Dupilumab's impact on nasal citology: Real life experience after 1 year of treatment.

BACKGROUND: Biologic agents are considered a new revolutionized therapy for severe and recurrent forms of CRSwNP which disease burden is not sufficiently controlled by conservative and/or surgical treatments. Recent Research has focused on evaluating their real-life efficacy in CRSwNP, as only limited reports on real-life data are available. However, in most studies, the response to treatment is evaluated in terms of improvement in Nasal Polyp Score (NPS) or in Sino-Nasal Outcome test (SNOT-22) scores. However, both criteria do not consider nasal immunophlogosis, which can be easily assessed by nasal cytology. The aim of our study was to evaluate changings in the nasal inflammatory infiltrate of CRSwNP patients treated with Dupilumab for 12 months. METHODS: 27 patients suffering from severe CRSwNP treated with Dupilumab were recruited. Nasal cytology findings, NPS, SNOT-22, ACT scores and blood eosinophil count at T0 (before treatment) and at T1 (after 1 year of treatment) were compared. RESULTS: After 1 year of biological therapy with Dupilumab, NPS, SNOT-22 and, among the 17 asthmatic patients, ACT scores improved significantly. At T1, a statistically significant percentage of patients showed negative citology. Moreover, a significant reduction in the mast cell-eosinophilic pattern and an increase of neutrophils and bacteria was reported. CONCLUSIONS: The response to treatment can be considered both in the case of negative nasal cytology and in the case of the appearance of neutrophils and bacteria. In this context, eosinophils, the specific target of biological therapies, play a crucial role in regulating tissue homeostasis and, consequently, the nasal immunophlogosis.

Local Allergic Rhinitis: Lights and Shadows of a Mysterious Entity.

Local allergic rhinitis (LAR) is, to date, a debated and complex entity, still orphan of global consideration and a multicentric approach. LAR does not seem to find a proper positioning in the classic classifications and phenotypes of chronic rhinitis, and its pathophysiology relies specifically on the presence of local IgE. These patients in fact have a suggestive clinical history of allergic rhinitis in the presence of negative skin prick tests and serum IgE tests for the suspect allergen. Nasal allergen challenge, assessment of local IgE, basophil activation test (BAT), and nasal cytology are, at the moment, the most used tests in the diagnostic approach to the disease, despite their limitations. Considering that the correct interpretation of diagnostic tests and their clinical relevance is fundamental in the assessment of the right diagnosis and the subsequent therapy, we propose a new diagnostic approach that encompasses all of these methodologies and suggest that several pragmatic randomized control trials as well as prospective, multicentric studies directed at the long-term follow-up of LAR be carried out to further investigate this debated entity.

Charcot-Leyden crystals: An ancient but never so current discovery.

From the first description of Charcot-Leyden crystals (CLCs) to the present, many steps have been taken to understand the mechanisms underlying their formation. In particular, to date not only eosinophils but also mast cells are known to be responsible for the production of CLCs, which represent the crystallized form of Galectin-10. Due to their characteristics, CLCs typically induce a crystallopathy and are responsible for an exacerbation of inflammation. Nasal cytology (NC) has allowed to better understand the correlation between the severity of several rhinopaties and the presence of CLCs in NC samples, which is strictly correlated with an eosinophiles and mast cells infiltration. As a matter of fact, rhinopaties with a mixed eosinophilic-mast cell inflammatory infiltrate, characterized by the presence of abundant CLCs, show a worse prognosis and a higher risk of relapse. This could have important therapeutic implications, since the treatments available today could be exploited to target both eosinophils and mast cells, to reduce the damage induced by CLCs.

Biofilm in sino-nasal infectious diseases: the role nasal cytology in the diagnostic work up and therapeutic implications.

BACKGROUD: Biofilm formation has been recently recognised as one of the most important etiopathological mechanisms underlying chronic rhinosinusitis (CRS) and its recalcitrance. In this context, nasal cytology (NC) has become an integral part of diagnostic work up of patients suffering from sino-nasal diseases, since it is an easy-to-apply, reproducible and non-invasive diagnostic tool that allows to assess both the nasal inflammatory infiltrate and the presence of biofilms on nasal mucosal surface, further orienting the therapeutic choices in case of infectious diseases for eradicating infections and biofilms. Nevertheless, biofilms are typically resistant to common antibiotic treatments and may trigger or maintain chronic inflammation. Hence, the importance of correctly detecting the presence of biofilm and identifying new effective treatments. PURPOSE: The aim of this brief review is to better clarify the role of biofilm in the pathogenesis and recurrence of sino-nasal disorders and to highlight the role of nasal cytology (NC) in the rhino-allergologic diagnostic path and in the evaluation of the effectiveness of new treatments.

General classification of rhinopaties: the need for standardization according to etiology and nasal cytology.

BACKGROUND: Rhinitis is as an inflammation of the nasal mucosa, characterized by high prevalence, widespread morbidity, and a significant financial burden on health care systems. Nevertheless, it is often considered as no more than a mere annoyance. This point of view has progressively led to underestimate and trivialize the disease. Therefore, there are numerous, mostly overlapping classifications of rhinopaties, but clear and standardized guidelines for diagnosis and treatment are still lacking. In the context of Precision Medicine, the development of a classification system focused on the endotypes of rhinitis to be widely adopted appears of utmost importance, also by virtue of study of the nasal immunophlogosis that, thanks to nasal cytology (NC), has recently allowed to better define the different forms of rhinitis, giving a new nosological dignity to several rhinopaties. AIM: We aimed to summarize the current knowledge regarding rhinitis and to propose a systematic classification of rhinitis, based on both etiology and cytological findings.

Middle meatus nasal cytology compared to inferior turbinate cytology in non allergic rhinitis.

PURPOSE: Non allergic rhinitis (NAR) comprises different clinical definitions and phenotypes, including non inflammatory non allergic (NINAR) and cellular inflammatory forms. Nasal cytology, usually performed by scraping the inferior turbinate, is a non invasive, cheap and point-of-care tool to distinguish among the different NAR phenotypes, but still a relevant proportion of patients evaluated by nasal cytology receive a non precise definition of NAR phenotype. We hypothesize that collecting nasal cytology samples from middle meatus could increase the diagnostic accuracy. METHODS: Consecutive patients with chronic rhinitis without evidence of allergic sensitization were assessed for nasal cytology by means of scraping both the inferior turbinate and the middle meatus (lateral-inferior wall of the middle turbinate). RESULTS: 107 consecutive patients with NAR were enrolled in the study. According to inferior turbinate cytology, 42.1% were defined as affected by NINAR, 2.8% by bacterial rhinitis, 10.3% by non allergic rhinitis with eosinophils (NARES), 15.0% non allergic rhinitis with neutrophils (NARNE), 19.6% non allergic rhinitis with mast-cells (NARMA) and 10.3% non allergic rhinitis with eosinophils and mast-cells (NARESMA). Middle meatus cytology was in accordance with inferior turbinate cytology in only 37.6% of cases. Eosinophils and mast-cells were detectable more frequently in middle meatus samples (49.5% vs 19.6%, p < 0.01, 59.8% vs 29.9%, p < 0.01, respectively). 93.3% of NINAR patients received an inflammatory NAR phenotype at middle meatus cytology: 26.7% NARES, 24.4% NARNE, 31.1% NARMA and 11.1% NARESMA. CONCLUSION: Middle meatus cytology is more reliable than inferior turbinate cytology in phenotyping patients with NAR. Our study strengthen that nasal cytology should be implemented in clinical practice collecting samples at the middle meatus level.

The Underestimated Role of Mast Cells in the Pathogenesis of Rhinopathies.

Mast cells (MCs) are involved in several biological processes, such as defense against pathogens, immunomodulation, tissue repair after injury, and angiogenesis. MCs have been shown to change from protective immune cells to potent pro-inflammatory cells, influencing the progression of many pathological conditions, including autoimmune diseases and cancers. The role of MCs in the pathogenesis of rhinopathies has often been underestimated, since previous studies have focused their attention on eosinophils and neutrophils, while MCs were considered involved exclusively in allergic rhinitis. However, recent nasal cytology findings have shown the involvement of MCs in several rhinopathies, such as NARMA, NARESMA, and CRSwNP. These recent evidences highlight the crucial role that MCs play in orchestrating the inflammation of the nasal mucosa, through complex biological mechanisms, not yet fully understood. In this context, a better understanding of these mechanisms is fundamental for practicing Precision Medicine, which requires careful population selection and stratification into subgroups based on the phenotype/endotype of the patients, in order to guarantee the patient a tailored therapy. Based on this background, further studies are needed to understand the pathophysiological mechanisms involving MCs and, consequently, to develop targeted therapies aimed to obtain a selective inhibition of tissue remodeling and preventing MC-mediated immune suppression.

Endotyping allergic rhinitis in children: A machine learning approach.

INTRODUCTION: The diversity of allergic rhinitis (AR) phenotypes is particularly evident in childhood, suggesting the need to analyze and identify new approaches to capture such clinical heterogeneity. Nasal cytology (NC) is a very useful diagnostic tool for identifying and quantifying nasal inflammation. Data-driven approaches such as latent class analysis (LCA) assign subjects to classes based on their characteristics. We hypothesized that LCA based on NC, including the assessment of neutrophils, eosinophils, and mast cells, may be helpful for identifying AR endotypes in children. METHODS: A total of 168 children were enrolled. Sociodemographic characteristics and detailed medical history were obtained from their parents. All children performed NC and skin prick tests. LCA was applied for identifying AR endotypes based on NC, using the R package poLCA. All the statistical analyses were performed using R 4.0.5 software. Statistical significance was set at p ≤ .05. RESULTS: LCA identified two classes: Class 1 (n = 126, 75%): higher frequency of children with moderate/large number of neutrophils (31.45%); almost all the children in this class had no mast cells (91.27%) and Class 2 (n = 42, 25%): higher frequency of children with moderate/large number of eosinophils (45.24%) and moderate/large number of mast cells (50%). CONCLUSIONS: The present study used a machine learning approach for endotyping childhood AR, which may contribute to improve the diagnostic accuracy and to deliver personalized health care in the context of precision medicine.

Clinical Evidence of Type 2 Inflammation in Non-allergic Rhinitis with Eosinophilia Syndrome: a Systematic Review.

PURPOSE OF REVIEW: Non-allergic rhinitis (NAR) includes different subtypes, among which NAR with eosinophilia syndrome (NARES) is the most important because of severity of symptoms and the high risk of comorbidities. Its pathophysiology is still object of debate, but a crucial role of chronic eosinophilic inflammation has been recognized. The aim of this review is to critically analyze the current evidence regarding the hypothesis that NARES may be considered a type 2 inflammatory disorder. RECENT FINDINGS: The definition and diagnostic criteria for NARES are not universally shared and adopted, thus generating difficulties in reproducing the results. At present, there is extreme heterogeneity in sampling methods and disagreement in the cut-off of local eosinophilic count to determine a diagnosis of NARES. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standard was applied to identify English-language experimental and clinical articles regarding NARES. The search was performed in April 2021. Twenty-six articles were included. Our data suggest a particular heterogeneity regarding sampling and specific cut-offs adopted for diagnosis of NARES and consensus should be reached. We suggest that eosinophil count should be reported as an absolute value for at least 10 observed rich fields in order to increase the level of standardization. Consensus among authors on this topic should be reached with particular attention to the cut-off for diagnosis. In the future, this limitation may be overcome by the identification of repeatable biomarkers to refine diagnosis and prognosis of NARES. Furthermore, our data strongly suggest that NARES have numerous similarities with clinical features of the most common type 2 diseases such as eosinophilic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP): late onset, association with type 2 comorbidities, selective eosinophilic tissue infiltration, remarkable response to oral and intranasal corticosteroids, and progression in a type 2 CRSwNP.

Mometasone furoate nasal spray in Italian children with seasonal allergic rhinitis: a comprehensive assessment.

OBJECTIVE: Seasonal allergic rhinitis (SAR) is a common disease of childhood and is characterized by type 2 inflammation, bothersome symptoms, and impaired quality of life (QoL). Intranasal corticosteroids are effective medications in managing SAR. In addition, mometasone furoate nasal spray (MFNS) is a well-known therapeutic option. However, the literature provided no data about the effects of MFNS in European children with SAR. Thus, this study addressed this unmet requirement. METHODS: MFNS was compared to isotonic saline. Both treatments were prescribed: one drop of spray per nostril, twice a day, for 3 weeks. Nasal cytology, total symptom score (TSS), visual analogic scale concerning the parental perception of severity of symptoms, and the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) were assessed at baseline, after 7 and 21 days, and 1 month after discontinuation. RESULTS: MFNS significantly reduced eosinophil and mast cell counts, improved QoL, and relieved symptoms, as assessed by doctors and perceived by parents. These effects persisted over time, even after discontinuation. Both treatments were safe and well-tolerated. CONCLUSIONS: The present study documented that a 3-week MFNS treatment was able to significantly dampen type 2 inflammation, improve QoL, and reduce severity of symptoms in Italian children with SAR, and was safe.

Long-term evaluation of nasal polyposis recurrence: A focus on multiple relapses and nasal cytology.

PURPOSE: Recurrence of chronic rhinosinusitis with nasal polyps (CRSwNP) is highly variable, reaching 55-60% of cases. Different results about clinical parameters as recurrence predictors has been reported. The aim of this retrospective study was to evaluate CRSwNP recurrence risk after a long-term follow-up (up to 20 years). Moreover, the role of nasal cytology was assessed. MATERIALS AND METHODS: Sixty-one patients who underwent functional endoscopic sinus surgery for CRSwNP were enrolled. Clinical parameters were recorded. Nasal cytology was performed at follow-up examinations. The Kaplan-Meier method was used to obtain the recurrence-free survival curves. The median number of recurrences per year was evaluated. RESULTS: Five- and 10-year recurrence rates were 30.29% and 66.06%, respectively. Median recurrence-free survival was 106 months. Asthma and Aspirin-Exacerbated Respiratory Disease represented predictors of multiple recurrences (p < 0.05). Intranasal steroids were the main treatment to prevent relapses (p < 0.05). Patients with normal cytology at follow-up evaluation had a lower probability to have first recurrence within 10 years (59% of cases), compared to neutrophil or eosinophil infiltrate (100% and 88% of cases, respectively) (p < 0.05). CONCLUSIONS: CRSwNP has a high recurrence risk, also more than 10 years after surgery. Nasal cytology may identify subjects with a higher risk of early recurrence.

Diagnostic performance of nasal cytology.

PURPOSE: Nasal pathologies are characterized by a symptomatology that hardly allows to distinguish allergic rhinitis (AR), non-allergic rhinitis (NAR), and chronic rhinosinusitis (CRS). Nasal cytology (NC) has shown increasing importance in helping the clinician to differentiate the various phenotypes of rhinitis. NC allows us to evaluate nasal cellularity by distinguishing AR and various types of NAR. The objective of the study is to assess the diagnostic performance of the NC by evaluating its sensitivity, specificity, and predictive value. METHODS: We recruited 387 patients with persistent rhinitis symptoms, and nasal cytology was performed. The rhinocytogram was obtained by reading for fields and the cellular count was made using quantitative and semi-quantitative grading together. RESULTS: Two hundred and fifteen patients (55.5%; 38 had acute rhinitis, 24 acute sinusitis, 153 chronic rhinosinusitis) out of 387 referred nasal symptoms. Cytological specimen showed a mean of 94 ± 4% ciliated cells, 29 ± 0.2% mucinous cells, 16 ± 0.1% neutrophils, 11 ± 0.08% eosinophils, 4 ± 0.03 lymphocytes, 4 ± 0.03% mast cells, and 4 ± 0.01% other cells. NC was positive in 271 cases (70%). After revision of medical history, 153 patients (39%) were considered positive for NAR. Test sensibility was 100% (95% CI 97-100), specificity was 49.6% (95% CI 43-56%). Positive predictive value (PPV) was 56% (95% CI 50-62%), and negative predictive value (NPV) was 100% (95% CI 96-100%). The positive likelihood ratio was 1.98 (95% CI 1.75-2.25). Accuracy of the test was 69.5% (95% CI 64.6-74.0%). CONCLUSION: Our data showed ability to identify the true-positive patients with NAR but a low ability to identify the true-negative patients, with a global accuracy of 69.5%.

Nasal cytology can predict clinical efficacy of subcutaneous immunotherapy in intermittent allergic rhinitis.

Introduction: Allergen immunotherapy (AIT) is the only disease-modifying treatment option available for patients with IgE-mediated allergic rhinitis. The identification of specific biomarkers, which may predict response to AIT, is currently an active field of research in the aspect of recommended personalization of medicine. Aim: To assess the changes in rhinological parameters in intermittent allergic rhinitis (IAR) patients resulting from subcutaneous immunotherapy (SCIT). Material and methods: Forty-two patients (female: 19; 45%) with IAR qualified for subcutaneous immunotherapy were enrolled in this study. Fourteen (33.3%) patients were desensitized with grass pollen allergen extracts, 12 (28.6%) with tree pollen allergen extracts, and 16 (38.1%) with grass and tree pollen allergen extracts. The patients were evaluated before AIT during the pollen season and in the next pollen season after introduction of subcutaneous immunotherapy. On both occasions, determination of total nasal symptom score (TNSS), rhinomanometry and nasal cytology were performed. Results: All examined parameters significantly improved after one course of allergen immunotherapy: the percentage of eosinophils in nasal mucosa, TNSS and nasal resistance decreased, whereas the nasal flow rate increased. The decrease in percentage of nasal eosinophils significantly correlated with improvement in TNSS (rs = 0.39, p < 0.05) and was the highest in the subgroup sensitive to grass pollen (44.5 (40-52)). Conclusions: The rhinological assessment confirmed high effectiveness of SCIT in intermittent allergic rhinitis. A high percentage of eosinophils in nasal cytology before subcutaneous immunotherapy can predict its clinical efficacy for intermittent allergic rhinitis, especially in grass pollen allergy.

Nasal Cytology in Radiofrequency Turbinate Volume Reduction.

INTRODUCTION: Radiofrequency turbinate volume reduction (RFTVR) is an effective treatment of inferior turbinate hypertrophy. RFTVR can reduce epithelial cell alterations in nasal mucosa. The aim of this observational study was to evaluate the effects of RFTVR on nasal obstruction and cytology, stratifying for different types of rhinitis. METHODS: Nasal cytology and subjective nasal obstruction were evaluated on 113 patients before RFTVR (T0) and after 3 months (T1). The patients were divided into groups on the basis of the underlying disease: allergic rhinitis, nonallergic rhinitis, rhinitis medicamentosa, and other diseases (e.g., hormonal-based turbinate hypertrophy). RESULTS: Nasal cytology at T0 identified 42 patients with allergic rhinitis, 40 with nonallergic rhinitis, 19 with rhinitis medicamentosa, and 12 with other diseases. An improvement of nasal cytology at T1 was observed in 29.2% of cases. They mainly consisted of patients with nonallergic rhinitis with neutrophils, whose neutrophil infiltrate decreased. Only 2 cases (1.7%) showed a worsening of nasal cytology at T1. A statistically significant decrease in subjective nasal obstruction was observed for every group (p < 0.05). Higher differences of nasal obstruction between T0 and T1 were found in patients with rhinitis medicamentosa or other diseases. CONCLUSION: RFTVR represents a safe and effective treatment for turbinate hypertrophy of various etiology. It is not responsible for a worsening of inflammatory infiltrate of the nasal mucosa.

Effectiveness of micronized nasal irrigations with hyaluronic acid/isotonic saline solution in non-polipoid chronic rhinosinusitis: A prospective, randomized, double-blind, controlled study.

BACKGROUND: Sodium hyaluronate has been proposed as a treatment for improving the symptoms of chronic rhinosinusitis. The present study evaluated the effect of the intranasal administration of hyaluronic acid in a group of patients affected by chronic rhinosinusitis without nasal polyps (CRSsNP). MATERIALS AND METHODS: Thirty subjects aged 18-65 years affected by CRSsNP were enrolled. The subjects were randomly administered hyaluronic acid or isotonic saline solution by nasal nebulizer twice per day for 30 days. They were evaluated before (T0) and after the treatment (T1) with Sino-Nasal Outcome Test-22, visual analogue scale for rhinorrhea, nasal obstruction, facial pain and hyposmia/hypogeusia, nasal endoscopy, active anterior rhinomanometry, peak nasal inspiratory flow and nasal cytology. RESULTS: Comparing the study and the control group, at T1 no significant differences were observed in both objective and subjective parameters. Being included in the study group rather than in the control group did not have a significant effect on the variation of the considered parameters between T0 and T1. Considering the effects of the micronized douches independently from the type of solution used (either hyaluronic acid or isotonic saline solution), although no difference emerged between study and control group for any of the objective parameters, there was an improvement of Sino-Nasal Outcome Test-22 scores (p = .0005), visual analogue scale for nasal obstruction (p = .0006) and for hyposmia/hypogeusia (p = .04). CONCLUSIONS: The treatment with micronized nasal douches can improve the sino-nasal symptoms of CRSsNP, in particular nasal obstruction and olfactory ability. No advantage of the use of hyaluronic acid over isotonic saline solution emerged.

Focus on the Involvement of the Nose and Paranasal Sinuses in Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome): Nasal Cytology Reveals Infiltration of Eosinophils as a Very Common Feature.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing vasculitis that predominantly affects small- to medium-sized vessels. It is characterized by a wide spectrum of extrapulmonary symptoms, including sinonasal and paranasal sinus abnormalities. These are the most common features of this disease, constituting diagnostic criteria for EGPA. However, the actual clinical features, cellular mechanisms and impact on patients' quality of life (QoL) are still a matter of study. METHODS: Thirty-nine EGPA patients underwent multidimensional rhinological evaluations, including rhinofibroscopy, nasal cytology, and QoL questionnaires. This was coupled with respiratory and rheumatological assessments. RESULTS: Twenty-eight patients were diagnosed with chronic rhinosinusitis (CRS). Of these, 18 had nasal polyposis (NP). Chronic rhinitis was diagnosed in 10 patients. Of these, 3 had allergic rhinitis (AR) and seven had non-AR (NAR). Overall, only 1 patient (2.6%) was normal. Nasal cytology showed that hypereosinophilia was present in 17/28 patients with CRS, 4/7 patients with NAR and all patients with AR. SNOT-22 and SF-36 showed a severe impact of nasal symptoms on QoL. No differences in asthma control or rheumatological patterns for EGPA were observed among patients with or without NP. CONCLUSIONS: Even when the rheumatological assessment scored EGPA "under control" according to the Birmingham Vasculitis Activity Score and Vasculitis Damage Index, sinonasal diseases and related nasal inflammatory processes were not controlled. Therefore, there is a need for clinical monitoring and targeted treatment to control the inflammatory processes and improve the QoL of EGPA patients.

Efficacy of Buffered Hypertonic Saline Nasal Irrigation for Nasal Symptoms in Children with Seasonal Allergic Rhinitis: A Randomized Controlled Trial.

BACKGROUND: Saline nasal irrigation is labelled as an add-on treatment in patients with allergic rhinitis (AR). The primary aim of this study was to compare the efficacy of 21-day use of buffered hypertonic saline (BHS) versus normal saline solution (NSS) on reducing nasal symptoms in children with seasonal AR (SAR). Comparing their efficacy on nasal cytology counts (NCC), quality of life, and sleep quality was the secondary aim. METHODS: In this 21-day, open-label, randomized controlled study, 36 SAR children (aged 6-13 years) with a Total 5 Symptom Score (T5SS) ≥5 received twice-daily BHS or NSS delivered through a nasal douche. Efficacy measures were least square mean changes (LSmc) in T5SS, NCC, Paediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ), and Pittsburgh Sleep Quality Index (PSQI) scores. RESULTS: BHS improved the T5SS total score to a greater extent than NSS (LSmc -6.45 vs. -5.45, p < 0.001). Concerning NCC, BHS significantly reduced the scores of neutrophils (LSmc -0.76, p = 0.004) and eosinophils (LSmc -0.46, p = 0.018), while NSS did not. Similarly, only BHS yielded a significant improvement in the PRQLQ score (LSmc -0.57, p = 0.009), whereas the improvement in PSQI score was comparable between the BHS (LSmc -0.77, p = 0.025) and NSS (LSmc -1.39, p < 0.001) groups. Overall, BHS was well tolerated. CONCLUSIONS: In children with SAR, BHS is effective in improving nasal symptoms and NCC, with an associated beneficial effect on quality of life.