Improvement of clinical and immunopathologic parameters in asthmatic children treated for concomitant chronic rhinosinusitis

Improvement of clinical and immunopathologic parameters in asthmatic children treated for concomitant chronic rhinosinusitis Maria Angela Tosca, MD*; Cristina Cosentino, MD*; Eugenio Pallestrini, MD†; Giacomo Caligo, MD†; Manlio Milanese, MD*; and Giorgio Ciprandi, MD*

Background: Chronic rhinosinusitis is frequently associated with asthma. A Th2 cytokine pattern has been recently reported in chronic rhinosinusitis in asthmatic children. Objective: To evaluate the effects of treating concomitant chronic rhinosinusitis on respiratory symptoms and function and immunopathological parameters in asthmatic children. Methods: Eighteen children with moderate asthma (age range, 5 to 12 years) poorly controlled by high doses of inhaled corticosteroids and chronic rhinosinusitis were evaluated for symptoms, spirometry, and inflammation at baseline, after treatment, and 1 month after suspension of treatment. All of the children were treated with a combination of amoxicillin and clavulanate (20 mg/kg twice daily) and fluticasone propionate aqueous nasal spray (100 ␮g/d) for 14 days. A short course of oral corticosteroids was also prescribed (deflazacort, 1 mg/kg daily for 2 days, 0.5 mg/kg daily for 4 days, and 0.25 mg/kg daily for 4 days). Rhinosinusal lavage for cytokine measurements and a nasal scraping for cytologic analysis were performed in all patients before and after medical treatment. Results: A negative endoscopy result was demonstrated in 15 children after treatment. Symptoms and respiratory function significantly improved after treatment and 1 month later; 8 children had intermittent asthma and 10 had mild asthma. A significant reduction of inflammatory cell numbers was detected in all asthmatic children. Interleukin 4 levels significantly decreased (P ⬍ 0.001), whereas interferon-␥ levels increased (P ⬍ 0.001). Conclusion: Treatment of chronic rhinosinusitis is able to improve symptoms and respiratory function in asthmatic children, reducing inflammatory cells and reversing the cytokine pattern from a Th2 toward a Th1 profile. Ann Allergy Asthma Immunol. 2003;91:71–78.

INTRODUCTION Sinusitis is a common disorder that places a significant burden on society. The US National Health Interview Survey reports that sinusitis affects approximately 15% of the US population.1 Sinusitis is probably underestimated during childhood and adolescence. Even so, it is the fifth leading reason for antibiotic prescription in the United States. Overall costs have been estimated at $5.8 billion annually, and approximately $1.8 billion of this was spent on patients younger than 12 years.2 The more appropriate definition of rhinosinusitis is based on a pathophysiological point of view, since coexistence of rhinitis and sinusitis has been broadly reported.3 There is general agreement that upper respiratory airways diseases, including allergic rhinitis, viral infections, and rhinosinusitis, may induce a worsening of asthma.4 Unrecognized rhinosinusitis has been considered by several authors as a significant pathogenic factor in asthmatic patients.4 –7

* Allergy, Department of Internal Medicine, University of Genoa, Genoa, Italy. † Head and Neck Department, San Martino Hospital, Genoa, Italy. Received for publication September 13, 2002. Accepted for publication in revised form January 8, 2003.

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The obstruction of the ostiomeatal complex, which is a crucial area for the ventilation and drainage of the paranasal sinuses, is the first pathogenic event that leads to a process of acute or chronic rhinosinusitis.7 Nasal infections and allergic inflammation can induce mucosal edema, alter mucociliary clearance, produce cytokines and chemokines, and finally up-regulate adhesion molecules.8 All these factors are involved in the genesis and maintenance of inflammatory process of paranasal mucous membranes. We previously reported that rhinosinusitis was diagnosed in 44% of 128 asthmatic children evaluated by nasal endoscopy.9 If symptoms of rhinosinusitis persist longer than 12 weeks, chronic rhinosinusitis is considered.10 Chronic rhinosinusitis is sustained by mucosal edema, subepithelial fibrosis, basement membrane thickening, goblet cell hyperplasia, and inflammatory cell infiltrate.11,12 The pathophysiologic features of chronic rhinosinusitis have been related to the effects of Th2 cytokines in allergic patients.10 Increased levels of granulocyte macrophage– colony stimulating factor (GMCSF), interleukin (IL)-3, IL-4, IL-5, and IL-13 were reported in allergic rhinosinusitis, whereas in nonallergic sinusitis only GM-CSF, IL-3, and interferon-␥ (IFN-␥) levels were increased.12,13 A reduced expression of IL-12 has been reported in both allergic and nonallergic patients with chronic rhinosinusitis.14 Recently, we reported that a similar Th2 cytokine

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pattern was present in allergic and nonallergic chronic rhinosinusitis in asthmatic children.15 These findings would suggest the existence of a common immunopathologic mechanism shared by upper and lower airways and are consistent with the concept of united airways disease.16,17 Rhinosinusitis should be adequately diagnosed and treated, since it represents a crucial step in the management of asthmatic children, as reported by some authors.18 –20 The aim of our study was to evaluate the effects and course of a standardized medical treatment for concomitant chronic rhinosinusitis in children with poorly controlled asthma on respiratory symptoms and function and immunopathological parameters. MATERIALS AND METHODS Patients Eighteen asthmatic outpatient children were evaluated (10 boys and 8 girls; mean age, 8.3 years; range, 5 to 12 years). A detailed clinical history and a complete physical examination were performed by an allergist-pediatrician. The diagnosis of associated allergy was made on the basis of a skin prick test for a panel of common allergens as previously described,9,15 and asthma was classified as stated by the Global Initiative for Asthma (GINA) guidelines.21 Lung function was measured using a spirometer (SensorMedics, Yorba Linda, CA) at baseline and 15 minutes after administration of 200 ␮g of salbutamol by a metered-dose inhaler with an Aerochamber according to American Thoracic Society (ATS) recommendations.22 All children were steadily treated with inhaled corticosteroids at high dosages (ie, fluticasone, 125 ␮g twice daily, or budesonide, 200 ␮g twice daily) and short-acting ␤2-agonists on an as needed basis for at least 3 months. None of the children had used antibiotics, nasal corticosteroids, or oral corticosteroids in the previous 4 weeks. However, patients were symptomatic and their conditions not optimally controlled. For this reason, their pediatricians contacted our clinic for a more detailed diagnosis. Patients were evaluated by an ear, nose, and throat (ENT) specialist by nasal endoscopy with optical fibers and otoscopy. The diagnosis of chronic rhinosinusitis was based on nasal symptoms (mucopurulent rhinorrhea, nasal obstruction), postnasal drip, and cough, occurring for more than 3 months, and evidence of endoscopic signs of rhinosinusitis, according to validated criteria.9,10,15 We did not perform x-ray examinations because they do not guarantee sufficient diagnostic sensibility.23–25 Study Design Patients were evaluated in 3 visits. At baseline (visit 1, day 0), after treatment (visit 2, day 14), and 1 month after treatment suspension (visit 3, day 44). Treatment consisted of a combination of oral amoxicillin and clavulanate (20 mg/kg twice daily) and fluticasone propionate aqueous nasal spray (100 ␮g/d, ie, 50 ␮g per nostril in the morning) for 14 days. We chose a relatively low-dose antibiotic because rhinosinusitis was chronic. A short course of oral corticosteroids was also prescribed (deflazacort, 1 mg/kg daily for 2 days, 0.5 mg/kg

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daily for 4 days, and 0.25 mg/kg daily for 4 days) to achieve a faster response. A placebo group was not considered, since our ethics committee deemed this approach unethical. During each visit, a complete clinical examination and spirometry were performed. On visits 1 and 2, samples of venous blood were taken for eosinophil counts. Rhinorrhea, nasal obstruction, wheezing, and cough were evaluated by clinicians at each visit, scoring them according to an arbitrary 4-point rating scale, from 0 to 3 (0, absent; 1, mild; 2, moderate; and 3, severe). Rhinosinusal lavage and nasal cytologic analysis were performed at days 0 and 14 in all patients before and after medical treatment. An ENT examination was performed at days 0 and 14. The study was approved by the institutional review board, and an informed oral consent was obtained from their parents. Diary Cards Parents and children answered questions on a diary card daily. Diary questions evaluated daytime asthma symptoms (dyspnea, wheezing, and cough) and nasal symptoms (rhinorrhea and nasal obstruction). Symptoms were scored according to an arbitrary 4-point rating scale, from 0 to 3 (0, absent; 1, mild; 2, moderate; 3, severe). Nasal Endoscopy The endoscopy was performed as previously described in detail.9,15 After each ENT examination and rhinosinusal endoscopy, all clinical data were registered on a proper form. Nasal Scraping Nasal cytologic specimens were obtained by scraping the head of the inferior turbinate with a cotton swab, as previously reported.26,27 Briefly, after the nasal scraping, the cotton tip of the swab was immersed in a plastic tray with phosphate-buffered saline and transferred to a 10-mL polypropylene tube. The recovered fluids were centrifuged at 220g per minute for 10 minutes, and each pellet was resuspended in phosphate-buffered saline (2 mL). Cell suspensions were filtered to reduce the quantity of mucus, and cytospin slides were prepared by using standard techniques. Smears were stained with Diff Quik stain (Sigma, Milan, Italy) to differentiate among eosinophils, neutrophils, lymphocytes, monocytes/macrophages, and epithelial cells and were analyzed by optic microscope (Olympus U-SPT; Olympus, Rome, Italy). The number of inflammatory cells was expressed as a mean of 10 optical fields at 100⫻ magnification. Samples were examined in a blinded fashion. Rhinosinusal Lavage Cytokine fluids were obtained by a lavage of the rhinosinusal cavity using 5 mL of physiologic saline, according to standard methods as previously described.9,15 This procedure was performed with the patient’s head bent backward during closure of the soft palate. The recovered fluid was comparable in all groups; it was collected to dose cytokine levels and stored at ⫺20° C.

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Figure 1. Median (⫾SE) change from baseline in individual symptom scores during 14 days of treatment. Therapy was associated with a significant improvement in the severity of rhinorrhea since day 4 (P ⬍ 0.001) and nasal obstruction since day 4 (P ⫽ 0.007). On the 0to 3-point diary scale, the median baseline scores were 3 (interquartile range, 2.3–2.8) for rhinorrhea and 2.5 (interquartile range, 2.2–2.8) for nasal obstruction.

Cytokine Evaluation Cytokines were measured with the enzyme-linked immunosorbent assay method (R&D Systems, Denver, CO). This assay used the quantitative sandwich enzyme immunoassay technique. The minimum detectable level was typically less than 10 pg/mL for IL-4 and less than 8 pg/mL for IFN-␥. A monoclonal antibody specific for each cytokine was precoated onto a microplate. Standards and samples were pipetted into the wells, and each cytokine present was bound by the immobilized antibody. After washing away any unbound substances, an enzyme-linked polyclonal antibody specific for cytokine was added to the wells. Following a wash to remove any unbound antibody-enzyme reagent, a substrate solution was added to the wells and color developed in proportion to the amount of cytokine bound in the initial step. The color development was stopped and its intensity measured.

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Statistical Analysis Differences among conditions were detected by analysis of variance (forced expiratory volume in 1 second [FEV1] and ratio of FEV1 to forced vital capacity) and paired t test (blood eosinophils) for parametric data and by Wilcoxon matched paired test for inflammatory cells, cytokines, and symptom scores. Correlations were detected by Spearman rank test. Parametric data are expressed as mean ⫾ SD. Data were considered statistically significant at P ⬍ 0.05. RESULTS Patients All children had moderate asthma (class 3, GINA guidelines) and were sensitized to Dermatophagoides mix, whereas 3 of them were also sensitized to grass and Parietaria judaica. A significant response to salbutamol was obtained in all chil-

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Figure 2. Median (⫾SE) change from baseline in individual symptom scores during 14 days of treatment. Therapy was associated with a significant improvement in the severity of dyspnea since day 3 (P ⫽ 0.008), wheezing since day 3 (P ⬍ 0.001), and cough since day 3 (P ⫽ 0.04). On the 0- to 3-point diary scale, the median baseline scores were 2 (interquartile range,1.9 –2.5) for dyspnea, 2 (interquartile range, 2.1–2.7) for wheezing, and 3 (interquartile range, 2.4 –2.9) for cough.

dren according to ATS recommendations.22 Endoscopic signs of rhinosinusitis (ie, mucopurulent drainage) were detected in all children. All children underwent the prescribed therapy without significant adverse effects.

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Symptoms at Visits and on Diary Cards All children showed a significant (P ⬍ 0.001) decrease of asthma and nasal symptoms (rhinorrhea, nasal obstruction, wheezing, and cough) at days 14 and 44. On day 14, rhinorrhea

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(P ⬍ 0.001) and nasal obstruction (P ⫽ 0.006) as listed on diary cards had significantly decreased from day 4 (Figs 1 and 2) and cough (P ⫽ 0.03), wheezing (P ⬍ 0.001), and dyspnea (P ⫽ 0.009) had significantly decreased from day 3. Laboratory Results A significant increase of FEV1 (P ⬍ 0.001) was measured at days 14 and 44, without any difference between the 2 visits. Blood eosinophils and cells from nasal scrapings (Fig 3) were significantly reduced at day 14 (P ⬍ 0.001 and P ⬍ 0.005, respectively). IL-4 levels significantly decreased (P ⬍ 0.001), whereas IFN-␥ levels significantly increased (P ⬍ 0.001) at day 14 (Fig 4). Signs of rhinosinusitis disappeared in all 15 children at day 14, after treatment. Eight children had intermittent asthma and 10 had mild asthma at day 44, 1 month after treatment suspension. At baseline, a significant positive correlation was found between FEV1 values and IFN-␥ levels (r ⫽ 0.49, P ⫽ 0.04; Fig 5). DISCUSSION The main finding of this study is that children with poorly controlled moderate asthma can obtain a relatively long-term benefit from a successful 14 days of medical treatment of their concomitant rhinosinusitis. Results are documented by improvement of symptoms and spirometry, reduction of inflammatory nasal cell numbers, and IL-4 and IFN-␥ inversion. Furthermore, these clinical and functional effects persist 1 month after treatment, allowing classification of the asthma as intermittent or mild persistent. A placebo group was not introduced, since it was not considered ethical by our ethics committee. In addition, our ethics committee and we did not consider it ethically correct to not optimally treat children with poorly controlled moderate asthma when rhinosinusitis was diagnosed. For this reason, we prescribed a burst oral corticosteroid. We are aware

Figure 4. Median (⫾SE) interleukin 4 (IL-4) and interferon-␥ (IFN-␥) levels evaluated at baseline (open bars) and after treatment (darkened bars) (P ⬍ .001 for both).

that results on asthma outcomes would be altered by this aggressive treatment, but our study was performed not only to evaluate the efficacy after 14 days of rhinosinusitis-asthma therapy but also its effectiveness 1 month after therapy suspension and its action on nasal immunopathologic conditions. For many years, the association between asthma and rhinosinusitis has been described. In 1981, Businco et al18 reported that asthmatic children with clinical and radiologic findings of sinusitis showed significant improvement in sinus x-ray examination results and asthma symptoms after therapy for sinusitis. In 1984, Rachelefsky et al19 observed that children with asthma showed remarkable improvement of lower airway symptoms and pulmonary function after diagnosis and concomitant treatment of sinusitis. Other studies showed the

Figure 3. Median (⫾SE) number of eosinophils, neutrophils, lymphocytes, monocytes, and total cells (sum of all the cells) evaluated at baseline (open bars) and after treatment (darkened bars; P ⫽ 0.002 for all parameters).

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Figure 5. Forced expiratory volume in 1 second (FEV1) as a function of the concentration of interferon-␥ (IFN-␥) in rhinosinusal lavage fluid of asthmatic children before treatment.

same results whether the sinus disease was treated clinically28 or surgically.29 More recently, Oliveira et al20 showed an improvement of bronchial hyperresponsiveness in asthmatic children treated for concomitant sinusitis. These authors recommend that all asthmatic children be investigated to check for a sinus disease, particularly asthmatic children with severe asthma, those who do not respond to appropriate therapy, those who have no obvious causes for their asthma, and those who have associated significant upper airway symptoms.18,20 In our study, medical treatment induced a consistent and persistent (ie, 1 month after suspension) improvement in asthma, as evidenced by the inclusion of children with lower GINA classes. This evidence indirectly confirms the pathogenetic role exerted by upper airways in asthmatic children. Furthermore, the present study corroborates the recommendation of a multidisciplinary approach in the management of asthmatic children. In fact, we demonstrated that inadequate control of asthma with conventional anti-inflammatory therapy (ie, inhaled corticosteroids) may be correct only with an appropriate diagnosis of chronic rhinosinusitis and pharmacologic treatment. Chronic rhinosinusitis is characterized by a persistent inflammatory infiltrate, which has been reported to be similar to that observed in allergic rhinitis.30 Like allergic rhinitis, the pathophysiological features of chronic rhinosinusitis have been broadly considered to depend on the effects of Th2 cytokines in allergic patients.11 Recently, we reported that allergic asthmatic children with chronic rhinosinusitis had a typical Th2 cytokine pattern with high levels of IL-4 and low levels of IFN-␥.15 On the other hand, high levels of IL-4 and low levels of IFN-␥ were reported also in nonallergic asthmatic children with chronic rhinosinusitis.15 A possible explanation may be that a polarization of Th2 response characterizes the inflammation of bronchi in both variants of asthma.31 A standard pharmacologic protocol was chosen according to the literature.32–34 This protocol consisted of the association of oral amoxicillin-clavulanate plus fluticasone propionate

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aqueous nasal spray administered for 2 weeks and a short course of oral deflazacort. Amoxicillin-clavulanate is considered a reasonable initial antibiotic choice in patients with uncomplicated rhinosinusitis. The combination of amoxicillin and clavulanate is typically effective against most ␤-lactamase–producing bacteria (such as Moraxella catarrhalis, Haemophilus influenzae, Staphylococcus aureus) and many other anaerobic bacteria.35 Fluticasone propionate aqueous nasal spray is a topically active corticosteroid molecule based on the androstane nucleus.36 Several studies have demonstrated the efficacy of its formulation as aqueous nasal spray in the treatment of allergic rhinitis and chronic rhinosinusitis, reducing both clinical and inflammatory parameters.36,37 Furthermore, fluticasone propionate aqueous nasal spray inhibits both early-phase and late-phase responses following allergenspecific nasal challenge, including symptoms, eosinophil infiltrate, and adhesion molecule expression.38 Finally, deflazacort is a systemic glucocorticoid with few systemic adverse effects and is highly effective in reducing symptoms and inflammatory events following allergen challenge.39 All drugs mentioned herein are able to reduce inflammation. Even, amoxicillin-clavulanate has been reported to reduce cytokines (including IL-6, IL-8, IL-10, transforming growth factor ␤, and IFN-␥) in both in vitro40 and in vivo41,42 studies. Fluticasone reduced IL-4 and IL-13 levels in allergic patients with chronic rhinosinusitis and the numbers of cells expressing receptors for IL-4, IL-5, and GM-CSF.43,44 Aside from directly reducing the synthesis of Th2-type cytokines, corticosteroids may also increase the level of Th1-type cytokines, particularly IFN-␥ and IL-12, which in turn can suppress the transcription of IL-4.44 – 46 Our results confirm that Th2 profile reversibility is probably the most important mechanism in reducing persistently nasal airway inflammation and its consequences on asthma outcomes. Furthermore, we demonstrated a significant correlation between IFN-␥ concentrations at rhinosinusal level and FEV1 values, confirming the results of a previous study

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performed in children with moderate atopic asthma.47 Hoekstra et al47 demonstrated that the FEV1 was directly related to the concentration of IFN-␥ in supernatants of cultures of stimulated peripheral blood mononuclear cells, suggesting an important part in the pathophysiology of childhood atopic asthma. Our findings highlight this role and demonstrate that an adequate treatment of concomitant rhinosinusitis is capable of increasing IFN-␥ levels and improving clinical and functional parameters. In our study, medical treatment induced a consistent and persistent (ie, 1 month after suspension) improvement of asthma, as evidenced by the inclusion of children with lower GINA classes. This evidence indirectly confirms the pathogenetic role exerted by upper airways in asthmatic children. In conclusion, we suggest considering the presence of upper airway disease in asthmatic children, even in the case of mild symptoms as previously reported,9 to achieve optimal control of clinical, functional, and inflammatory events. Further studies should be addressed to confirm these findings in more conspicuous cohorts of children and during a more prolonged time of observation. REFERENCES 1. Ray NF, Baraniuk JN, Thamer M, et al. Healthcare expenditures for sinusitis in 1996: contributions of asthma, rhinitis, and other airway disorders. J Allergy Clin Immunol. 1999;103:408 – 414. 2. McCuig LF, Hughes JM. Trends in antimicrobial drug prescribing among office based physicians in the United States. JAMA. 1995;273:214 –219. 3. Gwaltney JM, Phillips CD, Miller RD, Riker DK. Computed tomographic study of the common cold. N Engl J Med. 1994; 330:25–30. 4. Osguthorpe JD, Hadley JA. Rhinosinusitis: current concepts in evolution and management. Med Clin North Am. 1999;83: 27– 41. 5. Benninger MS, Anon J, Mabry RL. The medical management of rhinosinusitis. Otolaryngol Head Neck Surg. 1997;117: S41–S49. 6. Adinoff AD, Cummings NP. Sinusitis and its relationship to asthma. Pediatr Ann. 1989;18:785–790. 7. Kaliner MA, Osguthorpe JD, Fireman P, et al. Sinusitis: bench to bedside. Current findings, future directions. J Allergy Clin Immunol. 1997;99:S829 –S848. 8. Bachert C, Wagenmann M, Rudack C, et al. The role of cytokines in infectious sinusitis and nasal polyposis. Allergy. 1998; 53:2–13. 9. Tosca MA, Riccio AM, Marseglia GL, et al. Nasal endoscopy in asthmatic children: assessment of rhinosinusitis and adenoiditis incidence, correlations with cytology and microbiology. Clin Exp Allergy. 2001;31:609 – 615. 10. Report of the Rhinosinusitis Task Force Committee meeting. Otolaryngol Head Neck Surg. 1997;117:7–14. 11. Christodoupoulos P, Cameron L, Durham S, Hamid Q. Molecular pathology of allergic disease II: upper airway disease. J Allergy Clin Immunol. 2000;105:211–223. 12. Hamilos DL, Leung DY, Wood R, et al. Chronic hyperplastic sinusitis: association of tissue eosinophilia with mRNA expression of granulocyte-macrophage colony-stimulating factor and interleukin-3. J Allergy Clin Immunol. 1993;92:39 – 48.

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Requests for reprints should be addressed to: Giorgio Ciprandi, MD Allergy & ENT Padiglione Specialita` (piano terzo) Ospedale San Martino Largo R. Benzi 10 16132 Genoa, Italy E-mail: [email protected]

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