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Upper airway ? 2: , and Thorax: first published as 10.1136/thx.2008.112870 on 1 December 2009. Downloaded from M R Loebinger,1 D Bilton,2 R Wilson1

1 Host Defence Unit, Royal ABSTRACT damage the and stimu- Brompton Hospital, London, UK; The nose and are contiguous with the late excess production, and mucosal swel- 2 Cystic Fibrosis Unit, Royal Brompton Hospital, London, UK lower . Patients with bronchiectasis and ling blocks the ostia, further impairing mucus cystic fibrosis commonly have sinonasal , which is clearance. Bacterial and damage caused Correspondence to: thought to have the same aetiology and pathophysiology by the host inflammatory response interact, Dr R Wilson, Host Defence Unit, as the chronic disease. Despite this, the conditions perpetuating the disease process, and in chronic Royal Brompton Hospital, Sydney Street, London SW3 are rarely considered together and there is very little rhinosinusitis the disease can become independent 6NP, UK; [email protected] literature on the treatment of sinonasal disease in of continued bacterial infection. Similarly, bronchiectasis. In addition to being a common cause of impaired clearance from the lower airways leads Received 7 May 2009 comorbidity, there is evidence suggesting that sinonasal to chronic respiratory infection and inflammation Accepted 31 May 2009 disease may directly influence the bronchial condition. that has been termed a ‘‘vicious circle’’, leading to This article reviews sinonasal disease in bronchiectasis the progression of bronchiectasis.2 It is therefore and cystic fibrosis and addresses the possible interactions not surprising that bronchiectasis and sinusitis between the health and disease of the upper and lower often coexist. airways. Other important host defences in the upper respiratory tract include immunoglobulins, defen- sins and antibacterial components of the mucus The upper respiratory tract comprising the nose such as lysozyme. The defences can be impaired by and paranasal sinuses has the same mucosal lining primary or secondary abnormalities (table 1). The as the lower airways, and both compartments are upper respiratory tract is often exposed first to an involved together in health and disease. The infectious agent and to higher concentrations of relevance of this ‘‘single airway’’ concept has been inhaled matter and, for this reason, the initial demonstrated with , allergic and symptoms may come from this site and may be nasal polyposis, but it may be similarly useful in more severe. chronic infective respiratory conditions. Investigation of the upper airway may be useful SINONASAL DISEASE as a marker of disease in the less accessible lower The nasal cavity conditions the air we breathe, and http://thorax.bmj.com/ airway. In addition, treatment of one compart- it also acts as a first line of defence by impacting ment may have benefits throughout the whole unwanted particles on the mucosa and excluding respiratory tract. Improvements in sinus health them from the lower respiratory tract. The have been reflected in improved lower airway paranasal sinuses (frontal, maxillary, ethmoid and 1 disease in asthma. This has not been studied in sphenoid) are air-filled spaces within the skull. bronchiectasis or cystic fibrosis, but the implica- They reduce the weight of the skull and humidify tions are similar in that viral and bacterial and heat inhaled air. These cavities connect with on October 1, 2021 by guest. Protected copyright. can pass from one to the other. the nose via small orifices called ostia, which may is an important first-line become blocked by swelling of inflamed mucosa. defence of both the upper and lower respiratory Rhinosinusitis is defined as inflammation of the tracts. The nose, sinuses, and bronchi are nose and paranasal sinuses. Diagnostic criteria lined by ciliated and mucus-producing cells which include the presence of two or more symptoms form the mucociliary escalator and trap inhaled which should include one of nasal obstruction/ matter and propel it to the nasopharynx, where it congestion or anterior/posterior rhinorrhoea. can be expectorated or swallowed. Mucus trans- Other symptoms include and facial depends on both the integrity and function of or pressure. The patient’s symptom score can the ciliated epithelium and the properties of the describe severity of disease on a visual analogue mucus. The cilia beat at a rate of between 12 and scale.3 Patients should also have evidence of 16 strokes per second in a consistent direction and rhinosinusitis on examination with polyps, muco- in a coordinated fashion. The periciliary fluid layer purulent discharge or oedema around the middle is of the required depth equalling the vertical meatus on nasendoscopy or mucosal changes height of a , and the mucus must be of evident on the CT scan.4 suitable rheology for transport. rhinosinusitis consists of symptoms last- Impaired sinonasal clearance leads to stasis of ing ,12 weeks, and can be subdivided into acute secretions, which are only removed from the nasal viral rhinosinusitis with a duration of ,10 days cavity by blowing or postnasal drip. This makes and acute non-viral rhinosinusitis with symptoms the host prone to bacterial infection which results lasting between 10 days and 12 weeks. in neutrophilic inflammation leading to chronic Chronic rhinosinusitis is defined by persistent rhinosinusitis. Bacterial products and neutrophilic symptoms lasting .12 weeks. It can be subdivided

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Table 1 Host defence abnormalities leading to chronic bacterial Table 2 Common causes of bronchiectasis and chronic rhinosinusitis Thorax: first published as 10.1136/thx.2008.112870 on 1 December 2009. Downloaded from infection of the upper and lower airways Prevalence of Host defence Primary Secondary chronic Disorder Examples rhinosinusitis References Cilia Kartagener’s syndrome Viral infection Primary ciliary dyskinesia Cigarette smoke Idiopathic 45–84% 11, 12 Mucus Young’s syndrome Viral infection Abnormal mucociliary PCD Up to 100% 13 clearance Cigarette smoke CF 14 Young’s syndrome 15 Periciliary fluid Cystic fibrosis Air conditioning Immunocompromise HIV Up to100% 16 Dehydration Common variable hypogammaglobulinaemia Antibacterial Common variable HIV Postinfective 50% 11 Unknown Idiopathic bronchiectasis Panbronchiolitis Non-tuberculous mycobacteria (eg, MAC) Whooping Excessive immune ABPA 40–90% 17 response GvHD Depends on by the presence or absence of nasal polyps. Nasal polyposis is a severity of chronic inflammatory disease of the nose and sinus mucosa. The bronchiectasis polyps occur when the oedematous lining of the Inflammatory bowel disease becomes dependent, causing some obstruction of the nasal Mechanical Tumour Infrequent cavity. They can be found throughout the upper respiratory obstruction Foreign body tract but are most commonly located around the ostiomeatal complex. Nasal polyposis is frequently associated with asthma, ABPA, allergic bronchopulmonary ; CF, cystic fibrosis; GvHD, graft versus cystic fibrosis (CF), primary ciliary dyskinesia (PCD) and aspirin host disease; HIV, human immunodeficiency ; MAC, avium sensitivity. Polyps are classified as: 0, no polyps; 1, mild (not complex; PCD, primary ciliary dyskinesia. reaching the upper edge of the inferior turbinate); 2, moderate (between the upper and lower edges of the inferior turbinate); characterised by excess mucus production and recurrent lower and 3, severe (reaching the lower edge of the inferior turbinate).5 respiratory tract infections. It is the end result of several The aetiology of chronic rhinosinusitis may be infective or non- different aetiologies (table 2). The most common causes of infective. The pathogenic role played by in chronic bronchiectasis are idiopathic and postinfective damage.10 11 rhinosinusitis is unknown. On the one hand they may be an Chronic rhinosinusitis occurs in 45–84% of patients with important stimulus of neutrophilic inflammation, whereas they idiopathic bronchiectasis11 12 and is less common in patients can also be seen as passengers taking advantage of the with postinfective bronchiectasis where an acute infection has 11 inflammatory milieu created by poor drainage from obstructed damaged the bronchial tree. It is almost universal, and often http://thorax.bmj.com/ ostia. The role of anaerobic bacteria in these circumstances is more severe, when the sinusitis and bronchiectasis share a also uncertain. It is also unknown whether the different common aetiology due to the host defence abnormalities listed sinonasal pathologies are independent or part of a in table 1. These conditions include ciliary defects in PCD and spectrum with nasal polyps, the result of chronic rhinosinusitis mucous abnormalities in CF. which arises from an episode of acute rhinosinusitis. Complications of chronic sinusitis include mucocele formation Primary ciliary dyskinesis (PCD) which are lined by respiratory epithelium. They occur in Each ciliated epithelial cell contains 50–200 motile cilia responsible the sinus cavities and can cause erosion of the surrounding bony for the removal of mucus and attached foreign material. The cilia on October 1, 2021 by guest. Protected copyright. structures. Less commonly, orbital and intracranial spread of are 5–7 mm in length and consist of nine peripheral microtubule infection, and cavernous sinus thrombosis may pairs with dynein arms and radial spokes and two central occur. microtubules. The cilia have a forward extended stroke which Between 2.7% and 6.6% of the population are thought to contacts the viscous outer mucous layer, followed by a reverse 6 have chronic rhinosinusitis. There is an increased incidence in stroke where it returns back to the starting point within the patients with chronic inflammatory lower watery periciliary layer.18 PCD is an autosomal recessive condition and associations have been demonstrated with asthma and whereby ciliary motility is absent or severely impaired leading to 7 chronic obstructive pulmonary disease (COPD), in addition to sinusitis, , glue ear, chronic , bronchiectasis bronchiectasis. Chronic rhinosinusitis can impact heavily on and male infertility. The association of characterises quality of life with significant impairments noted on both Kartagener’s syndrome. There are many different ultrastructural general and specific health status instruments. One study cilial defects, with abnormalities in the dynein arms most showed that patients with chronic rhinosinusitis had more frequent. Patients have congested noses from birth and often general body pain and worse social functioning than those with have difficulty breast feeding due to the inability to nose breathe. 8 COPD or heart failure. Despite this, there is no clear correlation This history should alert the paediatrician to the need for cilia 9 between the severity of sinonasal disease and quality of life. investigation.19 A common physical sign is pooling of mucus in the floor of the nasal cavity. BRONCHIECTASIS Bronchiectasis is defined as the abnormal dilation of the bronchi Young’s syndrome due to the loss of elastic and muscular components of the wall Young’s syndrome is characterised by bronchiectasis, chronic thought to be due to destruction by enzymes such as rhinosinusistis and male infertility. Ciliary function is found to collagenase and from . Clinically, it is be normal and clearance is impaired because the mucus is

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viscous. There is an association with mercury poisoning in as a primary investigation in rhinosinusitis but in cases of failure Thorax: first published as 10.1136/thx.2008.112870 on 1 December 2009. Downloaded from childhood from teething powders and treatment of worm of treatment, preoperatively and for complications of sinonasal infections.20 Diagnosis is made on exclusion of CF and PCD, or disease.31 Mucosal changes at the ostiomeatal complex or in the the characteristic finding of obstruction by waxy material at the sinuses are most commonly seen on CT scans. The Lund- caput during scrotal exploration for infertility. Mackay scoring system scores from 0 to 2 depending on the absence, partial or complete opacification of each sinus.32 Cystic fibrosis (CF) CF is a single gene autosomal recessive condition characterised SINONASAL DISEASE IN NON-CF BRONCHIECTASIS by a defect in the CF transmembrane conductance regulator In a Japanese study, 5% of patients with chronic rhinosinusitis gene product that leads to abnormalities of ion flux at the were found to have bronchiectasis whereas 45% of patients epithelial surface. The increased sodium absorption leads to with idiopathic bronchiectasis had chronic rhinosinusitis.12 In a periciliary liquid depletion and abnormal mucus movement. UK study, 84% of patients with idiopathic bronchiectasis and Clinically, patients progress to chronic caused 50% of those with postinfective bronchiectasis had chronic by bacterial infections and have pancreatic insufficiency. rhinosinusitis.11 The major symptoms include anterior and posterior rhinorrhoea, anosmia and nasal obstruction. Nasal 33 CLINICAL ASSESSMENT OF SINONASAL DISEASE IN polyps occur in up to 40%. , coagulase BRONCHIECTASIS negative staphylococcus and anaerobic and Gram-negative bacteria are the most frequent upper airway microbes in Assessment of mucociliary clearance bronchiectasis.34 Sinonasal disease is universal in PCD and Nasal mucociliary clearance can be tested by a saccharin method Young’s syndrome. Characteristic radiological findings include whereby a small saccharin particle is placed on the medial side poorly developed frontal sinuses in PCD. of the inferior turbinate and the time taken to experience the taste recorded, with abnormal values typically .20 min.21 More objective measures include the use of colloid particles labelled SINONASAL DISEASE IN CF with technetium-99 and a gamma camera for detection.22 Almost every patient with CF has nasal and paranasal sinus The structure and function of the cilia is assessed following a disease.14 Furthermore, heterozygote CF carriers appear to have nasal brush biopsy, whereby a cytology brush (or equivalent) is an increased incidence of sinonasal disease.35 The main used to scrape epithelial cells from the inferior turbinate. Ciliary symptoms include nasal obstruction, rhinorrhoea, beat pattern can then be assessed under a light microscope, and and anosmia. Despite this, fewer than 10% of patients with CF the frequency measured by the interruption of a light beam typically report significant symptoms.36 This is probably with a photometer.23 Electron microscopy is used to assess because they have come to accept the symptoms as ‘‘normal’’. ciliary ultrastructure and to determine orientation.24 Abnormalities in endoscopic examinations are almost always The above tests are relatively simple and minimally invasive found and consist of turbinate congestion in 88% and nasal and, in addition to giving information regarding the mucociliary polyposis in one-third of patients.37 38 Histologically, the polyps escalator in the nose, can be extrapolated to the lower in CF are different from those in asthma with a lack of dense http://thorax.bmj.com/ respiratory tract. Studies have shown a correlation between eosinophilic infiltrate and the preponderance of acid mucin in the saccharin test results and the pulmonary clearance of an the glands of CF polyps.39 40 Characteristic CT changes in CF inhaled radiolabelled isotope, and nasal and tracheal beat include bulging of the lateral nasal wall, demineralisation of the frequencies have also been shown to be correlated.25 uncinate process and hypoplasia of the paranasal sinuses.37 Expired nitric oxide levels may be useful in the assessment of Repeat CT scans are not, however, useful in following response a patient with bronchiectasis. They can be used as a screening to treatments.41 Sinus cultures in patients with CF are mostly tool for PCD.26 In PCD the nitric oxide levels are low, positive with S aureus and prevalent in particularly in the nose, possibly due to the reduced activity the younger age group and important in on October 1, 2021 by guest. Protected copyright. of nitric oxide synthase.27 This contrasts with non-PCD older patients.42 Other positive cultures include anaerobes and bronchiectasis where the bronchial levels are higher than in other microbes commonly seen in lower respiratory tract healthy controls. It is important to note that reduced nitric infections. In addition, fungi were isolated from the sinuses in oxide levels are also found in CF28 and both acute and chronic up to one-third of patients with CF undergoing endoscopic rhinosinusitis,29 but not to the same degree. sinus .42 The importance of fungi in chronic rhinosinu- sitis is unknown, however an IgE-mediated inflammatory Assessment of upper airway response may occur. Allergic was diagnosed in 6.7% of the patients with CF, which is the same incidence as in Assessment of the upper airway begins with a review of the chronic rhinosinusitis in the general population.42 symptoms experienced by the patient and an assessment of The incidence of polyposis is greater in patients with DF 508 their severity. The amount and type of discharge, and any facial mutations.43 There are no associations between the different pain or smell disturbance should be recorded. The degree of sinonasal manifestations and severity of CF.43 Interestingly, nasal obstruction is usually also a subjective measurement, children with nasal polyps generally have less severe lung although nasal peak flow can provide an objective measure and function parameters which has been speculated to be due to a other techniques such as rhinomanometry and acoustic proliferative airway repair mechanism.14 Complications of rhinometry may be available in some centres.3 sinonasal disease (eg, mucoceles) in CF are much rarer than in Anterior rhinoscopy is required for all patients with chronic the general population. nasal disease but may miss small polyps.3 signifi- cantly increases the detection of nasal polyps. of the sinuses can be misleading and, if needed, CT is the imaging MANAGEMENT modality of choice.30 Nevertheless, approximately one-third of There are few randomised controlled trials (RCTs) of the the population have abnormal CT scans so it should not be used management of chronic rhinosinusitis, and the evidence base is

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55 particularly poor in patients with concurrent CF or bronchiec- reduce lavage fluid markers of inflammation. are Thorax: first published as 10.1136/thx.2008.112870 on 1 December 2009. Downloaded from tasis. Initial should be medical with the aim to relieve thought to reduce inflammatory (eg, interleukin 8, symptoms, improve quality of life and avoid disease complica- tumour necrosis factor a), inflammatory cell recruitment and tions. Chronic rhinosinusitis often responds incompletely to free radical production.56–59 They also have been shown to treatment, which is usually continued long term.4 improve ciliary motility60 and reduce production.61 The macrolides have not yet been specifically studied in patients Medical with CF or bronchiectasis with chronic rhinosinusitis. Common medical treatments include irrigation, anti- biotics, topical or systemic , , antihista- Other agents mines (which may help with superadded allergic symptoms) The topical mucolytic, , has been assessed in two and N-acetylcysteine. RCTs in the postoperative management of sinonasal disease in patients with CF. Both studies found some improvement in Improved drainage endoscopic appearance and symptoms.62 63 N-acetylcysteine is Saline irrigation may help to clear secretions and nasal crustings. also commonly used in chronic rhinosinusitis, but there is no This can be with a simple saline (eg, Sterimar) or strong evidence of benefit. There are no RCTs for the use of more vigorous douching (eg, Sinu-rinse). Applications can be in chronic rhinosinusitis, although they have repeated several times per day to improve symptoms and before shown some benefit in a subgroup of patients with nasal polyps other topical treatments, such as steroids, to improve exposure and asthma.64 may be useful in patients with to the drug by the clearance of secretions. Douching is a safe and superadded allergic symptoms.65 The development of nasal inexpensive treatment and has been shown to improve nebulisers (Pari, USA) may lead to future —such as symptoms of chronic rhinosinusitis.44 The saline may also be hypertonic saline, DNase and —being delivered by hypertonic, which can lead to an osmotic mucosal this route if carefully controlled studies show benefit. effect and may assist mucus clearance. Topical decongestants can be used to relieve symptoms of blockage and facial congestion. They should only be used for short periods to avoid Surgery .45 They can be used before application The majority of sinus surgery is now performed endoscopically of topical when the nose is very blocked to with the aim of improving drainage. This includes sinus improve mucosal exposure. washout, increasing the size of the ostia and sinus scrapes to remove hypertrophied mucosa. The improvement in endoscopic surgery has removed the need for more invasive operations such Steroids as the removal of diseased maxillary tissue in the Caldwell-Luc The use of topical nasal steroids in chronic rhinosinusitis has operation. been associated with improvements in both symptoms and Endoscopic sinus surgery is generally reserved for patients objective measures in most randomised controlled studies.46 47

who do not respond to medical treatment. Endoscopic sinus http://thorax.bmj.com/ There is no evidence for the use of systemic corticosteroids in surgery is well tolerated in patients with CF,66 however the lack these patients. In patients who also have nasal polyps, topical of symptomatic complaints and the disparity between CT steroids have also been shown to reduce polyp size and findings and clinical disease in this population makes patient symptoms.48 Treatment with a 2-week course of systemic selection difficult. Sinus surgery has been shown to reduce corticosteroids in this group has improved symptoms and polyp 67 68 size compared with .49 Topical nasal steroids were symptoms in patients with CF, but there is a lack of evaluated in a small RCT of patients with CF and nasal polyps evidence suggesting a long-term improvement, particularly with with a reduction in polyp size, judged endoscopically, and an respect to further hospitalisation or lung function para- 68 69 improvement of symptoms. There was no long-term follow-up meters. Some authors have suggested persistent nasal on October 1, 2021 by guest. Protected copyright. in this study.50 Adopting an ‘‘upside down’’ head position for obstruction, particularly when demonstrated anatomically, 3 min can increase exposure to the topical . This has been severe symptoms and a correlation between pulmonary exacer- shown to improve objective measures of benefit.51 bations and sinus symptoms as possible markers of suitable patients.70 Antibiotics Topical ointments (eg, Bactroban () and Naseptin + (chlorhexidine hydrochloride sulphate)) can be Table 3 Consideration of sinonasal disease in bronchiectasis helpful when there is vestibulitis and crusting, however there are no studies supporting their clinical effectiveness. There are Importance of upper airway Value of upper airway assessment also limited data supporting the use of systemic antibiotics in Morbidity attached to upper airways Reduction in inflammation may improve chronic rhinosinusitis. Short-term antibiotics (2 weeks) can be disease quality of life used for acute exacerbations. There has been an increased use of Similar mucosal surfaces and Potential marker of lower airway disease inflammatory response systemic antibiotics for their anti-inflammatory Potential site for future research to assess drug responses properties for a variety of chronic inflammatory conditions Treatment may reduce lower respiratory 52 including bronchiectasis, CF, asthma and COPD. In particular, inflammation there has been a substantial improvement in the prognosis of Paranasal sinuses and nose may act as Pseudomonas eradication regimens may patients with with the use of macro- reservoir for respiratory require sinonasal elimination lides.53 In chronic rhinosinusitis, roxithromycin was trialled for Treatment of sinonasal disease may reduce 3 months in an RCT and demonstrated improvements in a frequency of lower respiratory infection Treatment for lung transplant patients may variety of indices including symptom scores and endoscopy reduce recolonisation of transplanted lung appearances.54 Long-term has also been shown to

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INTERACTION BETWEEN UPPER AND LOWER AIRWAYS pathophysiology of sinonasal and respiratory disease also makes Thorax: first published as 10.1136/thx.2008.112870 on 1 December 2009. Downloaded from Sinonasal disease is associated with significant morbidity in this important in bronchiectasis. Appreciation and treatment of patients with chronic respiratory disease. However, there is concomitant sinonasal disease may improve lower respiratory increasing evidence that it should not be considered in isolation health and reduce persistent infection and inflammation in the and that it can also significantly impact on lower respiratory bronchiectatic airway. health (table 3). Most research has been performed in asthma. Competing interests: None. 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