Aspects cliniques ORL dans la mucoviscidose Paris, 07/12/07 Aspects cliniques ORL dans la mucoviscidose Dia 1 First, I would like to thank the organizing committee and Pr Button for inviting me to this meeting. I’m an ENT surgeon and in my hospital we have a specialized care center for cystic fibrosis. André Coste Hôpitaux H Mondor et Intercommunal de Créteil France

Rhinosinusite chronique & CF: physiopathologie Cl- altération clearance mucociliaire CFTR mutation ? RGO ? défaut transport ions infection inflammation Dia 2 The pathophysiology of chronic sinusitis in CF is not fully understood. As in lower airways, the defect in epithelium ion transport is responsible of an increased viscosity of mucus and an impaired mucociliary clearance. This leads to recurrent infections of the paranasal sinuses and induces chronic inflammation. Inflammation with oedema also participate to the impairement of drainage and ventiillation of the sinuses. From recent advances it may also be hypothetized that the primary dysfunction of the epithelial cells could be involved directlly in the inflammatory process even in the absence of infection. Lastly, the gastro-oesophageal reflux, which has been reported to be frequent in CF, could also be involved in the development of sinonasal inflammation.

Rhinosinusite chronique & CF: physiopathologie Dia 2 The pathophysiology of chronic sinusitis in CF is not fully understood. As in lower airways, the defect in epithelium ion transport is responsible of an increased viscosity of mucus and an impaired mucociliary clearance. This leads to recurrent infections of the paranasal sinuses and induces chronic inflammation. Inflammation with oedema also participate to the impairement of drainage and ventiillation of the sinuses. From recent advances it may also be hypothetized that the primary dysfunction of the epithelial cells could be involved directlly in the inflammatory process even in the absence of infection. Lastly, the gastro-oesophageal reflux, which has been reported to be frequent in CF, could also be involved in the development of sinonasal inflammation. 50 enfants CF 28 adultes CF McShane D et al. Eur Respir J 2004

Rhinosinusite chronique & CF: physiopathologie 1 3 5 7 9 11 Macrophages Neutrophils Mast Cells T-Lymphocytes B-Lymphocytes Eosinophils 200 400 600 800 1000 1200 Polyposes primitives 1 2 3 4 5 6 Mast cells Neutrophils Macrophages Eosinophils T Lymphocytes B Lymphocytes 100 200 300 400 500 600 700 800 900 les pénétrations orbitaires semblent également relativement fréquentes et heureusement la plupart du temps sans conséquences elles se traduisent par l’issue de graisse orbitaire dans la cavité qui doit être reconnue par sa couleur jaune chamois distincte de celle rosée des polypes par sa mobilisation lors de la pression douce du globe par sa résistance à la traction qu’il ne vaut mieux pas tester cette issue de graisse impose l’arrêt des gestes à son niveau si la brèche est antérieure et basse, survenant en général lors d’une unciformectomie trop sagittale, le risque est quasi nul si le geste est arrêté à temps, les signes étant alors en post-op un hématome palpébral en lunette et parfois un emphysème mais sans exophtalmie et sans tendance à l’expansion de l’hématome la cavité ne doit pas être méchée pour permettre le drainage d’un éventuel léger saignement, les lavages post-opératoires doivent être différés et le patient doit être averti de ne pas se moucher PHOTO TDM UNCIFORME CORONAL Polyposes CF Lesprit E et al. Histol Histopathol. 2000

Quel bilan nez-sinus ? équipe ORL spécialisée (CRCM) expertise complète intégration de la pathologie nez-sinus dans le contexte de la CF évaluation systématisée symptômes endoscopie (+ bactério) imagerie Dia 3 Chronic sinusitis is very frequent in CF. From a radiologiical point of view, sinus opacities affect all patients. Actually, sinusitis is not aways symptomatic. We and others have studied cohorts of CF patients to precise sinus symptoms. Nasal obstruction is certainly the most common symptom affecting 80% of patients, but actually it is a real source of discomfort in only one third of cases. Rhinorrhea that may be anterior or posterior is allso very frequent, but it is reported to be a permanent problem by 20% of patients. Headaches and facial pain may affect daily one quarter of patients. Dysfunction of sense of smell is always difficult to precise in children but it may be one of the elements to think about in the loss of appetite. Finally, in some case we may observe a facial deformation with a broadened nasal bridge and sometimes telorbitism or hypertelorism.

Rhinosinusite chronique & CF: symptômes Slieker M et al., Arch Otolaryngol Head & Neck Surg 2002 - Gentile V et al., Laryngoscope 1996 Coste A et al., Rhinology 1995 - Brihaye P et al., Int J Pediatr Otorhinolaryngol 1994 obstruction nasale 81 % des patients inconfort permanent 32% rhinorrhée purulente antérieure et postérieure permanente 20% céphalées et douleurs faciales journalières 23% dysosmie difficile à préciser chez enfant (7%) déformation faciale élargissement pyramide nasale, hypertélorisme Dia 3 Chronic sinusitis is very frequent in CF. From a radiologiical point of view, sinus opacities affect all patients. Actually, sinusitis is not aways symptomatic. We and others have studied cohorts of CF patients to precise sinus symptoms. Nasal obstruction is certainly the most common symptom affecting 80% of patients, but actually it is a real source of discomfort in only one third of cases. Rhinorrhea that may be anterior or posterior is allso very frequent, but it is reported to be a permanent problem by 20% of patients. Headaches and facial pain may affect daily one quarter of patients. Dysfunction of sense of smell is always difficult to precise in children but it may be one of the elements to think about in the loss of appetite. Finally, in some case we may observe a facial deformation with a broadened nasal bridge and sometimes telorbitism or hypertelorism.

Rhinosinusite chronique & CF: endoscopie Slieker M et al., Arch Otolaryngol Head & Neck Surg 2002 - Gentile V et al., Laryngoscope 1996 Coste A et al., Rhinology 1995 - Brihaye P et al., Int J Pediatr Otorhinolaryngol 1994 L bombement de la paroi nasale externe R oedème et pus R polypes et pus (50%) Dia 4 Endoscopy is the best way to precise the lesions and it is rather easy to perform either with a rigid or flexible endoscope even in the youger children. It may frequently show a deformation of the lateral nasal wall which is bulging in the nasal cavity thus contributing to the obstruction. Of course, we may see those thick and sticky purulent secretions with mucosal oedema. And in 50% of cases, endoscopy helps to evidence the presence of nasal polyps.

Rhinosinusite chronique & CF: endoscopie Dia 4 Endoscopy is the best way to precise the lesions and it is rather easy to perform either with a rigid or flexible endoscope even in the youger children. It may frequently show a deformation of the lateral nasal wall which is bulging in the nasal cavity thus contributing to the obstruction. Of course, we may see those thick and sticky purulent secretions with mucosal oedema. And in 50% of cases, endoscopy helps to evidence the presence of nasal polyps. 34 patients CF 6 à 22 ans questionnaire + endoscopie + TDM Boari L et al., Rev Bras Otorrinolaringol 2005

Rhinosinusite chronique & CF: scanner Slieker M et al., Arch Otolaryngol Head & Neck Surg 2002 - Gentile V et al., Laryngoscope 1996 Coste A et al., Rhinology 1995 - Brihaye P et al., Int J Pediatr Otorhinolaryngol 1994 bombement du mur nasal externe & pseudomucocèle opacités bilaterales et diffuses larges pseudomucocèles avec élargissement pyramide nasale Dia 3 CT-scan is also of great help to precise the extension of sinusitis. However, we should not repeat the CTs. They are really helpful when we consider surgery. CT generally shows bilateral and diffuse lesions affecting most of the sinus cavities including the ethmoid and shenoid. Frontal sinus is generally pooorly developped. Some images are relatively typical of CF sinusitis like the bulging of the lateral nasal wall or the pseudomucocele aspect that we described 10 years ago. You see here these hyperdensity with a surrounding relative hypodensity. These pseuudomucoceles may affect all sinuses and thus participate in the nasal bridge broadening like in this particular case. hypoplasie sinus frontal

Rhinosinusite chronique & CF: mucocèles Dia 3 CT-scan is also of great help to precise the extension of sinusitis. However, we should not repeat the CTs. They are really helpful when we consider surgery. CT generally shows bilateral and diffuse lesions affecting most of the sinus cavities including the ethmoid and shenoid. Frontal sinus is generally pooorly developped. Some images are relatively typical of CF sinusitis like the bulging of the lateral nasal wall or the pseudomucocele aspect that we described 10 years ago. You see here these hyperdensity with a surrounding relative hypodensity. These pseuudomucoceles may affect all sinuses and thus participate in the nasal bridge broadening like in this particular case. 10 mucocèles chez enfant 6 étiologies CF Nicollas R et al., Int J Ped Otorhinolaryngol 2005

Rhinosinusite chronique & CF: mucocèles Dia 3 CT-scan is also of great help to precise the extension of sinusitis. However, we should not repeat the CTs. They are really helpful when we consider surgery. CT generally shows bilateral and diffuse lesions affecting most of the sinus cavities including the ethmoid and shenoid. Frontal sinus is generally pooorly developped. Some images are relatively typical of CF sinusitis like the bulging of the lateral nasal wall or the pseudomucocele aspect that we described 10 years ago. You see here these hyperdensity with a surrounding relative hypodensity. These pseuudomucoceles may affect all sinuses and thus participate in the nasal bridge broadening like in this particular case. 55 patients CF en bilan pré-greffe 3 mucocèles frontales asymptomatiques Solares CA et al., Am J Otolaryngol 2007

Rhinosinusite chronique & CF: bactériologie Dia 3 CT-scan is also of great help to precise the extension of sinusitis. However, we should not repeat the CTs. They are really helpful when we consider surgery. CT generally shows bilateral and diffuse lesions affecting most of the sinus cavities including the ethmoid and shenoid. Frontal sinus is generally pooorly developped. Some images are relatively typical of CF sinusitis like the bulging of the lateral nasal wall or the pseudomucocele aspect that we described 10 years ago. You see here these hyperdensity with a surrounding relative hypodensity. These pseuudomucoceles may affect all sinuses and thus participate in the nasal bridge broadening like in this particular case. 50 patients CF chirurgie sinus bactério oropharynx-sinus-trachée Sakano E et al., Int J Ped Otorhinolaryngol 2007

Rhinosinusite chronique & CF: poumon Dia 3 CT-scan is also of great help to precise the extension of sinusitis. However, we should not repeat the CTs. They are really helpful when we consider surgery. CT generally shows bilateral and diffuse lesions affecting most of the sinus cavities including the ethmoid and shenoid. Frontal sinus is generally pooorly developped. Some images are relatively typical of CF sinusitis like the bulging of the lateral nasal wall or the pseudomucocele aspect that we described 10 years ago. You see here these hyperdensity with a surrounding relative hypodensity. These pseuudomucoceles may affect all sinuses and thus participate in the nasal bridge broadening like in this particular case. 4866 patients CF 6 à 17 ans facteurs prédictifs du déclin du VEMS analyse multivariée Konstan MW et al., J Pediatr 2007

Comment traiter la rhinosinusite dans la CF? traitement médical : toujours la 1ère étape lavages solutions salées DNase antibiotiques corticoïdes chirurgie: symptômes sévères résistants au tt médical Dia 6 But let’s move now to the treatment. How can we treat sinusitis in CF. Of course, medical treatment should always be the first step. In order to try to immprove nasal muucociliary clearance we can use saline serum lavages or Dnase. Antibiotics are necessary to fight again infection. And to try to control inflammmation we may use steroids. When the medical approach fails to improve severe symptoms, surgery may be considered. The goal of surgery is first to retore as much as possible the ventilation and drainage of sinuses but it is also to facilitate the effects of local treatments. restaurer ventilation & drainage augmenter l ’efficacité des tt locaux

DNase 24 patients CF 7 à 15 ans ethmoïdectomie à 4 semaines Dia 8 DNase has been demonstrated to be useful in the bronchopulmonary disease in CF where it reduces the viscosity of secretions and lowers the neutrophilic inflammation. It seems to help to prevent the degradation of lung function and to decrease the number of yearly exacerbations. Only one study has tested its efficacy in CF sinusitis. In this study with a low number of cases, the authors didn’t evidence any affect on the stage of the disease, but it seems that there was less surgery revision cases in the group with Dnase. 24 patients CF 7 à 15 ans ethmoïdectomie nebulisation DNase post-op vs placebo Cimmino M et al., Arch Otolaryngol Head & Neck Surg 2005

Antibiotiques antibiothérapie pour la rhinosinusite quand exacerbations sinusite & poumon sont indépendantes en préparation à la chirurgie sinusienne antibiotiques locaux colimycine, tobramycine Lewiston N et al., Trans Proc 1991 - Davidson T et al., Laryngoscope 1995 - Moss R et al., Arch Otolaryngol Head & Neck Surg 1995 macrolides ? administration au long-cours et à faible dose efficacité dans les sinusites non CF Hashiba M et al., Acta Otolaryngol Suppl 1996 pas de data disponibles pour les sinusites chroniques CF Dia 10 Topical antibiotics may be interesting in CF and their usefulness has been demonstrated in the lungs. However, only few studies have focused on their use in the treament of sinusitis. In 3 studies, local instillations of tobramycin after surgery have been demonstrated to improve the surgical results. Finally, we might consider the use of long-term and low-dose macrolides. They seem to inhibitat least partially the virulence factors of Pseudomonas. And they have been demùonstrated to be efficient in the treatment of non-CF chronic sinusitis, especially in Japan where they are widely used. Unfortunately, today we have no data at all on their afficacy and tolerance in the treatment of sinusitis in CF.

Corticoïdes voie orale ? voie nasale utilisation délicate chez l ’enfant surtout CF aucune data disponible pour les sinusites CF voie nasale une étude prospective randomisée double-aveugle chez adultes CF Hadfield P et al., Rhinology 2000 22 patients: 200 mg de bétamethasone vs placebo pendant 6 semaines réduction significative de la taille des polypes effet très relatif en pratique quotidienne ... Dia 11 We donst have any more data on the usefulness of oral steroids in treating sinusitis in CF, and as their use is rather cirtical in children we may not recommend them. Another option to reduce inflammation is topical steroids. In one prospective and randomised study, Hadfield and co-workers demonstrated a significant reduction in polyp size in adults with CF. However, in my daily practice, they seem to have a relative poor effect.

Chirurgie: quelle intervention ? restaurer ventilation & drainage augmenter l ’efficacité des traitements locaux polypectomie ethmoïdectomie Caldwell-Luc Dia 12 Let’s talk about surgery. Different surgical procedures may be considered. First, polypectomy removes polyps from the nasal fossa and middle-meatus and may be associated with opening of the maxillary siinuses. Secondly, surgery can be extended to the ethmmoid in a more radical approach. Another choice is to perform a Caldwell-Luc procedure that is to say to open and clean the maxillary sinus via a sublabial approach. However, this surgery is not functional and as its tolerance is less good than endonasal surgery, we do not recommend it.

Chirurgie: quelle intervention ? polypectomie ethmoïdectomie PROS minimal-invasive courte durée (30 min.) pas de nettoyage post-op large ouverture des sinus bons résultats à moyen terme Dia 13 What are the pros and cons for polypectomy and ethmoidectomy? Polypectomy is a minimal-invasive procedure with low risks, short duration and no need for post-op cleaning. However, it poorly contributes to the restoration of sinus drainage, and many authors have shown that there is a highh recurrence rate of polyps. On the contrary, ethmodectomy provide a wide opening of sinus cavities and shows good mild-term results. Of course, the pprocedure is longer and there is a need for post-op cleaning that may require repeated general anesthesia in the younger patients. Finally, there are potential but exceptional severe risks concerning eyes and skull base. All the last studies claim that ethmoidectomy is the best choice when considering surgical treatment of sinusitis in CF. CONS pas d ’ouverture des sinus récidive +++ (80%) durée plus longue (90 min.) nettoyage(s) post-op risques plus importants ethmoïdectomie = intervention de choix pour les sinusites CF Davidson T et al., Laryngoscope 1995 - Moss R et al., Arch Otolaryngol Head & Neck Surg 1995 Rowe-Jones J et al., Laryngoscope 1996 - Triglia JM et al., Laryngoscope 1997 - Yung M et al., Ann Otol Laryngol 2002

Chirurgie: quels résultats ? 15 patients CF 9 à 19 ans ethmoïdectomie + Caldwell-Luc pré-op vs post-op à 6 mois Dia 14 Surgery, but for wht results ? We must all be aware that results are far from being perfect ! Recurrence of polyps ocurs in about 50% of cases and according to a large study from the Ian MacKay group in London there is a 50% chance of returning to pre-op symptoms or to have a second procedure in the 2 years following surgery. As said earlier, Moss and colleagues demonstrated beter results when surgery is followed by local instillations of tabramycin. Concerning infection, surgery only poorly helps to erradicate pseudomonas. However, the gruop from Triglia showed a decrease in the need for antibiotics following ethmoidectomy. One great question is wether surgery helps to imrove lung function. Even if Havlorson reported a significant imrovement in FEV after sinus surgery, it was in a small cohort and others did not evidence any difference. Shatz A Otolaryngol Head & Neck Surg 2006

Chirurgie: quels résultats ? n = 37 2 AB anti-pyo /15 jours ethmoïdectomie + LFN succès < 3 cultures sinus + succès partiel 4 ou 5 cultures sinus + et au moins 6 semaines avec cultures - échec > 5 cultures sinus + et moins de 6 semaines avec cultures - Dia 15 Finally, when should we treat sinusitis in CF ? Certainly when nasal symptoms are sevvere and affects daily life of our patients. There is no evidence that moderate symptomatic sinusitis should be treated in order to prevent worsening. There is no more evidence that sinusitis should be aggresively treated to prevent pulmonary exacerbations. In the particular case of lung-transpnatation, two teams support the need to operate the sinuses in order to prevent pseudomonas infection of the lungs, but it is more an expert advice that a clear demonstration. Holzman D et al., Transplantation 2004

En conclusion rhinosinusite fréquente et souvent invalidante bilan ORL régulier dans équipe référente souhaitable (CRCM) stratégie thérapeutique décidée après concertation pluridisciplinaire formes sévères de sinusite: traitement = vrai challenge ! Dia 16 To conclude, I would like to underline thhat treating sinusitis in CF is still a difficult challenge. However, even though CF patients nearly always have heavy and time-consuming treatments, sinusitis should not be neglected as it may affest severly their quality of life. More than in every other sinusitis, the therapeutical strategy must be decided according to a multidisciplinary approach. And finally, patients aand parents should receive a full informmation on these treatments especially when considering surgery. Thak you for your attention !