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The prevalence of non-allergic asthma in childhood is low, peaking in late adulthood. It is triggered by factors other than allergens, like cold and dry air, respiratory infections, hormonal changes, smoke and air pollution. In the literature, there are few studies that describe non-allergic asthma in pediatric age. Even though it is a less common disorder in kids, it is crucial to identify the causes in order to keep asthma under control, particularly in patients not responding to conventional treatments. In this review, we discuss non-IgE-mediated forms of asthma, collecting the latest research on etiopathogenesis and treatment.

Asthma is a common chronic disease that affects over 300 million people worldwide, resulting in a considerable socio-economic burden. Literature data suggest that asthma has a higher incidence in females, particularly at certain stages of pubertal development. Moreover, women seem to experience more asthma symptoms than men and to use more rescue medications, resulting in a reduced quality of life. Although several mechanisms have been proposed to explain these differences, there are not yet final data available in the literature on the role of gender in the pathogenesis of asthma and different behavior in females. Some study suggested a more prevalent hyper-responsiveness in women than in men. Nevertheless, in the literature definitive data on a possible different response to drugs used for asthma between males and females are not described. Understanding the mechanisms that underlie these gender differences in clinical history of asthma patients could give inspiration to new areas of research to obtain a more specific diagnostic and therapeutic approach gender-oriented.

INTRODUCCIÓN: El asma premenstrual (APM) se ha asociado con el asma grave y de difícil control. Las causas de esta exacerbación del asma en el periodo premenstrual no están claras. OBJETIVO: 1. Analizar el papel de las hormonas sexuales femeninas (estrógenos y progesterona) en el APM. 2. Analizar la relación entre marcadores de atopia (IgE total, Phadiatop® e IgE específicas) y APM. 3. Analizar el papel de los leucotrienos como mediadores inflamatorios en la etiopatogenia del APM. METODOLOGÍA: Se ha realizado en mujeres asmáticas en edad fértil un cuestionario de síntomas respiratorios (SR) y registro de PF durante un ciclo menstrual completo para clasificar a las pacientes como asmáticas con o sin APM. Se consideró APM al deterioro >/= 20 % clínico y/o funcional en el período premenstrual, respecto al preovulatorio. Se clasificó a cada una de ellas en función de los criterios de gravedad del asma (GINA). A todas ellas se les determinaron los niveles sanguíneos tanto en el periodo premenstrual como preovulatorio de: o Estrógenos y progesterona o Marcadores de atopia: IgE total y screening de neumoalérgenos (Phadiatop®) e IgE específicas en las que mostraron un screening positivo. o Leucotrienos LT C4. RESULTADOS: Las mujeres con asma premenstrual:  Mostraron en el período premenstrual (respecto al preovulatorio) un leve descenso de los estrógenos (111.49 pg/ml preovulatorio frente a 95.90 pg/ml premenstrual) y un claro aumento (p=0.001) de los niveles de progesterona (0.83 frente a 6.83 ng/ml). Las mujeres sin APM mostraron un comportamiento similar, ya que sus niveles de estrógenos no cambiaron entre los dos periodos (131.31 frente a 123.83 pg/ml) y aumentó la progesterona (1.39 frente a 6.31 ng/ml). El cociente estrógenos/progesterona en el período premenstrual fue similar para las mujeres con y sin APM (p=0.31).  Tenían valores de IgE total > 100 kU/l 26 (82.9 %) de las asmáticas premenstruales y 12 (46.7 %) de las que no cumplían criterios de APM (p=0.013). Fueron positivas al Phadiatop® 21 (67.7 %) de las pacientes con APM y 14 (50 %) de las que no tenían APM (p=0.17). Se realizaron IgE específicas a las mujeres con Phadiatop® positivo, sin encontrar relación con el APM, y hallándose valores superiores a 0.35 kU/l fundamentalmente para Lolium (62.9 %), Olivo (60 %) y Dermatophagoides pteronyssinus (54.3 %).  Los valores de leucotrienos LT C4 no mostraron diferencias entre los periodos preovulatorio y premenstrual en la mujeres con APM (1.50 ng/ml vs 1.31 ng/ml; p = 0.32) ni en las que no cumplían este criterio (1.40 ng/ml vs 1.29 ng/ml; p = 0.62). Tampoco hubo diferencias en los niveles de LT entre las mujeres con y sin APM. Los resultados fueron similares para cada grupo de gravedad del asma.CONCLUSIONES: 1. No encontramos diferencias en los niveles premenstruales de estrógenos y progesterona entre las mujeres asmáticas con o sin asma premenstrual. Se requieren más estudios para analizar posibles factores etiológicos relacionados con el asma premenstrual. 2. El asma premenstrual parece relacionarse más con los valores de IgE total y no con alérgenos específicos. La atopia influye en las manifestaciones clínicas premenstruales del asma en mujeres en edad fértil. 3. Los leucotrienos C4 no parecen estar implicados en la etiopatogenia del asma premenstrual, ni soportan el uso de los antileucotrienos en el tratamiento específico del asma premenstrual, al menos en su grado moderado. Esta situación se reproduce en nuestros datos en todos los distintos niveles de gravedad del asma de la GINA., INTRODUCTION: Premenstrual asthma (PMA) has been associated with severe and difficult asthma control. The causes of asthma exacerbation in the premenstrual period are unclear. OBJECTIVES: 1. To analyze the role of female sex hormones (estrogen and progesterone) in the PMA. 2. To analyze the relationship between markers of atopy (total IgE and specific IgE Phadiatop®) and PMA. 3. To analyze the leukotrienes such as inflammatory mediators in the pathogenesis of PMA. METHODS: It was conducted in asthmatic women of fertile age a questionnaire of respiratory symptoms and PF record for a full menstrual cycle to classify patients as asthma with or without PMA. PMA is considered to deterioration> / = 20% clinical and / or functional premenstrual respect to preovulatory. We classified each case according to the criteria of asthma severity (GINA). All of them underwent blood levels in both the premenstrual period as preovulatory: • Estrogen and progesterone • Atopy markers: total IgE and screening neumoalergenos (Phadiatop®) and specific IgE in which showed a positive screening. • Leukotriene C4. RESULTS: Women with premenstrual asthma:  They Showed premenstrual (relative to preovulatory) a slight decrease in estrogen (111.49 pg/ml preovulatory vs. 95.90 pg/ml premenstrual) and a significant increase (p = 0.001) levels of progesterone (0.83 versus 6.83 ng/ml). Women without PMA showed a similar behavior, as their estrogen levels were unchanged between the two periods (131.31 versus 123.83 pg/ml) and increased progesterone (1.39 vs. 6.31 ng/ml). The estrogen/progesterone ratio in the premenstrual period was similar for women with and without PMA (p = 0.31).  Had total IgE levels> 100 kU/l 26 (82.9%) and 12 of premenstrual asthma (46.7%) who did not meet the criteria of PMA (p = 0.013). Phadiatop® were positive in 21 (67.7%) of PMA and 14 patients (50%) of those without PMA (p = 0.17). We performed specific IgE-positive women Phadiatop® without finding regarding the PMA, and being values above 0.35 kU/l primarily for Lolium (62.9%), Olivo (60%) and Dermatophagoides pteronyssinus (54.3%).  Leukotriene C4 values showed no differences between the preovulatory and premenstrual periods in women with PMA (1.50 ng/ml vs 1.31 ng/ml; p = 0.32) or which did not meet this criterion (1.40 ng/ml vs 1.29 ng/ml; p = 0.62). There were no differences in leukotriene levels between women with and without PMA. The results were similar for each group of asthma severity. CONCLUSIONS: 1. No differences in premenstrual estrogen and progesterone levels between asthmatic women with or without PMA. Further studies are required to analyze possible etiologic factors related to PMA. 2. The PMA seems to relate more to the values of total IgE and not to specific allergens. Atopy influences the clinical manifestations of premenstrual asthma in women of fertile age. 3. Leukotriene C4 not appears to be involved in the pathogenesis of PMA, or support the use of leukotriene modifiers in the specific treatment of premenstrual asthma, at least in moderate degree. This situation is reproduced in our data at all different levels of asthma severity GINA.

Although premenstrual worsening of asthma is recognized, little is known about the pathophysiology. Monthly variation in endogenous progesterone and β-estradiol may be associated with the etiology of premenstrual asthma (PMA). T lymphocytes play an importanat role in the pathogenesis of asthma. Therefore, to clarify the pathogenesis of PMA, the clinical features and effects of progesterone and β-estradiol on lymphocyte activation were studied. 1) Thirty one asthmatic females of reproductive age were surveyed. Fourteen asthmatics (45%) claimed their asthma symptoms worsened just prior to or during the menses. Comparing asthmatics with and without PMA, the former group showed significantly more severe steroid dependent asthma. 2) Progesterone and β-estradiol suppressed lymphocyte blastogenesis stimulated by phytohemagglutinin (PHA), mite and Candida antigen. There was no significant difference in the suppression rate between asthmatics and normal subjects, or between male and female. These findings suggest that T lymphocytes may be activated by causal allergens when progesterone and β-estradiol levels decrease during the premenstrual period. Activated T lymphocytes may contribute to the pathogenesis of PMA.

This study was financed in part by grants from the Asociación de neumólogos del sur (Neumosur) in 2003 and the Health Ministry of the Regional Autonomous Government of Andalusia in 2005 (both Seville, Spain), Our aim is to analyse the differences in the prevalence of premenstrual asthma (PMA) according to a set of criteria, the relationship between them and the influence of asthma severity. The answer ‘‘Yes’’ to ‘‘Does your asthma get worse before menstruation?’’ was considered subjective PMA. A daily respiratory symptoms register of fertile asthmatic females was taken during two consecutive menstrual cycles. For the semi-objective diagnosis, an exacerbation of o20% was required in the symptoms register. Objective diagnosis was a premenstrual worsening of o20% of peak flow. We selected 103 patients. Subjective premenstrual deterioration was perceived in 43.7%. The semi-objective deterioration of symptoms in the first cycle occurred in 44.7%, and in 22.3% in both cycles. A total of 54.3% of females with semi-objective criteria in the first cycle perceived a subjective deterioration of symptoms, versus 35.1% of those without semi-objective criteria (p50.05). PMA was present at all levels of asthma severity, with no clear link to the degree of severity. The detection of PMA prevalence, the subjective perception of this deterioration and its presence at all levels of asthma severity lead us to urge research into possible premenstrual deterioration in all fertile asthmatic females, Asociación de neumólogos del sur (Neumosur) in 2003, Health Ministry of the Regional Autonomous Government of Andalusia in 2005 (both Seville, Spain)

IV ÖZET Doğan Tunçkol M, Premenstrüel astımda hava yolu inflamasyonu, klinik ve hormonal değişiklikler, Kırıkkale Üniversitesi Tıp Fakültesi Göğüs Hastalıkları ve Tüberküloz Anabilim Dalı Uzmanlık Tezi, Kırıkkale 2005. Premenstrüel Astım (PMA) menstrüel siklusun geç luteal fazında astım semptomlarında ve pulmoner fonksiyonlarında kötüleşmeyle giden klinik bir durumdur. Bu tezde menstrüasyon öncesi astım semptomlarında artış tanımlayan astımlı bayan hastalarda inflamatuar, klinik ve hormonal değişiklikleri araştırmak amaçlanmıştır. Bu amaçla çalışmaya yaşları 18-50 yaş arasında değişen, stabil dönemdeki 51 astımlı kadın hasta dahil edildi. Hastaların astım ve menstrüel siklus ilişkisini gösteren soruları içeren anket formu dolduruldu. 20 (% 39) hastada premenstrüel dönemde astım semptomlarının arttığı tespit edildi. Premenstrüel yakınması olan 20 hastanın (PMA) 11 'i (PMAİ) ve yakınması olmayan 31 hastanın (NPMA) 5'i (kontrol grup) iki menstrüel siklusun premenstrüel, menstrüel ve siklus ortası dönemlerinde değerlendirildi. îlk menstrüel siklusta hastaların astım semptom skoru belirlenip, solunum fonksiyon testleri, bronş provakasyon testleri (BPT) uygulandı. Ayrıca serumda kadın seks hormon seviyeleri, kortizol, Nitrik Oksit (NO) ve Thiobarbitürik Asit Reaktif Substance (TBARS) seviyesi ölçüldü. Ruhsal durumu değerlendirmek için Hastane Anksiyete Depresyon Skalası (HAD) kullanıldı. Hastaların yaşam kalitesi ise SF-36 (36-item short-form) formu ile değerlendirildi. İkinci menstrüel siklusta ise BPT, serumda NO ve TBARS ölçümü hariç diğer değerlendirmeler her 3 dönemde tekrarlandı. Astım ciddiyet skoru PMA ve PMAİ grubunda NPMA ve kontrol gruplarına göre anlamlı derecede yüksekti (sırasıyla pO.001 ve p