaciones y mejorar la calidad de vida,
en particular en pacientes adultos con asma no alrgica. Un factor que
contribuye a la eficacia de los macrlidos es su capacidad para reducir la tasa
de metabolismo de los esteroides. Las recomendaciones actuales no abogan
por el tratamiento macrlido para nios y adolescentes con asma grave, sin
embargo, puede desempear un papel en el tratamiento de las personas con
neutrfilos mediada por la inflamacin presunta o comprobada. El tratamiento
es a continuacin, en forma de azitromicina 10 mg / kg, dosis mxima 500 mg
tres veces por semana. Los beneficios del tratamiento deben sopesarse contra
el desarrollo de bacterias resistentes, hepatotoxicidad, ototoxicidad y el efecto
sobre el intervalo QT.
Theophylline
Treatment with low-dose theophylline (plasma concentrations around 30
mmol/l) has shown to have beneficial antiinflammatory effects. This is thought,
in part, to be due to downregulation of pro-inflammatory genes, to inhibition of
the late-phase hypersensitivity reaction, to increased neutrophil apoptosis as
well as to increased steroid sensitivity. Bronchodilator effect and risk of toxicity
are reduced at lower doses compared to the previously recommended
therapeutic doses (55110 mmol/l). In clinical studies, mainly undertaken in
adults, treatment has been shown to improve asthma control and reduce the
number of acute exacerbations [105]. This treatment, given twice daily at half
the recommended dose stated in the product leaflet, can also have a place in
the management of severe asthma with signs of untreated inflammation.
La teofilina
El tratamiento con teofilina en dosis bajas (concentraciones plasmticas
alrededor de 30 mmol / l) se ha demostrado que tienen efectos
antiinflamatorios beneficiosos. Esto se piensa, en parte, debido a la regulacin
de los genes pro- inflamatorias, a la inhibicin de la reaccin de
hipersensibilidad de fase tarda, a un aumento de la apoptosis de neutrfilos,
as como a una mayor sensibilidad de esteroides. El efecto broncodilatador y
riesgo de toxicidad se reducen a dosis ms bajas en comparacin con las dosis
teraputicas recomendadas anteriormente (55 a 110 mmol / l). En estudios
clnicos, realizados principalmente en los adultos, el tratamiento ha
demostrado que mejora el control del asma y reduce el nmero de
exacerbaciones agudas. Este tratamiento, dos veces al da a la mitad de la
dosis recomendada se indica en el prospecto del producto, tambin puede
tener un lugar en el tratamiento del asma grave con signos de inflamacin no
tratada.
Expert commentary
Management of children with severe asthma remains a clinical challenge.
Nevertheless, during the recent years considerable progress has been made in
defining this patient group, structuralizing the clinical work-up and establishing
the usefulness of various clinical methods in diagnosing and monitoring this
group of patients. In addition, several different treatment options are now
available for various phenotypes of the disease. Considering the heterogeneity
and the severity of the disease, the treating clinician has a formidable task to
integrate all the available information from each patient to provide the most
suitable treatment.
Comentarios de Expertos
La gestin de los nios con asma grave sigue siendo un desafo clnico. Sin
embargo, durante los ltimos aos se ha avanzado considerablemente en la
definicin de este grupo de pacientes, estructurando el trabajo clinico y el
establecimiento de la utilidad de los diferentes mtodos clnicos en el
diagnstico y el seguimiento de este grupo de pacientes . Adems, varias
opciones de tratamiento diferentes estn ahora disponibles para varios
fenotipos de la enfermedad. Teniendo en cuenta la heterogeneidad y la
gravedad de la enfermedad, el mdico tratante tiene una tarea formidable para
integrar toda la informacin disponible de cada paciente para proporcionar el
tratamiento ms adecuado.
Five-year view
The concept of personalized medicine in the clinical care of children with
severe asthma will continue to develop. Hopefully new, reliable and easily
attainable biomarkers or gene signatures will improve the phenotypic
characterization of these children, which will make it possible to adjust
treatment according to the patients phenotype. It is also hoped that new
treatment alternatives such as anti-IL5 and anti IL-13, which are currently being
investigated or introduced into adult care, will prove useful for children. Safer
and more effective routes of administration of immunotherapy, such as
intralymphatic or epicutaneous administration, might be introduced into clinical
practice making immunotherapy a more attractive treatment alternative for
these patients. Combining molecular allergy diagnostics together with
recombinant allergens is a particular attractive vision for future treatment of
children with severe allergic asthma. Furthermore, there is a possibility that
vaccination against rhinovirus will turn out to be a clinically available
alternative, and such case will probably have an impact on the prevalence of
pre-school wheeze and the subsequent development of asthma. Another area,
which is expected to develop quickly in the coming years, is the
implementation of mobile applications in the monitoring of children with
asthma. The full range of possibilities using mobile applications is yet to be
explored, but some obvious areas are symptom scoring, providing treatment
advice and assessment of adherence to the treatment plan.
Vista Cinco aos
El concepto de la medicina personalizada en la atencin clnica de los nios con
asma grave continuar desarrollndose. Nueva, fiable y fcilmente alcanzables
biomarcadores o firmas de genes mejorarn la caracterizacin fenotpica de
estos nios, lo que har posible ajustar el tratamiento segn el fenotipo de los