Management of patients with severe asthma: results from a survey among allergists and clinical immunologists of the Central Italy Inter-Regional Section of SIAAIC.

BACKGROUND: Asthma, and severe asthma in particular, is often managed within a specialized field with allergists and clinical immunologists playing a leading role. In this respect, the National Scientific Society SIAAIC (Società Italiana di Allergologia, Asma ed Immunologia Clinica), structured in Regional and Inter-Regional sections, interviewed a large number of specialists involved in the management of this respiratory disease. METHODS: A survey entitled "Management of patients with asthma and severe asthma" based on 17 questions was conducted through the SIAAIC newsletter in 2019 thanks to the collaboration between GlaxoSmithKline S.p.A. and the Inter-Regional Section of SIAAIC of Central Italy. RESULTS: Fifty-nine allergists and clinical immunologists participated to the survey, and 40 of them completed the entire questionnaire. Almost all of the specialists (88%) reported that asthma control was achieved in above 50% of their patients, even if only one third (32%) actually used validated clinical tools such as asthma control test (ACT). Poor adherence to inhaled therapy was recognized as the main cause of asthma control failure by 60% of respondents, and 2-5 min on average is dedicated to the patient inhaler technique training by two-thirds of the experts (65%). Maintenance and as-needed therapy (SMART/MART) is considered an appropriate approach in only a minority of the patients (25%) by one half of the respondents (52%). A high number of exacerbations despite the maximum inhalation therapy were recognized as highly suspicious of severe asthma. Patients eligible for biological therapies are 3-5% of the patients, and almost all the responders (95%) agreed that patients affected by severe asthma need to be managed in specialized centers with dedicated settings. Biological drugs are generally prescribed after 3-6 months from the initial access to the center, and once started, the follow-up is initially programmed monthly, and then every 3-6 months after the first year of treatment (96% of responders). After phenotyping and severity assessment, comorbidities (urticaria, chronic rhinosinusitis with or without nasal polyps, vasculitis, etc.) are the drivers of choice among the different biological drugs. In the management of severe asthma, general practitioners (GPs) should play a central role in selecting patients and referring them to specialized centers while Scientific Societies should train GPs to appropriately recognize difficult asthma and promote public disease awareness campaigns. CONCLUSIONS: This survey which collects the point of view of allergists and clinical immunologists from Central Italy highlights that asthma control is still not measured with validated instruments. There is a general consensus that severe asthma should be managed only in dedicated centers and to this aim it is essential to encourage patient selection from a primary care setting and develop disease awareness campaigns for patients.

Subcutaneous and sublingual allergen-specific immunotherapy: a tale of two routes.

Summary: Specific immunotherapy is the only treatment acting on the causes and not only on symptoms of respiratory allergy. It was first introduced as subcutaneous immunotherapy (SCIT) with the aim to induce immunological tolerance to the administered allergen(s). In the 1980s, sublingual immunotherapy (SLIT) was developed, mainly to improve the safety, which was a critical issue at that time. This article reviewed the available literature, including a large number of randomized controlled trials, meta-analyses, and real-life studies as well, on the outcomes of SCIT and SLIT concerning the treatment critical issues of the two routes, that are efficacy, safety, cost-effectiveness, and compliance to treatment. The efficacy of SCIT and SLIT is similar in respiratory allergy, providing, based on the induction of typical changes in the immunologic response, an early control of symptoms that steadily increases during the treatment and its efficacy lasts after the recommended duration of three years. Such results are the reason why SCIT and SLIT have economic advantage over symptomatic drugs.

Use of complementary medicine among patients with allergic rhinitis: an Italian nationwide survey.

BACKGROUND: A growing use of complementary alternative medicine (CAM) has been found in Europe as well in Italy for chronic diseases, including the allergic rhinitis. The study aims at investigating the prevalence and the pattern of use of CAM amongst patient with allergic rhinitis. METHODS: A 12-item questionnaire was developed by a panel of experts and administered to patients with moderate/severe allergic rhinitis consecutively referring during the study time-frame to seven allergy clinics placed all around Italy. The items covered several topics including reason for choosing CAM, its clinical efficacy, schedule of treatment, costs, type of therapy. RESULTS: Overall 359 questionnaires were analysed. 20% of patients declared CAM use. A significant correlation between the use of CAM and female sex (p < 0.01) and with a higher level of education (p < 0.01) was observed. CAM users were adults (36% in the range between 20 and 40 years and 32% between 41 and 60 years). Youngsters (< 20 years) (7%) and elderly (> 60) (25%) less frequently used CAM.The most used type of CAM was homoeopathy (77% of patients). 60% of users would recommend CAM despite a poor clinical efficacy according to 67% of them. CONCLUSIONS: Although no evidence supports CAM efficacy and safety, the number of patients who relies on it is not negligible. As allergic rhinitis is not a trivial disease, the use of CAM as the only treatment for it should be discouraged at any level, but by general practitioner and specialist in particular.

Hymenoptera Venom Allergy: Management of Children and Adults in Clinical Practice.

Hymenoptera venom allergy is an epidemiologically underestimated condition and a major cause of morbidity worldwide. Preventing future allergic reactions in patients who experience a systemic reaction is based on the correct management of the emergency followed by an accurate diagnosis, prescription of adrenaline autoinjectors, and, where indicated, specific venom immunotherapy. Some epidemiological studies highlight our poor knowledge of this disease and the frequent inadequacy of its management. Moreover, they emphasize the importance of such a life-saving treatment as specific immunotherapy. The availability of high-quality hymenoptera venom extracts for diagnostic and therapeutic use has dramatically improved the prognosis and quality of life of allergic patients. Subcutaneous venom immunotherapy is currently the most effective form of allergen-based immunotherapy, with a carry-over effect lasting up to several years after its interruption. This report on the management of hymenoptera venom-allergic children and adults was prepared by a panel of Italian experts. The main objective of this consensus document is to review the scientific evidence related to diagnosis, therapy, and management of patients allergic to hymenoptera venom. Thus, we can improve our knowledge of the disease and promote good clinical practices. The present document provides practical suggestions for correct diagnosis, prescription of emergency therapy and immunotherapy, and strategies for patient care.

Hymenoptera venom allergy: management of children and adults in clinical practice

Hymenoptera venom allergy is an epidemiologically underestimated condition and a major cause of morbidity worldwide. Preventing future allergic reactions in patients who experience a systemic reaction is based on the correct management of the emergency followed by an accurate diagnosis, prescription of adrenaline autoinjectors, and, where indicated, specific venom immunotherapy. Some epidemiological studies highlight our poor knowledge of this disease and the frequent inadequacy of its management. Moreover, they emphasize the importance of such a life-saving treatment as specific immunotherapy. The availability of high-quality hymenoptera venom extracts for diagnostic and therapeutic use has dramatically improved the prognosis and quality of life of allergic patients. Subcutaneous venom immunotherapy is currently the most effective form of allergen-based immunotherapy, with a carry-over effect lasting up to several years after its interruption. This report on the management of hymenoptera venom-allergic children and adults was prepared by a panel of Italian experts. The main objective of this consensus document is to review the scientific evidence related to diagnosis, therapy, and management of patients allergic to hymenoptera venom. Thus, we can improve our knowledge of the disease and promote good clinical practices. The present document provides practical suggestions for correct diagnosis, prescription of emergency therapy and immunotherapy, and strategies for patient care

La alergia al veneno de himenópteros es una condición subestimada epidemiológicamente que representa una causa importante de morbilidad en todo el mundo. La prevención de reacciones alérgicas futuras en pacientes que han desarrollado una reacción sistémica se basa en el manejo correcto de la emergencia, seguido de un diagnóstico correcto, la prescripción de autoinyectores de adrenalina y, en el caso de estar indicada, la prescripción de inmunoterapia específica con veneno (VIT). Varios estudios epidemiológicos destacan el escaso conocimiento de esta enfermedad y un frecuente tratamiento insuficiente. Además, enfatizan la importancia de la inmunoterapia específica, un tratamiento que puede salvar la vida del paciente. La disponibilidad de extractos de veneno de himenóptera de alta calidad para uso diagnóstico y terapéutico ha mejorado drásticamente el pronóstico y la calidad de vida de estos enfermos. La VIT subcutánea representa la forma más efectiva de inmunoterapia con alérgeno actualmente disponible, con una eficacia persistente que dura hasta varios años después de su interrupción. Este consenso sobre la evaluación clínica tanto de niños como de adultos alérgicos al veneno de himenópteros ha sido elaborado por un panel de expertos italianos. Su objetivo principal es revisar la evidencia científica disponible en el diagnóstico, la terapia y la evaluación clínica de los pacientes alérgicos al veneno de himenópteros con el propósito de mejorar el conocimiento sobre esta enfermedad y promover buenas prácticas clínicas. Se incluyen sugerencias prácticas para un diagnóstico correcto, la prescripción de terapia de emergencia e inmunoterapia, así como estrategias para el manejo de los pacientes

Mechanisms of allergic diseases in Otorhinolaryngology.

Allergic Rhinitis (AR) is an IgE-mediated hypersensitivity disease caused by inhalation of an allergen to which the patients is sensitized. Etiopathogenesis of AR comprises a sensitization phase, an immediate phase and a late phase. In the sensitization phase, inhaled allergens are processed in peptides and come into contact with the nasal mucosa cells. Antigen-Presenting Cells (APCs), especially represented by Dendritic Cells (DCs), capture them through the interaction with their own MHC class II complexes and migrate to lymph nodes. Then, allergenic peptides are presented to naïve CD4+ T lymphocytes and a differentiation of T cells in Th2 subset takes place. After Th2 lymphocyte induction due to allergen exposure, the most relevant cytokines that are produced are represented by IL-3, IL-4, IL-5, IL-9, IL-10, and IL-13 that are able to promote IgE synthesis and mast cell proliferation. The allergen reaction, when allergen meets its specific IgEs on mast cells surface, causes an early inflammatory reaction determined by mast cells and basophils degranulation with release of preformed mediators from the intracellular granules, resulting in symptoms such as rhinorrhea, itching and sneezing. This phase is followed by a late phase characterized by the release of newly formed mediators, like leukotrienes, chemokines and adhesion molecules, and by the recruitment of eosinophils, neutrophils, macrophages, mast cells, lymphocytes B and T in the nasal mucosa. Such mechanism is responsible for continuing inflammation sustained by chemoattractants, cytokines and adhesion receptors that induce cellular infiltration of eosinophils, basophils, Th2 lymphocytes and mast cells and is clinically mirrored by the prevalence of nasal congestion over sneezing, itching and rhinorrhea.

Periostin: The bone and beyond.

In recent years the relationship between bone, metabolism and many pathophysiologic mechanisms involving other organs and the immune system, was increasingly apparent. This observation concerns vitamin D, osteopontin and periostin (PO). PO is expressed in the periosteum of long bones but also in many other tissues and organs, including heart, kidney, skin and lungs, being enhanced by mechanical stress or injury. PO has a relevant physiological function in promoting injury repair in a large number of tissues. However, its overexpression was observed in different diseases characterized by inflammation, fibrosis and tumorigenesis. Here we review the current knowledge on the role of PO in physiologic and pathologic pathways of different diseases. A specific focus regards the correlation between the level of PO and lung diseases and the identification of PO also as an inflammatory key effector in asthma, strongly associated with airways eosinophilia. In fact PO seems to be a useful biomarker of "Th2-high" asthma compared to "Th2-low" asthma phenotype and a predictor of response to therapeutic agents. Currently, a growing number of studies suggests a possible role of PO as a new diagnostic marker and/or therapeutic target for different diseases and its usefulness in clinical practice should be supported and confirmed by further and larger studies.

Allergic rhinitis: pharmacotherapy in pregnancy and old age.

INTRODUCTION: Allergic rhinitis (AR) affects 20-30% of women in reproductive age and may worsen during pregnancy. About 10% of the elderly suffer from AR, and it could be under-diagnosed in these patients. Many drugs are currently available, however AR treatment during pregnancy and old age represents a challenging issue. AREAS COVERED: A review of the literature on the topic has been performed. Expert commentary: In pregnancy, drug avoidance should be carefully balanced with the need for AR optimal control. Topical drugs are suggested as a first approach. The safety and tolerability profile of second-generation antihistamines is well supported. If allergen immunotherapy (AIT) is ongoing and well tolerated, there is no reason for stopping it. AIT initiation in pregnancy is not recommended. For elderly patients, no specific concerns have been highlighted regarding topical treatments, except from nasal decongestionants. Second generation antihistamines are generally well tolerated. Old age should not preclude AIT.

Quality of sleep in allergic children and their parents

BACKGROUND: Quality of sleep is essential for physical and mental health and influences the perception of the patient's well-being during the day. In patients with chronic allergic diseases sleep disorders may increase the severity of the condition, complicate the management and impair their quality of life. When children are concerned, their parents are also affected by the problem. We evaluated the presence of disrupted sleep in parents of children with atopic disorders, and its relationship with clinical features and the presence of disturbed sleep in children. METHODS: Parents of children suffering from allergic diseases were recruited from the Pediatric Allergy Units of Parma University. Evaluation of sleep in parents was based on the Pittsburg Sleep Quality Index (PSQI), while in children it was based on the Sleep Disturbance Scale for Children (SDSC). RESULTS: Of the 102 parents invited, 92 filled in the questionnaire. Only the questionnaires with more than a 95% completion rate were considered for analysis. PSQI mean score in parents was 6.6 (SD 2.6); 75.6% of them had a PSQI ≥ 5, indicating that most parents had a sleep quality perceived as bad. The PSQI ≥ 5 was more common in parents of children with asthma and rhinitis. In children, SDSC mean score was 42.1 (SD: 9.4); 62.3% had a total score ≥ 39. The quality of sleep in parents and children was significantly correlated (p < 0.001). CONCLUSION: These findings make it apparent that an alteration of sleep in children can also affect the parents. Such effect further weighs the burden of respiratory allergy and needs to be considered in future studies

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Quality of sleep in allergic children and their parents.

BACKGROUND: Quality of sleep is essential for physical and mental health and influences the perception of the patient's well-being during the day. In patients with chronic allergic diseases sleep disorders may increase the severity of the condition, complicate the management and impair their quality of life. When children are concerned, their parents are also affected by the problem. We evaluated the presence of disrupted sleep in parents of children with atopic disorders, and its relationship with clinical features and the presence of disturbed sleep in children. METHODS: Parents of children suffering from allergic diseases were recruited from the Pediatric Allergy Units of Parma University. Evaluation of sleep in parents was based on the Pittsburg Sleep Quality Index (PSQI), while in children it was based on the Sleep Disturbance Scale for Children (SDSC). RESULTS: Of the 102 parents invited, 92 filled in the questionnaire. Only the questionnaires with more than a 95% completion rate were considered for analysis. PSQI mean score in parents was 6.6 (SD 2.6); 75.6% of them had a PSQI ≥ 5, indicating that most parents had a sleep quality perceived as bad. The PSQI ≥ 5 was more common in parents of children with asthma and rhinitis. In children, SDSC mean score was 42.1 (SD: 9.4); 62.3% had a total score ≥ 39. The quality of sleep in parents and children was significantly correlated (p<0.001). CONCLUSION: These findings make it apparent that an alteration of sleep in children can also affect the parents. Such effect further weighs the burden of respiratory allergy and needs to be considered in future studies.

Effects of pulmonary rehabilitation on lung function in chronic obstructive pulmonary disease: the FIRST study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) causes an impairment of respiratory function, well reflected by the progressive decrease in forced expiratory volume in 1 second (FEV1). The only interventions able to slow down the FEV1 decline are smoking cessation and drug treatment. Pulmonary rehabilitation (PR), is claimed to improve exercise tolerance, symptoms and quality of life, but its effects on lung function have been scantly investigated. AIM: The aim of this paper was to evaluate, by the study named "FEV1 as an Index of Rehabilitation Success over Time" (FIRST), the effects of PR on lung function in patients with COPD, under drug treatment with inhaled corticosteroids or long-acting ß2-agonists and/or tiotropium in various combinations, according to guidelines, during a 3-year period. DESIGN: Observational, prospective, with two parallel groups study. SETTING: PR setting in an urban hospital. POPULATION: Two hundred fifty-seven COPD patients, 190 (103 males, mean age 71.1 ± 7.1 years range 57-86 years) underwent PR and 67 (49 males, mean age 67.9 ± 7.9 years, range 58-79 years) were treated only with drugs. METHODS: Lung function was measured at baseline and at one-year intervals up to 3 years. The postbronchodilator FEV1 was used for statistical analysis. RESULTS: In the PR group, FEV1 increased from 1240 mL (57.3% of predicted value) to 1252.4 mL (60.8%) after 3 years, whereas in the controls the values were 1367 mL (55% of predicted) at baseline and 1150 mL (51%) after 3 years. This difference was statistically significant (P<0.001). CONCLUSION: In patients with COPD on standard pharmacotherapy, PR significantly affected the decline of FEV1 over time. CLINICAL REHABILITATION IMPACT: The ability to substantially stop the FEV1 decline seems exclusive of PR when added to drug treatment. This finding warrants confirmation from randomized trials.

Dropouts in sublingual allergen immunotherapy trials - a systematic review.

Participant dropouts can reduce the power of allergen immunotherapy clinical trials. Evaluation of the dropout rate and reasons for dropout are important not only in the planning of clinical studies but are also relevant for adherence to immunotherapy in daily clinical practice. A systematic review was carried out in order to establish the overall dropout rate among published double-blind, placebo-controlled randomized clinical trials of sublingual immunotherapy for respiratory allergic diseases. Dropouts were analysed in regards to allergen, formulation, treatment schedule, participant age, study size, number of centres and type of allergic disease. Relative dropout rates in placebo and active groups as well as reasons for dropout were also assessed. A total of 81 studies, comprising 9998 patients, were included. Dropout rates in sublingual immunotherapy controlled studies do not appear to be a major problem with a composite dropout percentage of 14% (95% CI:11.9-16). Furthermore, they are not different for active compared to placebo-treated participants. This lends support to the positive clinical outcomes seen in meta-analyses of these trials.

Illness perception, mood and coping strategies in allergic rhinitis: are there differences among ARIA classes of severity?

BACKGROUND: This study was designed to assess if illness perception, mood state and coping strategies differ according to allergic rhinitis (AR) persistence and severity. METHODS: Illness perception, mood profiles, coping behaviors and rhinitis symptoms were assessed by means of validated tools inpatients classified according to the Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines. RESULTS: Two hundred and thirty-one patients underwent data analysis. No difference in age, sex, socio-economic status, smoking habits was detected comparing patients according to AR severity, duration or 4 ARIA classes. Patients with intermittent AR reported higher scores than those with persistent AR in confusion-bewilderment of Profile of Mood States (POMS); patients with moderate/severe rhinitis had significantly higher scores than those with mild rhinitis in TSSS, Identity and Consequences. No differences were detected in all assessed outcomes in the 4 ARIA classes. CONCLUSIONS: The patient's perspective about AR is independent of persistence and severity of symptoms. This may explain why AR remains under-diagnosed and under-treated, even in its most severe forms. Self-management plans should consider the patient's perspective.

Heterogenity of IgE response to walnut and hazelnut in Italian allergic patients.

BACKGROUND: The prevalence of IgE reactivity against genuine walnut and hazelnut allergens is poorly defined. OBJECTIVE: The IgE response to walnut and hazelnut was investigated in Italian patients with primary allergy to these nuts. METHODS: Sera from 36 patients allergic to hazelnut and/or walnut, not reactive to PR-10, profilin, and LTP, underwent immunoblot analysis with extracts of both nuts. RESULTS: Most patients had a history of systemic symptoms following the ingestion of the offending food(s). Twelve patients were sensitized to both walnut and hazelnut, and 13 were sensitized to other nuts and seeds (cashew, peanut, sesame, pine nut, almond, Brazil nut, and pistachio). On walnut immunoblot, the 7 sera which scored positive showed much variability in their IgE profile. Two reacted uniquely at 10 kDa, and the others at 35 , 40, 45, 50, 67, and > 67 kDa. The profiles obtained under reducing and non-reducing conditions showed several differences. The 7 sera positive on hazelnut immunoblot under reducing conditions recognized sera at 10 kDa and at <10 kDa (n=1), 20 kDa (n=4), at about 22, 24, 30, 40, 43, 58, 60, and 90 kDa, and higher m.w. in other cases. Under non-reducing conditions IgE reactivity at 20, 28, 35, 40, 45, 60, 90, and 100 kDa, was detected. Only two sera scored positive under both conditions and showed an IgE profile that partly changed from one assay to another. CONCLUSION: The current list of walnut and hazelnut allergens is far from being complete. Both reducing and non-reducing conditions are needed to detect IgE reactivity in individual patients.

Allergen immunotherapy: clinical and practical education of Italian trainees in allergy and clinical immunology schools.

We performed a survey, based on a questionnaire including 20 items, submitted anonymously to Italian trainees in Allergology and Clinical Immunology, in order to obtain information about their specific allergen immunotherapy (AIT) practices. The questionnaire was sent to 40 trainees, who had attended the last two years of the training course. Thirty-four subjects (mean age: 27 years, 65% females) adequately completed the survey. The answers to the questionnaire showed that only 60% of the training programs included lectures on AIT. Among the trainees using AIT, only 40% declared being able to prescribe it independently, while 60% were guided by a tutor. Of the trainees who were able to prescribe AIT autonomously, 60% were familiar with both routes of administration, i.e. subcutaneous (SCIT) and sublingual immunotherapy (SLIT), while 25% of these used only SLIT. In 80% of the training institutions involved, the trainees could attend a dedicated AIT outpatient ward for SCIT administration; only 40% administered AIT personally, and in half of these cases, they were guided by a tutor. Only 70% of trainees had experience in the follow-up of patients still under treatment and of patients who had completed treatment. Analysis of the answers obtained for questions on venom immunotherapy (VIT) showed that, in 90% of cases, the trainees attended a dedicated outpatients ward where VIT is administered, but with a role limited to observation/cooperation. Only 30% were involved in the follow-up of patients who were under treatment or who had completed VIT. Only 20% of the trainees felt confident enough about VIT to prescribe this treatment independently, 80% knew there were several administration protocols, and the majority prescribed products from three different manufacturers. These findings suggest that there is significant room for improving the instructions provided regarding allergology and clinical immunology to trainees in Italy with respect to AIT.

RhinAsthma patient perspective: a short daily asthma and rhinitis QoL assessment.

BACKGROUND: The present study aimed to develop a short validated patient-completed questionnaire, the RhinAsthma Patient Perspective (RAPP), to assess the health-related quality of life (HRQoL) in patients with asthma and comorbid allergic rhinitis in clinical practice. METHODS: A provisional RAPP questionnaire was formed from candidate items identified through retrospective analysis of 333 RHINASTHMA questionnaires. This was then tested on 150 asthma patients with allergic rhinitis. RESULTS: Psychometric analyses identified eight items fitting a unidimensional model to form RAPP. Internal consistency (Cronbach's alpha coefficient > 0.8) and agreement with RHINASTHMA (r = -0.31, P = 0.0001) were excellent. Criterion, discriminant, and convergent validity were good. Reliability in 47 stable patients was very good (intra-class and concordance correlation coefficients were 0.90 and 0.89, respectively). Responsiveness in 103 patients with health improvement or deterioration was significantly associated with changes in Global Rating Scale (r = -0.4965, P < 0.01), Rhinitis Visual Analogue Scale (r = 0.5722, P < 0.01) and asthma control test (r = -0.6483, P < 0.01). Minimal clinical difference in the analyzed population was 2. CONCLUSION: RhinAsthma Patient Perspective is a simple eight-question questionnaire with good measurement properties and sensitivity to health changes, which will provide a valid, reliable and standardized HRQoL measurement in patients with asthma and comorbid allergic rhinitis in clinical practice.

Recommendations for assessing patient-reported outcomes and health-related quality of life in patients with urticaria: a GA(2) LEN taskforce position paper.

The aim of this Global Allergy and Asthma European Network (GA(2)LEN) consensus report is to provide recommendations and suggestions for assessing patient-reported outcomes (PROs) including health-related quality of life in patients with urticaria. We recommend that PROs should be used both in clinical trials and routine practice for the evaluation of urticaria patients. We suggest that PROs should be considered as the primary outcome of future clinical trials. Two validated and disease-specific instruments for assessing PROs are available, the urticaria activity score (for symptoms) and the chronic urticaria questionnaire on quality of life CU-Q(2)oL. This latter tool, CU-Q(2)oL, is available in many languages and should be preferred, where available, over more generic instruments for assessing urticaria-specific effects on quality of life. CU-Q(2)oL is only suited for the investigation of patients with chronic spontaneous urticaria. Similar instruments for other forms of urticaria have yet to be developed and validated. Also, tools for assessing other chronic spontaneous urticaria PROs besides quality of life and symptoms are needed.