- Email: [email protected]
Atopy: pediatric ENT manifestations in children
International Journal of Pediatric Otorhinolaryngology 73S (2009) S19–S25
Atopy: pediatric ENT manifestations in children Giuseppe Caruso a, *, Valerio Damiani b , Lorenzo Salerni a , Francesco Maria Passali c a
ENT Department, University of Siena, Italy ENT Department, Az. Osp. San Giovanni – Addolorata, Rome, Italy c ENT Department, Università Tor Vergata, Rome, Italy b
A R T I C L E
I N F O
Keywords: Atopy Rhinitis Otitis Rhinosinusitis Rhinobronchial syndrome Laryngitis Oral allergy syndrome
A B S T R A C T Objective: The aim of the present study is to discuss the basics of atopy in children in relationship to the principal ENT allergic disorders such as allergic rhinitis, rhinosinusitis and their impact on lower airways, allergic otitis media, and oral cavity focusing on their natural history. Methods: An updated and exhaustive review of principal literature on these topics is performed, underlining the constant but growing interest evoked by these disorders most of all the possible sequelae or complications. Considering the different districts which can be selectively or simultaneously affected by the allergic sensitisation, diagnosis can be a really hard task; in this paper, we tried to draw an integrated diagnostic approach to atopic children and some guidelines for a correct therapeutic approach. Conclusions: Atopic disorders could expose young patients to years of chronic diseases that interferes with their development and with many important aspects of their lives. For these reasons, and considering the high social and medical costs of this disease, it is extremely important to adequately treat allergic pathologies from the early phases of its natural history. Moreover, we cannot forget that an appropriate therapy of allergic pathologies should not be only able to decrease symptoms but, it should also be able to improve patients health related quality of life. © 2009 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . Atopy and nose: allergic rhinitis . . . . . . . . . . . . Atopy and paranasal sinuses: rhinosinusitis . . . . . Atopy and middle ear: allergic otitis media . . . . . . Atopy and larynx: allergic laryngitis . . . . . . . . . . Atopy and lower airways: rhinobronchial syndrome Allergy and oral cavity: oral allergy syndrome . . . . Diagnosis: attempts for an integrated approach . . . Brief notes on treatment . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
1. Introduction Atopy had been defined by the European Academy of Allergy and Clinical Immunology (EAACI) Nomenclature Task Force, as “. . . a personal or familiar tendency to produce IgE antibodies in response to low doses of allergens, usually proteins . . .”. It is the genetic predisposition, transmitted as a dominant factor, to become allergic to a definite number of specific allergens [1].
* Corresponding author: Dr. Giuseppe Caruso, MD, Clinica Otorinolaringoiatrica, Policlinico Universitario “Le Scotte”, Viale Bracci 16, 53100 Siena, Italy. Tel.: +39 0577585470. E-mail address: [email protected] (G. Caruso). 0165-5876/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
S19 S19 S20 S21 S22 S22 S23 S23 S24 S24
The clinical pictures of allergic pathologies represent the common physiopathological end of multiple interactions between the specific genetic predisposition of an individual and the environment in which he lives and, more specifically, in which he grew up. Concerning the otorhinolaryngological manifestations of this systemic pathology, nose, ear and larynx are the most commonly affected organs. Less frequently the oral mucosa also can be the target organ of an allergic reaction. 2. Atopy and nose: allergic rhinitis Allergic rhinitis is classically defined as an IgE-mediated inflammation of nasal mucosa, characterized by one or more of the
S20
G. Caruso et al. / International Journal of Pediatric Otorhinolaryngology 73S (2009) S19–S25
following major symptoms: nasal obstruction, rhinorrea, sneezing and nasal itching [2]. Moreover, other additional symptoms such as headache, impaired smell and conjunctival symptoms can be associated. Allergic rhinitis is certainly a high-prevalence disease and an important social medical problem in many industrialized countries, affecting about 20% of the general population [3]; however it is ever more frequently diagnosed among adults and children in many developing nations [4]. According to the duration of symptoms and to the modalities of allergens exposure, allergic rhinitis is classified as perennial, seasonal and occupational. Perennial allergic rhinitis is mainly due to dust mites or animal dander exposure. On the contrary, seasonal allergic rhinitis is associated to a wide range of pollen allergens such as Graminaceae, Ambrosia, Parietaria, olive, cypress and several others. In any case, it is conditioned by pollens seasonal variations of each specific geographical regions. Finally, occupational allergic rhinitis is strongly related with the kind of substances to which workers are exposed. The recent WHO document “Allergic Rhinitis and its impact on Asthma” (ARIA) [5], partially modified this classification; specifically in this document it is recommended to do not use the old terms “seasonal” and “perennial”, which effectively are not really useful in regions with perennial climatic seasons, and to replace them with the term “intermittent allergic rhinitis” (<4 days per week or <4 weeks) and “persistent allergic rhinitis” (>4 days per week and >4 weeks). However, when describing symptoms of pollen-induced allergic rhinitis during the pollen season, according to ARIA, the old term “seasonal allergic rhinitis” can be still used. Allergic rhinitis is certainly one of the most common chronic inflammatory disease worldwide, frequently affecting the pediatric age. Wright [6] recently reported that about one out of five children will be affected by allergic rhinitis during the first 3 years of life, up to 40% will develop typical symptoms by the age of 6 and up to 30% will become allergic during the adolescence. Moreover, Sly [7] showed that in United States allergic rhinitis affects about 20% of the adult general population, the symptoms starting typically before 30 years of age. From these evidences it is not surprising that this disease accounts for about 1.9 billion dollars in annual health care costs in USA [8]. Moreover, the persistent inflammation of the nasal mucosa predisposes to the development of severe complications such as chronic rhinosinusitis, nasal polyposis, asthma, otitis media, lower airways infections, with an annual public health cost, in the European community, of 1.5–2 billion Euros. In European countries the epidemiological impact of this disease is similar to USA: the prevalence of allergic rhinitis in adults is between 11% and 20% [9,10] in the majority of Nations, with the exception of Belgium and Russia where lowest values (5–8%) were found [11]. The prevalence in countries of Latin Americas was comparable to European values; for example, a recent analysis conducted by the ISAAC in Argentina found that about 34% of the 12000 children enrolled in the study were affected by allergic rhinitis [12]. In this continent the exceptions are represented by Mexico and Bolivia, in which nasal illnesses deriving from allergies affect close on half of the population [13]. The prevalence in Asia and Oceania appeared extremely high, with the exception of Malaysia, Korea and Indonesia [14,15]. Concerning the distribution of allergic rhinitis among different age groups, a higher frequency in the children was highlighted in Sweden, Great Britain, South America, Japan and the Philippines[13]; in the other nations, this disease appeared equally present in all the age classes [16,17]. Allergic rhinitis symptoms are classically distinguished in major and minor. Major symptoms are nasal obstruction, rhinorrea,
sneezing and nasal itching. Moreover, other additional symptoms such as headache, impaired smell and conjunctival symptoms can be associated (minor symptoms). Obviously all the above mentioned symptoms do not reach the same intensity in all the patients; according to the prevalence of one group of symptoms on the others, some authors classify rhinitic patients as “blockers”, “sneezers” and “runners” [2]. For blockers, nasal congestion is the most invalidating complaint, determining mouth breathing, nasal voice and sometimes snoring. Moreover, in the pediatric age, a prevalently oral respiration can lead to orthodontic disturbance such as palatal arching and flattened midface. Patients defined as “sneezers” are obviously mostly bothered by the symptom sneezing and the “runners” experience most problems with rhinorrea. Moreover, in this 2 last typologies of patients, the clinical picture is often completed by some degrees of allergic conjunctivitis. The Medical Outcome Study Short Form Health Survey (SF-36), a generic questionnaire, has been often used to evaluate the effect of allergic rhinitis on patients’ life, with special attention to physical and emotional limitations [18]; the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), a specific one, is the most widely used to assess symptoms and treatments impact as rated by patients [19]. In this context, it is interesting to highline that the typology of patients discomfort vary significantly in the different ages of life. Specifically, adolescent patients (12–20 years) experience very similar problems to adults except for the fact that insomnia is not so troublesome; on the contrary, they do have more problems for what concern concentration, specifically school work. Children (6–12 years) affected by allergic rhinitis present a very different symptomatic picture: they are certainly bothered by their symptoms and by the same practical problem of the other classes of patients (to care tissues and to take drugs), but they experience less interference with their normal daily activities and do not express particular emotional dysfunctions [20]. All these elements are essential in order to set up the right treatment in any patient, or, in other words, to individualize the therapy. An appropriate therapy of allergic rhinitis should not be only able to decrease, of course, rhinorrhea, sneezing, and nasal itching, but, more important, it should also be able to improve patients HRQL [21]. In conclusion, according to the data already exposed, we can affirm that all otorhinolayngologists, in order to efficaciously treat patients affected by allergic rhinitis, and not only their noses, must include, in the diagnostic and therapeutic strategies, a careful evaluation of allergic rhinitis-related quality of life. 3. Atopy and paranasal sinuses: rhinosinusitis The coexistence of allergic rhinitis and rhinosinusitis, both in adults and children, is well documented in medical literature. Shapiro found that about 70% of children with allergic rhinitis had abnormal sinus radiographs [22]. Moreover, in 1994, Newman et al. highlighted that in about 28% of patients affected by recurrent rhinosinusitis, nasal allergy coexists with the rhinosinusal pathology [23]. In 1997 McNally et al. analyzing a series of 200 children affected by chronic rhinosinusitis, showed that allergic rhinitis was present in more that half of the sample (56%), whereas septal deviation accounted for only 23% of cases [24]. From an experimental viewpoint, Pelikan et al. found that in patients affected by chronic rhinosinusitis, nasal allergen challenge induced sinusal radiological alteration in 86.4% of cases [25]. Moreover, in 1995, Georgitis et al found increased levels of leukotrienes C4/D4/E4 and of prostaglandin D2 in sinus lavage of patients affected by chronic rhinosinusitis [26].
G. Caruso et al. / International Journal of Pediatric Otorhinolaryngology 73S (2009) S19–S25
In this context, already 20 years ago, we screened for allergic rhinitis 1620 children, attending 7 state schools (4 primary schools and 3 secondary schools). A targeted questionnaire was handed out to collect an accurate clinical history and skin tests on the inner forearm were performed. 73 children resulted positive to skin tests. Positive skin test children went on in the study; specifically they underwent the following examinations: objective examination of nasal mucosa, active anterior rhinomanometry (AAR), muco-ciliary transport time determination by using a colored indicator (mixture of charcoal powder and 3% saccharin). In addition, radiological examination of paranasal sinuses in the four standard projections were performed and three degrees of alterations were defined (1st degree: darkening; 2nd degree: thickening of the mucosa;. 3rd degree: polypoid degeneration). Concerning the relationship between sinusal radiological lesions and skin positivity, a prevalence of 1st degree lesions was found, children positive to Graminaceae showing the lower number of pathological pictures; 3rd degree lesions were found only in association with sensitization to Dermatophagoides [27]. More recently, Alho et al. found that, in a group of patients with chronic rhinosinusitis, allergic subjects had higher TC score (Lund staging) compared with non allergic ones [28]. In another epidemiological analysis [29] performed together with 145 Italian Otorhinolaryngologists, who were asked to answer a questionnaire on most important epidemiological characteristics of allergic rhinitis in their ambulatory patients, we found that, in Italy, the probability for an allergic patient to develop rhinosinusitis is of 21.5 ± 3.4%. These results are comparable with those of the survey fitted in the WHO ARIA document, according to which rhinosinusitis develops in about 20% of patients affected by allergic rhinitis [5]. The key element in the development of chronic rhinosinusitis from an allergic inflammation of the nose is certainly the functional obstruction of the ostiomeatal complex; which leads to an alteration of air and secretion flows towards and out from the sinuses. Specifically, allergic rhinitis contributes to this process determining, in case of a nasal allergenic challenge, mucosal swelling and, if the stimulation persists, thickening of rhinosinusal mucosa. The accumulation of secretions, unable to pass through narrowed ostia, leads to further obstruction and to the development of an anaerobic environment that favors bacterial growth. Bacterial infection affects mucociliary functionality which, in turn, determines an increase in the thickening of the mucus and in the ostial obstruction. If this vicious circle is not stopped, the pathology evolves towards chronic rhinosinusal inflammation, namely chronic rhinosinusitis. According to the above mentioned data, the concept: “one airway, one disease”, in the field of rhinitis-rhinosinusitis relationship, acquires a strong rationale. 4. Atopy and middle ear: allergic otitis media It is nowadays well known that nose and middle ear are not independent entities, but they belong to a system of contiguous organs including the nose, Eustachian tube, palate, nasopharynx, middle ear and mastoid cells, the so-called rhinopharyngotubal unit. The key element of this anatomo-physiological unit is, considering its multiple functions, certainly the Eustachian tube. In recent years, our knowledge of its structure and functions greatly increased, revealing the major role played by the tube in the pathogenesis of otitis media [30]. Basically nasal allergic inflammation leads to swelling and obstruction of the Eustachian tube, which, in turn, determines a negative pressure in the middle ear and an improper ventilation and the inlet of fluids into the ear drum.
S21
Concerning the impact of atopy on otitis media, it had been shown that 21% of allergic children develop otitis media; moreover 50% of children with persistent otitis media with effusion have nasal allergy [31]. In this context, transient Eustachian tube opening results in aspiration into the middle ear cavity of nasopharyngeal secretions containing bacteria, viruses and allergens with the obvious physiopathological consequences. In 1994, Bernstein stressed the importance of immunoglobulin E-mediated hypersensibility in the development of otitis media with effusion: the release of biologic mediator of inflammation from basophils and mastcells of rhinopharyngeal mucosa leads to Eustachian tube edema and stenosis. This chronic inflammatory response, along with viral or bacterial infections, produces middle ear effusion [32]. Later, Meltzer, in 1995, found an increase of eosinophils, basophils and histamine levels in nasal mucosa of young children with chronic otitis [33]. Bernstein reviewed the various potential nasal-middle ear interactions that may lead to middle ear effusion [34]. First of all, nasal reflexes, triggered by a nasal allergenic challenge and mediated by the central nervous system, can affect middle ear blood flow with consequent liquid transudation. A second mechanism implies the rhinopharyngeal deposition of inflammatory mediators that may directly induce mucus production and vessels dilation at Eustachian tube level. At last, it is possible that the delivery of inflammatory mediators into the microcirculation of the nose can affect middle ear blood flow. Subsequently, irregardless from the specific pathogenetic mechanism, this chronic inflammatory response, along with viral or bacterial infections, produces middle ear effusion. In this context, we already showed, in an our previous study on secretory otitis media SOM) in children, that both total and specific IgEs are significantly increased, when compared with haematic values, in middle ear effusion of patients allergic to Dpt [35]. From an experimental viewpoint, Ebert demonstrated that, in rats, intranasal infusion of 10% histamine solution induces acute Eustachian tube dysfunction and, subsequently, middle ear effusion [36]. Focusing on humans, Nagamine reported the accumulation of activated eosinophils in middle ear mucosa of children with otitis media [37]. Moreover, Wright highlighted that elevated concentrations of eosinophil cationic protein (ECP) can be often detected in middle ear effusion of patients affected by SOM and allergy [38]. Jang and Kim, in 2003, showed that RANTES, which is a chemokine with known eosinophil and memory T cell chemoattractant properties, positively correlate with allergic sensitization in children affected by SOM [39]. Following our previous studies on the role of IgEs in the pathogenesis of SOM and in order to confirm the relationship existing between a prolonged or a periodic nasal allergenic stimulation and this pathology, we recently evaluated ECP concentrations in blood and middle ear effusion by fluoro enzime-immunoassay [40]. ECP is certainly the most important enzyme contained into of basic granules of eosinophils, and it represents one of the key elements in the development of mucosal inflammation in allergic patients. In our sample, mean ECP values (mean value ± standard deviation) in blood and middle ear effusion were 25.5 ± 16.3 μg/L and 251 ± 175.2 μg/L, respectively (p < 0.001). The finding of high values of ECP in middle ear effusions (when compared with those measured in blood, p < 0.001) together with the previous identification of our School of high IgEs values in middle ear effusion of young patients allergic to Dpt [35], confirm the possibility, in children sensitized to perennial allergens, of an allergic inflammatory process at middle ear level. In conclusion, our data point towards a direct involvement of
S22
G. Caruso et al. / International Journal of Pediatric Otorhinolaryngology 73S (2009) S19–S25
middle ear mucosa as shock organ in otitis media developing in patients affected by perennial allergic rhinitis. 5. Atopy and larynx: allergic laryngitis Despite the worldwide prevalence of allergic pathologies and the International Scientific community’s vivid interest in defining the etiopathogenetic correlations, most of the physicians does not acknowledge “allergic laryngitis” as a pathology of the upper airways, strictly correlated to allergic sensitisation in atopic patients. Nevertheless, since the second half of the last Century, several Authors hypothized and analysed the risk of developing oedema and/or an irritative symptomatology (itching, chough), as consequence of laryngeal mucosa stimulation, using inhalant or alimentary allergens [41–43]. Actually, even from the conceptual point of view, if we accept the hypothesis that rhino-pharyngo-laryngo-tubaric district is an anatomic–functional unit, it is arduous to maintain the position of those who say that IgE-mediated phlogosis, which has a great clinical relapse at nasal and bronchial level, should save just the larynx, fundamental and unique organ of the respiratory apparatus. As stated by Portman, it is called dysphonia an “alteration in tonal loudness, intensity and timbre of the voice” [44]. This definition refers to morpho-functional phonatory unit, whose constitutive elements are lungs, laryngeal effector and supraglottic resounding apparatus (or vocal tract): normal phonation depend on anatomic integrity and on functional coordination of these organs. It is easy to understand that the alteration of pulmonary dynamic, caused by the use of an allergenic stimulation, may be one of the first mechanisms that provoke dysphonia. Normal phonation implies an adequate infraglottic pressure and a sufficient phonatory flow; on their side, these two parameters deeply depend on normal cord contraction and on pulmonary efficiency. After broncho-provocation, significant FEV1 alterations are detectable in allergic patients: hence one may concludes in young patients with chronic asthma the reduction of bronchopulmonary efficiency, infraglottic pressure and phonatory flow may provoke a significant dysphonia. Besides, it is necessary to stress that at “vocal tract” mucosa level a wide population of proprioceptive receptors exists, whose specific function is to activate the reflected arches, which are able to balance eventual alterations of pulmonary bellows ventilatory dynamic. Specifically, if a reduction in pulmonary flows arises, mucosal proprioceptors allow the realization of compensative mechanisms, which induce a diffused overtone of pharyngo-laryngeal musculature. From an initial muscular hypertonia, we can easily move towards vocal folds hypertrophia. Therefore, allergy indirectly may provoke dysphonia not only interfering with pulmonary efficiency, but also, and in consequential way, through the specific alteration of the laryngeal functions. The identification of a direct correlation between allergy and laryngitis is a more arduous task. In fact, even though during the last twenty years a positive correlation between recurrent laryngitis in early years of life and atopy in children have been repeatedly reported by the Literature [45,46], researchers’ opinions are not homogeneous [47]. For example, a retrospective analysis of Zach and colleagues on 110 children, affected during their early years by recurrent laryngitis episodes, showed a statistically significant association between allergic nasal sensibilization and recurrent laryngeal pathologies [48]. On the contrary, in Litmanovitch and colleagues’ experiences, the potential correlation between upper or lower airways allergic pathologies and laryngeal dysfunctions had no statistical evidences [47].
Indeed, the great limit of all these correlative analysis is that they are retrospective and non-homogeneous as far as the sample; hence, it is not surprising that different researches obtained discordant results. Nevertheless, a perspective research, that enrolled 884 children, which were followed from birth up to their 13th age year, with the extent of studying the development of upper and lower airway pathologies and allergic sensibilization, revealed, in some cases, the existence of an hyperergic–dysergic etiology of infantile laryngitis [49]. Anyway, the greatest problem connected with the analysis of direct correlations between allergy and laryngeal dysfunction is the impossibility to document in an objective way the existence of allergic phenomena, whose shock organ is the laryngeal mucosa. Indeed, an analysis of the histological prerequisite of these phenomena was made by Grahne [50], about fifty years ago. He demonstrated the presence of mastocytes in human embryos’ laryngeal submucosa. The presence of that typology of cells in the larynx gave a rationale to the eventual development of an allergic reaction in this region. Such a histological analysis, nevertheless, was not followed and applied by the scientific community. An important step towards the identification of a direct clinic correlation between allergy and dysphonia is the important research of Haapanen [51], which may be considered the first attempt to set up a proper phonatory provocation test. Briefly, in the abovementioned research, a group of 24 patients, affected by recurrent dysphonia of indefinite origin, was administered with a little amount of allergenic extracts directly at the pharyngeal level. Then, phonation time, voice qualitative analysis and laryngeal objectivity were considered as test positivity parameters. Positive patients’ post-provocation sonogram alterations (noise, blown voice, reduced vocal intensity), on the laryngostroboscope point of view, were considered as adductor cord deficit, in this way confirming that signs and symptoms of a hypothetical allergic laryngitis are not oedema and dyspnoea but a neurovegetative dysponesis with the tone reduction of laryngeal striatum muscles. Further researches are needed, but an interesting route had been found. 6. Atopy and lower airways: rhinobronchial syndrome In daily clinical practice, upper and lower airways are frequently considered as two different functional district although their anatomical and pathophysiological links and epidemiological correlations are quite obvious. In this view, about 40–75% of patients affected by asthma have allergic rhinitis, too; moreover, about 20–30% of patients suffering from rhinitis show, in the natural history of their pathology, some asthmatic episodes [2]. These epidemiological data strongly support the existence of the so-called rhino-bronchial syndrome, the nosologic entity that occurs when upper airways inflammation involves all the tracheobronchial tract, inducing a bronco-constrictive syndrome asthmalike. Moreover, it is a common clinical evidence that allergic rhinitis often precedes asthma and that in asthmatic patients with severe allergic rhinitis, asthma symptoms are worse [52]. In the field of nose–larynx–bronchos interactions, it is moreover appropriate to remind that, the so-called rhino-bronchial syndrome, generally underestimated in pediatric age, is indeed present and frequent and is the consequence of chronic rhino-pharyngeal phlogosis. These constitute the primitive noxa, which may induce bronchial hyper-reactivity. According to literature, major connection mechanisms between upper and lower airways are represented by the eosinophilmediated injury, by the activation of rhino-bronchial reflexes, by the pulmonary aspiration of nasal contents (the so-called post-nasal drip) and by the mouth breathing caused by nasal obstruction
G. Caruso et al. / International Journal of Pediatric Otorhinolaryngology 73S (2009) S19–S25
that leads, because of the lack of nasal air “conditioning”, to the presentation of air-borne allergens to lower airway immune system cells [53]. In view of the lack of long-term follow up studies focused on the analysis of these so important aspects of the airway-related allergic pathology, in a study enough recently published, we followed the evolution of allergic rhinitis in a group of patients in the last 20 years to highlight the efficacy of different treatments in the prevention of complications, specifically asthma [27]. Specifically 73 positive skin test patients were yearly examined for a period of 20 years: each patient underwent an ear, nose and throat objective examination, an active anterior rhinomanometry and a muco-ciliary transport time determination. 46 of them completed the follow up. At the end of the follow up, 21 subjects were found to be without any allergic symptom at nasal level; of them, 11 were treated with symptomatic drugs, 6 received immunotherapy and 4 were not treated. For 12 patients the clinical picture appeared unchanged, of them, 6 didn’t receive any treatment, 4 had immunotherapy and 2 symptomatic drugs. 10 patients (8 untreated and 2 treated with symptomatic drugs) developed rhino-otitis or rhinosinusitis, and 3 (all untreated) had become asthmatic. On the basis of these data, we can conclude that, when approaching a patient with allergic rhinitis, the best treatment is an early one (obviously supported by a correct diagnosis) and it’s always to be preferred to therapeutic abstention which exposes patients to otological, sinusal and/or tracheo-bronchial complications. 7. Allergy and oral cavity: oral allergy syndrome Oral allergy syndrome (OAS) introduced first by Amlot in 1987 [54] is an IgE-mediated allergic manifestation also known as pollen-food allergy syndrome, prevalent in young adults. It affects approximately 20–70% of patients with allergic rhinitis to inhalant pollens: the cause must be found in the cross-reactivity between protein present in pollens and those expressed by fruits, vegetables and nuts [55]. Cross-reactivity are typical: in grass pollen allergy with melons and kiwi fruit, in tree pollen allergy with apples, carrots and potatoes. The symptoms – usually mild – appear immediately after eating these raw products and they are characterized by tingling, pruritus, erythema or angioedema of lips and tongue and by throat itching or tightness. These local symptoms quickly disappear, but in some patients also abdominal discomfort, nausea and vomiting may be present. The risk of anaphylaxis is rare and may be related to the heat-stable and protease-resistant lipid transfer proteins and storage proteins found in specific fruits and vegetables [56]. The diagnosis is based on the patient’s history, prick tests and RAST; the treatment is no standardized except avoiding implicated food. An improvement of OAS sympomts has been reported in 30% to even 84% of patients with airborne pollen allergy treated with specific immunotherapy [55]. 8. Diagnosis: attempts for an integrated approach Considering the different districts (nose, ear, larynx, lungs) which can be selectively or simultaneously affected by the allergic sensitization, in the atopic children to draw an unique diagnostic approach represents a really hard task. In a first phase, the key element of the diagnostic process is certainly the collection of an accurate clinical history. Not only specific (nasal, auricular, respiratory) symptoms should be accurately recorded, but also the nature of major triggers and the timing of symptomatology should be investigated. In order to
S23
correctly define the examined pathology, clinical data have to be integrated with the definition of the condition under which they appear, with the presence of familiarity and so on. The next diagnostic step is certainly the objective evaluation of the rhino-pharyngo-laryngo-tubal district, using, when possible, rigid or flexible endoscope. Specifically, rhinosinusal and pharyngo-laryngeal districts should be carefully examined in order to identify the presence of anatomical abnormalities; moreover, the objective characteristics of the tympanic membrane must be promptly evaluated. Aspect of rhinosinusal, pharyngeal and laryngeal mucosa has to be examined and type, quantity and location of secretions should be noted. The natural complement of the objective examination of rhinopharyngotubal unit is the instrumental evaluation of nasal and middle ear functionality. Rhinomanometry, eventually associated with a nasal decongestion test, gives, by quantitatively measuring nasal pressures, resistances and flows, essential information for the understanding of physiopathology of the rhinosinusal district [57]. Acoustic rhinometry, analysing sound pulses reflected from the interior of the nasal fossa and deriving cross-sectional areas and volumes of the nasal cavities, allows an accurate and sequential quantification of abnormalities induced by the congestion of the mucosa and their modification after pharmacological decongestion[58]. Nasal mucociliary function, one of the most important defence mechanisms of airways against environmental pollutants, can be easily evaluated by measuring the time in which a colored substance (we use charcoal powder and 3% saccharine), placed on the head of the inferior turbinate of the patient, reaches his pharynx (mucociliary transport time) [59]. In case of middle ear involvement, this first diagnostic level is completed by the evaluation of the mobility of the tympanic membrane (analyzed by using tympanometry), by the audiometric exams (to define the degree of hearing loss) and by performing tubal functionality tests. Besides, in case of laryngeal involvement, it is useful a videostroboscoping investigation , which may reveal eventual vocal folds mobility alterations. At last, allergological tests become mandatory in order to confirm the allergic origin of the pathology studied. Most commonly used are skin tests (first level investigations) total serum IgEs or serum specific IgEs (second level investigations) and, in case of nasal pathologies, elimination and provocation tests (third level investigations) [60]. Skin-prick test is the most widely used and represents the primary diagnostic tool for allergy. It is simple, cheap and easily reliable in the majority of patients, and, if properly carried out (positive and negative controls, etc.) and correctly interpreted, it allows to identify the causative allergens in most cases. Among second level tests, total IgEs dosages (PRIST or ELISA) lack of specificity, since other conditions can raise total haematic IgEs and more than half of patients affected by seasonal allergic rhinitis have total IgEs in the physiological range. Specific IgEs dosages (RAST or ELISA), both in serum and nasal secretion, are more precise and well correlate with prick test and nasal challenge results. High costs and low sensitivity, when compared with in vivo tests, are the main limitations of these investigations. Third level test, specifically nasal specific provocation test (NPT), find its rational in the pathophysiologic mechanisms of allergic nasal sensitisation. In fact, symptoms and signs of allergic rhinitis depend mainly on the prevalent or exclusive localization of previously primed mastocytes in the shock organ: the nose. Proposed and carried out for over a century now, NPT can be considered as the most correct, and etiological, quantitative method
S24
G. Caruso et al. / International Journal of Pediatric Otorhinolaryngology 73S (2009) S19–S25
for the diagnosis and the follow up of treatment of allergic rhinitis [61]. Imaging is of limited use in the diagnosis of allergic pathologies, but can be necessary in some specific cases to rule out other diseases. Specifically, chest X-ray may be useful when an involvement of lower airways is suspected or when a systemic disease such as sarcoidosis or Wegener’s granulomatosis must be excluded. MRI is not commonly used in this context. At last, CT scan is certainly useful in case of rhinosinusitis or rhinosinusal polyposis [62]. 9. Brief notes on treatment Although patients affected by allergic pathologies normally do not die from their disease, they endure years of chronic nose disease that interferes with many important aspects of their lives. Moreover they are exposed to the risk of developing severe complications. For these reasons, and considering the high social and medical costs of this disease, it is extremely important to adequately treat allergic pathologies from the early phases of its natural history. Briefly, the treatment of allergy consists in avoiding the allergen to interact with the patient, in prescribing symptomatic and etiologic drugs. In patients affected by perennial allergic rhinitis, the avoidance of allergens is certainly a critical therapeutic step; however, in most cases, a complete elimination of the allergen from the indoor environment is impossible both for practical and economical reasons. In practice, major avoidance measures, especially in case of house-dust sensitization, should ideally include the removal of carpets and soft toys from the environment, the use of allergenimpermeable covers for mattress, pillows, etc., a careful weekly vacuum-cleaning of beds and the washing of bedclothes at 60°C. If all these measures are performed, a good control of house-dust sensitization is in some cases reachable [2]. Things are more complex in pollen-related allergic rhinitis; in these cases, to keep all windows and doors closed and to use an air-conditioner can eliminate most pollens from the indoor environment. Moreover, patients should be suggested to avoid outdoor activities during the hours of highest pollens air concentration. However, such recommendations are generally not well tolerated by patients, and, for these reasons, allergens avoidance is of scarce utility in these forms of allergic rhinitis. If allergens avoidance is, as it happens in most cases, not sufficient, a pharmacological approach to control symptoms become mandatory. First-line therapy consists of second-generation antihistamines, which lack many of the unwanted side effects caused by firstgeneration compounds (they do not cause somnolence and they don’t affect performance and don’t have anticholinergic effect) [5,63] and intranasal corticosteroids, which are the preferred agents for children with persistent symptoms. The use of intranasal corticosteroids is currently recommended in Italy for children older than 5 years of age; however, prospective randomized placebo controlled studies for the evaluation of safety and tolerability in children of 3 to 12 years of age showed that mometasone has the same side effects of placebo in this group of patients [64,65]. Other pharmacologic options include decongestants, leukotriene-receptor antagonists, and intranasal cromolyn sodium. Local nasal immunotherapy represents nowadays the only really etiologic treatment of allergic rhinitis; basically, it consists in the administration of progressively increasing doses of the allergen to which the patient is sensitized. It has to be performed as pre-seasonal or perennial treatment. A meta-analysis of 14 placebo-controlled, double blind studies showed that local nasal immunotherapy is able to determine a statistically significant decrease in symptoms of allergic rhinitis and in the need for medication in patients with both seasonal and perennial allergic rhinitis
[66]. Till now, no life-threatening reactions or deaths have been ever described in patients treated with local nasal immunotherapy. Conflict of interest None declared. References [1] EAACI Nomenclature Task Force. A revised nomenclature for allergy. Allergy 2001;56:813–824. [2] International Rhinitis Management Working Group. International Consensus Report on the Diagnosis and management of Rhinitis. Allergy 1994;49:1–34. [3] Mygind N, Dahl R. Epidemiology of allergic rhinitis. Pediatr Allergy Immunol 1996;7(Suppl 9):57–62. [4] Quah BS, Rassan MH, Razak AR. Prevalence of asthma, rhinitis and eczema among schoolchildren in Kelantan, Malaysia. Acta Paediatric Jpn 1997;39:329– 335. [5] ARIA: Allergic Rhinitis and its impact on Asthma, Workshop report, 2001. [6] Wright AL, Holberg CJ, Martinez FD. Epidemiology of physician-diagnosed allergic rhinitis in childhood. Pediatrics 1994;94:895–901. [7] Sly RM. Changing prevalence of allergic rhinitis and asthma. Ann Allergy Asthma Immunol 1999;82:233–248. [8] Ray NF, Baraniuk JN, Thamer M, Rinehart CS, Gergen PJ, Kaliner M. Direct expenditures for the treatment of allergic rhinoconjunctivitis in 1996, including the contributions of related airways illnesses. J Allergy Clin Immunol 1999;103:401–407. [9] Saval P, Fuglsang G, Madsen C, Osterballe O. Prevalence of atopic disease among Danish schoolchildren. Pediatr Allergy Immunol 1993;4:117–122. [10] Wutfhuch B, Ackermann Liebrich U, Leunberger P, Schindler C. Prevalence of atopy and pollinosis in the adult population of Switzerland (SAPALDIA Study). Swiss Study on Air pollution and Lung Diseases in Adults. Int Arch Allergy Immunol. 1995;106:149–156. [11] Dotterund LK, Kvammen B, Bolle R, Falk ES. A survey of atopic diseases among schoolchildren in Sor Varanger community. Possible effects of subarctic climate and industrial pollution from Russia. Acta Derm Venereol 1994;74:124–128. [12] Salmun N, Cerqueiro C, Kohan M, Neffen H. Rhinitis incidence and risk factors in argentine children. J allergy Clin Immunol 1997;99:1–39. [13] Okuda M, Passàli D. Epidemiological Surgery on Allergic Rhinitis Worldwide. IFOS Newsletter, Summer, 1998. [14] Leung R, Lai CK, Douglass C. Prevalence of asthma and allergy in Hong Kong schoolchildren: an ISAAC study. Eur Respir J. 1997;10:354–360. [15] Goh DY, Lee BW, Quek SC, Cbew FT. Prevalence and severity of asthma, rhinitis, and eczema in Singapore schoolchildren. Arch Dis Child 1996;74:131– 135. [16] Selcuk ZT, Topal T, Enunlu T, Caglar T. The prevalence of allergic disease in primary schoolchildren in Edirme, Turkey. Clin Exp Allergy 1997;27:262–269. [17] Bener A, Abdulrazzaq M, Debuse P, Al Mutawwa J. Prevalence of asthma among Emirates schoolchildren. Eur J Epidemiol 1994;10:271–278. [18] Bousquet J, Duchateau J, Pignat JC, et al. Improvement of quality of life by treatment with cetirizine in patients with allergic rhinitis as determined a French version of the SF-36 questionnaire. J Allergy Clin Immunol. 1996;98:309–316. [19] Juniper EF, Guyatt GH. Development and testing of a new measure of health status for clinical trials in rhinoconjunctivitis. Clin Exp Allergy 1991;21:77–83. [20] Juniper EF. Impact of upper respiratory allergic diseases on quality of life. J Allergy Clin Immunol 1998;101:S386–S391. [21] Blaiss MS. Quality of life in allergic rhinitis. Ann Allergy Asthma Immunol 1999;83:449–454. [22] Shapiro GC. The role of nasal airway obstruction in sinus disease and facial development. J Allergy Clin Immunol 1988;82:935–940. [23] Newman LJ, Platts-Mills TAE, Phillips CD, Hazen KC, Gross CW. Chronic sinusitis: relationship of computed tomography finding to allergy, asthma and eosinophilia. JAMA 1994;271:363–367. [24] McNally PA, White MV, Kaliner MA. Sinusitis in an allergist’s office: analysis of 200 consecutive cases. Allergy Astham Proc 1997;18(3):169–175. [25] Pelikan Z. The role of allergy in sinus disease. Children and adults. Clin Rev Allergy Immunol 1998;16(1–2):55–156. [26] Georgitis JW, Matthews BL, Stone B. Chronic sinusitis: characterization of cellular influx and inflammatory mediators in sinus lavage fluid. Int Arch Allergy Immunol 1995;106(4):416–421. [27] Passàli D, Damiani V, Passàli FM, Mora R, Passali GC, Bellussi L. Natural history of allergic rhinitis: our experience in Italy. Clin Exp All Rev 2003;3:28–32. [28] Alho OP, Karttunen R, Juokko H, Koskela M, Suramo L, Uhari M. Subjects with allergic rhinitis show signs of more severely impaired paranasal sinus functioning during viral cold than nonallergic subjects. Allergy 2003;58(8):767– 771.
G. Caruso et al. / International Journal of Pediatric Otorhinolaryngology 73S (2009) S19–S25
[29] Passàli D, Bellussi L, Damiani V, Passali GC, Passali FM, Celestino D. Allergic rhinitis in Italy: epidemiology and definition of most commonly used diagnostic and therapeutic modalities. Acta Otorhinolaryngol Ital 2003;23(4):257–264. [30] Bluestone CD, Doyle WJ. Anatomy and physiology of the Eustachian tube and middle ear related to otitis media. J Allergy Clin Immunol 1998;81:997–1003. [31] Alles R, Parikh A, Hawk L, Darby Y, Romero JN, Scadding G. The prevalence of atopic disorders in children with chronic otitis media with effusion. Pediatr Allergy Imnmunol 2001;12:102–106. [32] Bernstein JM. Role of IgB-mediated hypersensitivity in otitis media with effusion: pathophysiologic considerations. Ann Otol Rhinol Laryngol Suppl 1994;163:15–19. [33] Meltzer EO et al. Histamine levels and nasal cytology in children with chronic otitis media and rhinitis. Ann Allergy Asthma Immunol 1995;74:406–410. [34] Bernstein JM. Role of allergy in Eustachian tube blockage and otitis media with effusion: a review. Otolaryngol Head Neck Surg 1996;114:562–568. [35] Passàli D, Bellussi L. IgE and secretory otitis media. In: Mogi G, et al., editors. Recent advanced of Otitis Media. Amsterdam/New York: 1994;543–545. [36] Ebert CS, Pollock HW, Dubin MG, Scharer SS, Prazma J, McQueen CT, Pillsbury HC. Effect of intranasal histamine challenge on Eustachian tube function. Int J Pediatr Otorhinolaryngol 2002;63:189–198. [37] Nagahime H, Lino Y, Kojima C, Miyazawa T, Lida T. Clinical characteristic of so called eosinophilic otitis media. Auris Nasus Larynx 2002;29:19–28. [38] Wright ED, Hurst D, Miotto D, Giguere C, Hamid Q. Increased expression of major basic protein (MBP) and interleukin-5 in middle ear biopsy specimens from atopic patients with persistent otitis media with effusion. Otolaryngol Head Neck Surg 2000;123:533–538. [39] Jang CH., Kim YH. Demonstration of RANTES and eosinophil cationic protein in otitis media with effusion with allergy. Int J Pediatr Otorhinolaryngol 2003;67:531–533. [40] Passàli D, Damiani V, Passàli GC, Passàli FM, Bellussi L. The impact of persistent allergic rhinitis on the middle ear. Data from the observation of 100 children. Allergy Clin Immunol Int – J World Allergy Org 2005;17:114–116. [41] Moses P. The Voice of Neurosis. New York: Grune & Stratton, 1954;121. [42] Wolf IJ. Allergic factors in the etiology of spasmodic croup and laryngotracheitis. Am Allergy 1966;24:79–82. [43] Williams AJ, Baghat MS, De Stableforth, Cayton RM, Shenoi PM, Skinner C. Dysphonia caused by inhaled steroids: recognition of a characteristc laryngeal abnormality. Thorax 1983;38:813–821. [44] Portman M. La Dysphonie. Paris: Laboratoires du Dr. E. Buchara, 1982. [45] Weiss ST, Tager IB, Munoz A, Speizer FE. The relationship of respiratory infections in early childhood to the occurrence of increased levels of bronchial responsiveness and atotpy. Am Rev Respir Dis 1985;131(4):573–578. [46] Pearlman DS. The relationship between allergy and croup. Allergy Proc 1989;10(3):227–231. [47] Litmanovitch M, Kivity S, Soferman R, Topilsky M. Relation between recurrent croup and airway hyperreactivity. Ann Allergy 1990;65(3):239–241. [48] Zach M. Air pollution and pediatric respiratory disease: croup. Lung 1990;168 (Suppl):353–357.
S25
[49] Castro-Rodriguez JA, Holberg CJ, Morgan WJ, Wright AL, Alonen M, Taussig LM, Martinez FD. Relation of two subtypes of croup before age of three to wheezing, atopy, and pulmonary function during childhood: a prospective study. Pediatrics 2001;107(3):512–518. [50] Grane B. The mast cell count in the subepithelial tissue of the larynx, trachea and bronchi of human embryos. Acta Path Microbiol Scand 1959;46(131):1– 64. [51] Haapanen ML. Provoked laryngeal dysfunction. Folia Phoniatr 1990;42:157– 169. [52] Corren J. The relationship between allergic rhinitis and bronchial asthma. Curr Opin Pulm Med 1999;5(1):35–37. [53] Passàli D, Kern EB, Bellussi L, Damiani V, Galli J, Lauriello M, Passali GC, Passali FM, Salerni L. Acute, recurrent and chronic rhinosinusitis. Collana di Aggiornamento AUORL 2007;5:1–140. [54] Doroszewska G, Winiarski P, Bartuzi Z. Oral allergy syndrome-problem. Otolaryngol Pol 2006;60:917–922. [55] Czarnecka-Operacz M, Jenerowicz D, Silny W. Oral allergy syndrome in patients with airborne pollen allergy treated with specific immunotherapy. Acta Dermatovenerol Croat 2008;16:19–24. [56] Tatachar P, Kumar S. Food-induced Anaphylaxis and Oral Allergy Syndrome. Pediatr Rev 2008,4:24–27. [57] Clement PAR. Committee report on standardization of rhinomanometry. Rhinology 1984;22:151–155. [58] Hilberg O, Jackson AC, Swift DL. Acoustic rhinometry: evaluation of nasal cavity geometry by acoustic reflection. J Appl Physiol 1989;66:295–303. [59] Passàli D, Bellussi L, Bianchini-Ciampoli M, De Seta E. Our experiences in nasal mucociliary transport time determination. Acta Otolaryngol (Stockh) 1984;97:319–323. [60] Collins-Williams C, Nirami RM, Lamenza C, Chin. Nasal provocative testing with molds in the diagnosis of perennial allergic rhinitis. Ann Allergy 1972;30:557–561. [61] Passàli D, Anselmi M, Bellussi L, Passàli FM, Passali GC. Storia delle metodiche utilizzate quali test di provocazione nasale aspecifica (TPNA) alla luce di esperienze personali. Riv Orl Aud Fon 1999;3-4:121–130. [62] Lloyd GAS, Lund VJ, Scadding GK. CT of the paranasal sinuses and bronchial endoscopic surgery: a critical analysis of 100 symptomatic patients. J Laryngol Otol 1991;105:181–185. [63] Howarth PH. Assessment of antihistamine efficacy and potency. Clin Exp Allergy 1999;86:87–97. [64] Brannan MD, Herron JM, Affrime MB. Safety and tolerability of once-daily mometasone furoate aqueous nasal spray in children. Clin Ther 1986;65:449– 456. [65] Passàli D, Fokkens WJ, van Cawenberge P, Ferrara A, Scadding GK. Allergy in children. Int J Pediatr Otorhinolaryngol 1995;32:S81–S86. [66] EAACI working group on immunotherapy. Local immunotherapy. Allergy 1998;53:933–944.
Atopy: pediatric ENT manifestations in children Giuseppe Caruso a, *, Valerio Damiani b , Lorenzo Salerni a , Francesco Maria Passali c a
ENT Department, University of Siena, Italy ENT Department, Az. Osp. San Giovanni – Addolorata, Rome, Italy c ENT Department, Università Tor Vergata, Rome, Italy b
A R T I C L E
I N F O
Keywords: Atopy Rhinitis Otitis Rhinosinusitis Rhinobronchial syndrome Laryngitis Oral allergy syndrome
A B S T R A C T Objective: The aim of the present study is to discuss the basics of atopy in children in relationship to the principal ENT allergic disorders such as allergic rhinitis, rhinosinusitis and their impact on lower airways, allergic otitis media, and oral cavity focusing on their natural history. Methods: An updated and exhaustive review of principal literature on these topics is performed, underlining the constant but growing interest evoked by these disorders most of all the possible sequelae or complications. Considering the different districts which can be selectively or simultaneously affected by the allergic sensitisation, diagnosis can be a really hard task; in this paper, we tried to draw an integrated diagnostic approach to atopic children and some guidelines for a correct therapeutic approach. Conclusions: Atopic disorders could expose young patients to years of chronic diseases that interferes with their development and with many important aspects of their lives. For these reasons, and considering the high social and medical costs of this disease, it is extremely important to adequately treat allergic pathologies from the early phases of its natural history. Moreover, we cannot forget that an appropriate therapy of allergic pathologies should not be only able to decrease symptoms but, it should also be able to improve patients health related quality of life. © 2009 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . Atopy and nose: allergic rhinitis . . . . . . . . . . . . Atopy and paranasal sinuses: rhinosinusitis . . . . . Atopy and middle ear: allergic otitis media . . . . . . Atopy and larynx: allergic laryngitis . . . . . . . . . . Atopy and lower airways: rhinobronchial syndrome Allergy and oral cavity: oral allergy syndrome . . . . Diagnosis: attempts for an integrated approach . . . Brief notes on treatment . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
1. Introduction Atopy had been defined by the European Academy of Allergy and Clinical Immunology (EAACI) Nomenclature Task Force, as “. . . a personal or familiar tendency to produce IgE antibodies in response to low doses of allergens, usually proteins . . .”. It is the genetic predisposition, transmitted as a dominant factor, to become allergic to a definite number of specific allergens [1].
* Corresponding author: Dr. Giuseppe Caruso, MD, Clinica Otorinolaringoiatrica, Policlinico Universitario “Le Scotte”, Viale Bracci 16, 53100 Siena, Italy. Tel.: +39 0577585470. E-mail address: [email protected] (G. Caruso). 0165-5876/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
S19 S19 S20 S21 S22 S22 S23 S23 S24 S24
The clinical pictures of allergic pathologies represent the common physiopathological end of multiple interactions between the specific genetic predisposition of an individual and the environment in which he lives and, more specifically, in which he grew up. Concerning the otorhinolaryngological manifestations of this systemic pathology, nose, ear and larynx are the most commonly affected organs. Less frequently the oral mucosa also can be the target organ of an allergic reaction. 2. Atopy and nose: allergic rhinitis Allergic rhinitis is classically defined as an IgE-mediated inflammation of nasal mucosa, characterized by one or more of the
S20
G. Caruso et al. / International Journal of Pediatric Otorhinolaryngology 73S (2009) S19–S25
following major symptoms: nasal obstruction, rhinorrea, sneezing and nasal itching [2]. Moreover, other additional symptoms such as headache, impaired smell and conjunctival symptoms can be associated. Allergic rhinitis is certainly a high-prevalence disease and an important social medical problem in many industrialized countries, affecting about 20% of the general population [3]; however it is ever more frequently diagnosed among adults and children in many developing nations [4]. According to the duration of symptoms and to the modalities of allergens exposure, allergic rhinitis is classified as perennial, seasonal and occupational. Perennial allergic rhinitis is mainly due to dust mites or animal dander exposure. On the contrary, seasonal allergic rhinitis is associated to a wide range of pollen allergens such as Graminaceae, Ambrosia, Parietaria, olive, cypress and several others. In any case, it is conditioned by pollens seasonal variations of each specific geographical regions. Finally, occupational allergic rhinitis is strongly related with the kind of substances to which workers are exposed. The recent WHO document “Allergic Rhinitis and its impact on Asthma” (ARIA) [5], partially modified this classification; specifically in this document it is recommended to do not use the old terms “seasonal” and “perennial”, which effectively are not really useful in regions with perennial climatic seasons, and to replace them with the term “intermittent allergic rhinitis” (<4 days per week or <4 weeks) and “persistent allergic rhinitis” (>4 days per week and >4 weeks). However, when describing symptoms of pollen-induced allergic rhinitis during the pollen season, according to ARIA, the old term “seasonal allergic rhinitis” can be still used. Allergic rhinitis is certainly one of the most common chronic inflammatory disease worldwide, frequently affecting the pediatric age. Wright [6] recently reported that about one out of five children will be affected by allergic rhinitis during the first 3 years of life, up to 40% will develop typical symptoms by the age of 6 and up to 30% will become allergic during the adolescence. Moreover, Sly [7] showed that in United States allergic rhinitis affects about 20% of the adult general population, the symptoms starting typically before 30 years of age. From these evidences it is not surprising that this disease accounts for about 1.9 billion dollars in annual health care costs in USA [8]. Moreover, the persistent inflammation of the nasal mucosa predisposes to the development of severe complications such as chronic rhinosinusitis, nasal polyposis, asthma, otitis media, lower airways infections, with an annual public health cost, in the European community, of 1.5–2 billion Euros. In European countries the epidemiological impact of this disease is similar to USA: the prevalence of allergic rhinitis in adults is between 11% and 20% [9,10] in the majority of Nations, with the exception of Belgium and Russia where lowest values (5–8%) were found [11]. The prevalence in countries of Latin Americas was comparable to European values; for example, a recent analysis conducted by the ISAAC in Argentina found that about 34% of the 12000 children enrolled in the study were affected by allergic rhinitis [12]. In this continent the exceptions are represented by Mexico and Bolivia, in which nasal illnesses deriving from allergies affect close on half of the population [13]. The prevalence in Asia and Oceania appeared extremely high, with the exception of Malaysia, Korea and Indonesia [14,15]. Concerning the distribution of allergic rhinitis among different age groups, a higher frequency in the children was highlighted in Sweden, Great Britain, South America, Japan and the Philippines[13]; in the other nations, this disease appeared equally present in all the age classes [16,17]. Allergic rhinitis symptoms are classically distinguished in major and minor. Major symptoms are nasal obstruction, rhinorrea,
sneezing and nasal itching. Moreover, other additional symptoms such as headache, impaired smell and conjunctival symptoms can be associated (minor symptoms). Obviously all the above mentioned symptoms do not reach the same intensity in all the patients; according to the prevalence of one group of symptoms on the others, some authors classify rhinitic patients as “blockers”, “sneezers” and “runners” [2]. For blockers, nasal congestion is the most invalidating complaint, determining mouth breathing, nasal voice and sometimes snoring. Moreover, in the pediatric age, a prevalently oral respiration can lead to orthodontic disturbance such as palatal arching and flattened midface. Patients defined as “sneezers” are obviously mostly bothered by the symptom sneezing and the “runners” experience most problems with rhinorrea. Moreover, in this 2 last typologies of patients, the clinical picture is often completed by some degrees of allergic conjunctivitis. The Medical Outcome Study Short Form Health Survey (SF-36), a generic questionnaire, has been often used to evaluate the effect of allergic rhinitis on patients’ life, with special attention to physical and emotional limitations [18]; the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), a specific one, is the most widely used to assess symptoms and treatments impact as rated by patients [19]. In this context, it is interesting to highline that the typology of patients discomfort vary significantly in the different ages of life. Specifically, adolescent patients (12–20 years) experience very similar problems to adults except for the fact that insomnia is not so troublesome; on the contrary, they do have more problems for what concern concentration, specifically school work. Children (6–12 years) affected by allergic rhinitis present a very different symptomatic picture: they are certainly bothered by their symptoms and by the same practical problem of the other classes of patients (to care tissues and to take drugs), but they experience less interference with their normal daily activities and do not express particular emotional dysfunctions [20]. All these elements are essential in order to set up the right treatment in any patient, or, in other words, to individualize the therapy. An appropriate therapy of allergic rhinitis should not be only able to decrease, of course, rhinorrhea, sneezing, and nasal itching, but, more important, it should also be able to improve patients HRQL [21]. In conclusion, according to the data already exposed, we can affirm that all otorhinolayngologists, in order to efficaciously treat patients affected by allergic rhinitis, and not only their noses, must include, in the diagnostic and therapeutic strategies, a careful evaluation of allergic rhinitis-related quality of life. 3. Atopy and paranasal sinuses: rhinosinusitis The coexistence of allergic rhinitis and rhinosinusitis, both in adults and children, is well documented in medical literature. Shapiro found that about 70% of children with allergic rhinitis had abnormal sinus radiographs [22]. Moreover, in 1994, Newman et al. highlighted that in about 28% of patients affected by recurrent rhinosinusitis, nasal allergy coexists with the rhinosinusal pathology [23]. In 1997 McNally et al. analyzing a series of 200 children affected by chronic rhinosinusitis, showed that allergic rhinitis was present in more that half of the sample (56%), whereas septal deviation accounted for only 23% of cases [24]. From an experimental viewpoint, Pelikan et al. found that in patients affected by chronic rhinosinusitis, nasal allergen challenge induced sinusal radiological alteration in 86.4% of cases [25]. Moreover, in 1995, Georgitis et al found increased levels of leukotrienes C4/D4/E4 and of prostaglandin D2 in sinus lavage of patients affected by chronic rhinosinusitis [26].
G. Caruso et al. / International Journal of Pediatric Otorhinolaryngology 73S (2009) S19–S25
In this context, already 20 years ago, we screened for allergic rhinitis 1620 children, attending 7 state schools (4 primary schools and 3 secondary schools). A targeted questionnaire was handed out to collect an accurate clinical history and skin tests on the inner forearm were performed. 73 children resulted positive to skin tests. Positive skin test children went on in the study; specifically they underwent the following examinations: objective examination of nasal mucosa, active anterior rhinomanometry (AAR), muco-ciliary transport time determination by using a colored indicator (mixture of charcoal powder and 3% saccharin). In addition, radiological examination of paranasal sinuses in the four standard projections were performed and three degrees of alterations were defined (1st degree: darkening; 2nd degree: thickening of the mucosa;. 3rd degree: polypoid degeneration). Concerning the relationship between sinusal radiological lesions and skin positivity, a prevalence of 1st degree lesions was found, children positive to Graminaceae showing the lower number of pathological pictures; 3rd degree lesions were found only in association with sensitization to Dermatophagoides [27]. More recently, Alho et al. found that, in a group of patients with chronic rhinosinusitis, allergic subjects had higher TC score (Lund staging) compared with non allergic ones [28]. In another epidemiological analysis [29] performed together with 145 Italian Otorhinolaryngologists, who were asked to answer a questionnaire on most important epidemiological characteristics of allergic rhinitis in their ambulatory patients, we found that, in Italy, the probability for an allergic patient to develop rhinosinusitis is of 21.5 ± 3.4%. These results are comparable with those of the survey fitted in the WHO ARIA document, according to which rhinosinusitis develops in about 20% of patients affected by allergic rhinitis [5]. The key element in the development of chronic rhinosinusitis from an allergic inflammation of the nose is certainly the functional obstruction of the ostiomeatal complex; which leads to an alteration of air and secretion flows towards and out from the sinuses. Specifically, allergic rhinitis contributes to this process determining, in case of a nasal allergenic challenge, mucosal swelling and, if the stimulation persists, thickening of rhinosinusal mucosa. The accumulation of secretions, unable to pass through narrowed ostia, leads to further obstruction and to the development of an anaerobic environment that favors bacterial growth. Bacterial infection affects mucociliary functionality which, in turn, determines an increase in the thickening of the mucus and in the ostial obstruction. If this vicious circle is not stopped, the pathology evolves towards chronic rhinosinusal inflammation, namely chronic rhinosinusitis. According to the above mentioned data, the concept: “one airway, one disease”, in the field of rhinitis-rhinosinusitis relationship, acquires a strong rationale. 4. Atopy and middle ear: allergic otitis media It is nowadays well known that nose and middle ear are not independent entities, but they belong to a system of contiguous organs including the nose, Eustachian tube, palate, nasopharynx, middle ear and mastoid cells, the so-called rhinopharyngotubal unit. The key element of this anatomo-physiological unit is, considering its multiple functions, certainly the Eustachian tube. In recent years, our knowledge of its structure and functions greatly increased, revealing the major role played by the tube in the pathogenesis of otitis media [30]. Basically nasal allergic inflammation leads to swelling and obstruction of the Eustachian tube, which, in turn, determines a negative pressure in the middle ear and an improper ventilation and the inlet of fluids into the ear drum.
S21
Concerning the impact of atopy on otitis media, it had been shown that 21% of allergic children develop otitis media; moreover 50% of children with persistent otitis media with effusion have nasal allergy [31]. In this context, transient Eustachian tube opening results in aspiration into the middle ear cavity of nasopharyngeal secretions containing bacteria, viruses and allergens with the obvious physiopathological consequences. In 1994, Bernstein stressed the importance of immunoglobulin E-mediated hypersensibility in the development of otitis media with effusion: the release of biologic mediator of inflammation from basophils and mastcells of rhinopharyngeal mucosa leads to Eustachian tube edema and stenosis. This chronic inflammatory response, along with viral or bacterial infections, produces middle ear effusion [32]. Later, Meltzer, in 1995, found an increase of eosinophils, basophils and histamine levels in nasal mucosa of young children with chronic otitis [33]. Bernstein reviewed the various potential nasal-middle ear interactions that may lead to middle ear effusion [34]. First of all, nasal reflexes, triggered by a nasal allergenic challenge and mediated by the central nervous system, can affect middle ear blood flow with consequent liquid transudation. A second mechanism implies the rhinopharyngeal deposition of inflammatory mediators that may directly induce mucus production and vessels dilation at Eustachian tube level. At last, it is possible that the delivery of inflammatory mediators into the microcirculation of the nose can affect middle ear blood flow. Subsequently, irregardless from the specific pathogenetic mechanism, this chronic inflammatory response, along with viral or bacterial infections, produces middle ear effusion. In this context, we already showed, in an our previous study on secretory otitis media SOM) in children, that both total and specific IgEs are significantly increased, when compared with haematic values, in middle ear effusion of patients allergic to Dpt [35]. From an experimental viewpoint, Ebert demonstrated that, in rats, intranasal infusion of 10% histamine solution induces acute Eustachian tube dysfunction and, subsequently, middle ear effusion [36]. Focusing on humans, Nagamine reported the accumulation of activated eosinophils in middle ear mucosa of children with otitis media [37]. Moreover, Wright highlighted that elevated concentrations of eosinophil cationic protein (ECP) can be often detected in middle ear effusion of patients affected by SOM and allergy [38]. Jang and Kim, in 2003, showed that RANTES, which is a chemokine with known eosinophil and memory T cell chemoattractant properties, positively correlate with allergic sensitization in children affected by SOM [39]. Following our previous studies on the role of IgEs in the pathogenesis of SOM and in order to confirm the relationship existing between a prolonged or a periodic nasal allergenic stimulation and this pathology, we recently evaluated ECP concentrations in blood and middle ear effusion by fluoro enzime-immunoassay [40]. ECP is certainly the most important enzyme contained into of basic granules of eosinophils, and it represents one of the key elements in the development of mucosal inflammation in allergic patients. In our sample, mean ECP values (mean value ± standard deviation) in blood and middle ear effusion were 25.5 ± 16.3 μg/L and 251 ± 175.2 μg/L, respectively (p < 0.001). The finding of high values of ECP in middle ear effusions (when compared with those measured in blood, p < 0.001) together with the previous identification of our School of high IgEs values in middle ear effusion of young patients allergic to Dpt [35], confirm the possibility, in children sensitized to perennial allergens, of an allergic inflammatory process at middle ear level. In conclusion, our data point towards a direct involvement of
S22
G. Caruso et al. / International Journal of Pediatric Otorhinolaryngology 73S (2009) S19–S25
middle ear mucosa as shock organ in otitis media developing in patients affected by perennial allergic rhinitis. 5. Atopy and larynx: allergic laryngitis Despite the worldwide prevalence of allergic pathologies and the International Scientific community’s vivid interest in defining the etiopathogenetic correlations, most of the physicians does not acknowledge “allergic laryngitis” as a pathology of the upper airways, strictly correlated to allergic sensitisation in atopic patients. Nevertheless, since the second half of the last Century, several Authors hypothized and analysed the risk of developing oedema and/or an irritative symptomatology (itching, chough), as consequence of laryngeal mucosa stimulation, using inhalant or alimentary allergens [41–43]. Actually, even from the conceptual point of view, if we accept the hypothesis that rhino-pharyngo-laryngo-tubaric district is an anatomic–functional unit, it is arduous to maintain the position of those who say that IgE-mediated phlogosis, which has a great clinical relapse at nasal and bronchial level, should save just the larynx, fundamental and unique organ of the respiratory apparatus. As stated by Portman, it is called dysphonia an “alteration in tonal loudness, intensity and timbre of the voice” [44]. This definition refers to morpho-functional phonatory unit, whose constitutive elements are lungs, laryngeal effector and supraglottic resounding apparatus (or vocal tract): normal phonation depend on anatomic integrity and on functional coordination of these organs. It is easy to understand that the alteration of pulmonary dynamic, caused by the use of an allergenic stimulation, may be one of the first mechanisms that provoke dysphonia. Normal phonation implies an adequate infraglottic pressure and a sufficient phonatory flow; on their side, these two parameters deeply depend on normal cord contraction and on pulmonary efficiency. After broncho-provocation, significant FEV1 alterations are detectable in allergic patients: hence one may concludes in young patients with chronic asthma the reduction of bronchopulmonary efficiency, infraglottic pressure and phonatory flow may provoke a significant dysphonia. Besides, it is necessary to stress that at “vocal tract” mucosa level a wide population of proprioceptive receptors exists, whose specific function is to activate the reflected arches, which are able to balance eventual alterations of pulmonary bellows ventilatory dynamic. Specifically, if a reduction in pulmonary flows arises, mucosal proprioceptors allow the realization of compensative mechanisms, which induce a diffused overtone of pharyngo-laryngeal musculature. From an initial muscular hypertonia, we can easily move towards vocal folds hypertrophia. Therefore, allergy indirectly may provoke dysphonia not only interfering with pulmonary efficiency, but also, and in consequential way, through the specific alteration of the laryngeal functions. The identification of a direct correlation between allergy and laryngitis is a more arduous task. In fact, even though during the last twenty years a positive correlation between recurrent laryngitis in early years of life and atopy in children have been repeatedly reported by the Literature [45,46], researchers’ opinions are not homogeneous [47]. For example, a retrospective analysis of Zach and colleagues on 110 children, affected during their early years by recurrent laryngitis episodes, showed a statistically significant association between allergic nasal sensibilization and recurrent laryngeal pathologies [48]. On the contrary, in Litmanovitch and colleagues’ experiences, the potential correlation between upper or lower airways allergic pathologies and laryngeal dysfunctions had no statistical evidences [47].
Indeed, the great limit of all these correlative analysis is that they are retrospective and non-homogeneous as far as the sample; hence, it is not surprising that different researches obtained discordant results. Nevertheless, a perspective research, that enrolled 884 children, which were followed from birth up to their 13th age year, with the extent of studying the development of upper and lower airway pathologies and allergic sensibilization, revealed, in some cases, the existence of an hyperergic–dysergic etiology of infantile laryngitis [49]. Anyway, the greatest problem connected with the analysis of direct correlations between allergy and laryngeal dysfunction is the impossibility to document in an objective way the existence of allergic phenomena, whose shock organ is the laryngeal mucosa. Indeed, an analysis of the histological prerequisite of these phenomena was made by Grahne [50], about fifty years ago. He demonstrated the presence of mastocytes in human embryos’ laryngeal submucosa. The presence of that typology of cells in the larynx gave a rationale to the eventual development of an allergic reaction in this region. Such a histological analysis, nevertheless, was not followed and applied by the scientific community. An important step towards the identification of a direct clinic correlation between allergy and dysphonia is the important research of Haapanen [51], which may be considered the first attempt to set up a proper phonatory provocation test. Briefly, in the abovementioned research, a group of 24 patients, affected by recurrent dysphonia of indefinite origin, was administered with a little amount of allergenic extracts directly at the pharyngeal level. Then, phonation time, voice qualitative analysis and laryngeal objectivity were considered as test positivity parameters. Positive patients’ post-provocation sonogram alterations (noise, blown voice, reduced vocal intensity), on the laryngostroboscope point of view, were considered as adductor cord deficit, in this way confirming that signs and symptoms of a hypothetical allergic laryngitis are not oedema and dyspnoea but a neurovegetative dysponesis with the tone reduction of laryngeal striatum muscles. Further researches are needed, but an interesting route had been found. 6. Atopy and lower airways: rhinobronchial syndrome In daily clinical practice, upper and lower airways are frequently considered as two different functional district although their anatomical and pathophysiological links and epidemiological correlations are quite obvious. In this view, about 40–75% of patients affected by asthma have allergic rhinitis, too; moreover, about 20–30% of patients suffering from rhinitis show, in the natural history of their pathology, some asthmatic episodes [2]. These epidemiological data strongly support the existence of the so-called rhino-bronchial syndrome, the nosologic entity that occurs when upper airways inflammation involves all the tracheobronchial tract, inducing a bronco-constrictive syndrome asthmalike. Moreover, it is a common clinical evidence that allergic rhinitis often precedes asthma and that in asthmatic patients with severe allergic rhinitis, asthma symptoms are worse [52]. In the field of nose–larynx–bronchos interactions, it is moreover appropriate to remind that, the so-called rhino-bronchial syndrome, generally underestimated in pediatric age, is indeed present and frequent and is the consequence of chronic rhino-pharyngeal phlogosis. These constitute the primitive noxa, which may induce bronchial hyper-reactivity. According to literature, major connection mechanisms between upper and lower airways are represented by the eosinophilmediated injury, by the activation of rhino-bronchial reflexes, by the pulmonary aspiration of nasal contents (the so-called post-nasal drip) and by the mouth breathing caused by nasal obstruction
G. Caruso et al. / International Journal of Pediatric Otorhinolaryngology 73S (2009) S19–S25
that leads, because of the lack of nasal air “conditioning”, to the presentation of air-borne allergens to lower airway immune system cells [53]. In view of the lack of long-term follow up studies focused on the analysis of these so important aspects of the airway-related allergic pathology, in a study enough recently published, we followed the evolution of allergic rhinitis in a group of patients in the last 20 years to highlight the efficacy of different treatments in the prevention of complications, specifically asthma [27]. Specifically 73 positive skin test patients were yearly examined for a period of 20 years: each patient underwent an ear, nose and throat objective examination, an active anterior rhinomanometry and a muco-ciliary transport time determination. 46 of them completed the follow up. At the end of the follow up, 21 subjects were found to be without any allergic symptom at nasal level; of them, 11 were treated with symptomatic drugs, 6 received immunotherapy and 4 were not treated. For 12 patients the clinical picture appeared unchanged, of them, 6 didn’t receive any treatment, 4 had immunotherapy and 2 symptomatic drugs. 10 patients (8 untreated and 2 treated with symptomatic drugs) developed rhino-otitis or rhinosinusitis, and 3 (all untreated) had become asthmatic. On the basis of these data, we can conclude that, when approaching a patient with allergic rhinitis, the best treatment is an early one (obviously supported by a correct diagnosis) and it’s always to be preferred to therapeutic abstention which exposes patients to otological, sinusal and/or tracheo-bronchial complications. 7. Allergy and oral cavity: oral allergy syndrome Oral allergy syndrome (OAS) introduced first by Amlot in 1987 [54] is an IgE-mediated allergic manifestation also known as pollen-food allergy syndrome, prevalent in young adults. It affects approximately 20–70% of patients with allergic rhinitis to inhalant pollens: the cause must be found in the cross-reactivity between protein present in pollens and those expressed by fruits, vegetables and nuts [55]. Cross-reactivity are typical: in grass pollen allergy with melons and kiwi fruit, in tree pollen allergy with apples, carrots and potatoes. The symptoms – usually mild – appear immediately after eating these raw products and they are characterized by tingling, pruritus, erythema or angioedema of lips and tongue and by throat itching or tightness. These local symptoms quickly disappear, but in some patients also abdominal discomfort, nausea and vomiting may be present. The risk of anaphylaxis is rare and may be related to the heat-stable and protease-resistant lipid transfer proteins and storage proteins found in specific fruits and vegetables [56]. The diagnosis is based on the patient’s history, prick tests and RAST; the treatment is no standardized except avoiding implicated food. An improvement of OAS sympomts has been reported in 30% to even 84% of patients with airborne pollen allergy treated with specific immunotherapy [55]. 8. Diagnosis: attempts for an integrated approach Considering the different districts (nose, ear, larynx, lungs) which can be selectively or simultaneously affected by the allergic sensitization, in the atopic children to draw an unique diagnostic approach represents a really hard task. In a first phase, the key element of the diagnostic process is certainly the collection of an accurate clinical history. Not only specific (nasal, auricular, respiratory) symptoms should be accurately recorded, but also the nature of major triggers and the timing of symptomatology should be investigated. In order to
S23
correctly define the examined pathology, clinical data have to be integrated with the definition of the condition under which they appear, with the presence of familiarity and so on. The next diagnostic step is certainly the objective evaluation of the rhino-pharyngo-laryngo-tubal district, using, when possible, rigid or flexible endoscope. Specifically, rhinosinusal and pharyngo-laryngeal districts should be carefully examined in order to identify the presence of anatomical abnormalities; moreover, the objective characteristics of the tympanic membrane must be promptly evaluated. Aspect of rhinosinusal, pharyngeal and laryngeal mucosa has to be examined and type, quantity and location of secretions should be noted. The natural complement of the objective examination of rhinopharyngotubal unit is the instrumental evaluation of nasal and middle ear functionality. Rhinomanometry, eventually associated with a nasal decongestion test, gives, by quantitatively measuring nasal pressures, resistances and flows, essential information for the understanding of physiopathology of the rhinosinusal district [57]. Acoustic rhinometry, analysing sound pulses reflected from the interior of the nasal fossa and deriving cross-sectional areas and volumes of the nasal cavities, allows an accurate and sequential quantification of abnormalities induced by the congestion of the mucosa and their modification after pharmacological decongestion[58]. Nasal mucociliary function, one of the most important defence mechanisms of airways against environmental pollutants, can be easily evaluated by measuring the time in which a colored substance (we use charcoal powder and 3% saccharine), placed on the head of the inferior turbinate of the patient, reaches his pharynx (mucociliary transport time) [59]. In case of middle ear involvement, this first diagnostic level is completed by the evaluation of the mobility of the tympanic membrane (analyzed by using tympanometry), by the audiometric exams (to define the degree of hearing loss) and by performing tubal functionality tests. Besides, in case of laryngeal involvement, it is useful a videostroboscoping investigation , which may reveal eventual vocal folds mobility alterations. At last, allergological tests become mandatory in order to confirm the allergic origin of the pathology studied. Most commonly used are skin tests (first level investigations) total serum IgEs or serum specific IgEs (second level investigations) and, in case of nasal pathologies, elimination and provocation tests (third level investigations) [60]. Skin-prick test is the most widely used and represents the primary diagnostic tool for allergy. It is simple, cheap and easily reliable in the majority of patients, and, if properly carried out (positive and negative controls, etc.) and correctly interpreted, it allows to identify the causative allergens in most cases. Among second level tests, total IgEs dosages (PRIST or ELISA) lack of specificity, since other conditions can raise total haematic IgEs and more than half of patients affected by seasonal allergic rhinitis have total IgEs in the physiological range. Specific IgEs dosages (RAST or ELISA), both in serum and nasal secretion, are more precise and well correlate with prick test and nasal challenge results. High costs and low sensitivity, when compared with in vivo tests, are the main limitations of these investigations. Third level test, specifically nasal specific provocation test (NPT), find its rational in the pathophysiologic mechanisms of allergic nasal sensitisation. In fact, symptoms and signs of allergic rhinitis depend mainly on the prevalent or exclusive localization of previously primed mastocytes in the shock organ: the nose. Proposed and carried out for over a century now, NPT can be considered as the most correct, and etiological, quantitative method
S24
G. Caruso et al. / International Journal of Pediatric Otorhinolaryngology 73S (2009) S19–S25
for the diagnosis and the follow up of treatment of allergic rhinitis [61]. Imaging is of limited use in the diagnosis of allergic pathologies, but can be necessary in some specific cases to rule out other diseases. Specifically, chest X-ray may be useful when an involvement of lower airways is suspected or when a systemic disease such as sarcoidosis or Wegener’s granulomatosis must be excluded. MRI is not commonly used in this context. At last, CT scan is certainly useful in case of rhinosinusitis or rhinosinusal polyposis [62]. 9. Brief notes on treatment Although patients affected by allergic pathologies normally do not die from their disease, they endure years of chronic nose disease that interferes with many important aspects of their lives. Moreover they are exposed to the risk of developing severe complications. For these reasons, and considering the high social and medical costs of this disease, it is extremely important to adequately treat allergic pathologies from the early phases of its natural history. Briefly, the treatment of allergy consists in avoiding the allergen to interact with the patient, in prescribing symptomatic and etiologic drugs. In patients affected by perennial allergic rhinitis, the avoidance of allergens is certainly a critical therapeutic step; however, in most cases, a complete elimination of the allergen from the indoor environment is impossible both for practical and economical reasons. In practice, major avoidance measures, especially in case of house-dust sensitization, should ideally include the removal of carpets and soft toys from the environment, the use of allergenimpermeable covers for mattress, pillows, etc., a careful weekly vacuum-cleaning of beds and the washing of bedclothes at 60°C. If all these measures are performed, a good control of house-dust sensitization is in some cases reachable [2]. Things are more complex in pollen-related allergic rhinitis; in these cases, to keep all windows and doors closed and to use an air-conditioner can eliminate most pollens from the indoor environment. Moreover, patients should be suggested to avoid outdoor activities during the hours of highest pollens air concentration. However, such recommendations are generally not well tolerated by patients, and, for these reasons, allergens avoidance is of scarce utility in these forms of allergic rhinitis. If allergens avoidance is, as it happens in most cases, not sufficient, a pharmacological approach to control symptoms become mandatory. First-line therapy consists of second-generation antihistamines, which lack many of the unwanted side effects caused by firstgeneration compounds (they do not cause somnolence and they don’t affect performance and don’t have anticholinergic effect) [5,63] and intranasal corticosteroids, which are the preferred agents for children with persistent symptoms. The use of intranasal corticosteroids is currently recommended in Italy for children older than 5 years of age; however, prospective randomized placebo controlled studies for the evaluation of safety and tolerability in children of 3 to 12 years of age showed that mometasone has the same side effects of placebo in this group of patients [64,65]. Other pharmacologic options include decongestants, leukotriene-receptor antagonists, and intranasal cromolyn sodium. Local nasal immunotherapy represents nowadays the only really etiologic treatment of allergic rhinitis; basically, it consists in the administration of progressively increasing doses of the allergen to which the patient is sensitized. It has to be performed as pre-seasonal or perennial treatment. A meta-analysis of 14 placebo-controlled, double blind studies showed that local nasal immunotherapy is able to determine a statistically significant decrease in symptoms of allergic rhinitis and in the need for medication in patients with both seasonal and perennial allergic rhinitis
[66]. Till now, no life-threatening reactions or deaths have been ever described in patients treated with local nasal immunotherapy. Conflict of interest None declared. References [1] EAACI Nomenclature Task Force. A revised nomenclature for allergy. Allergy 2001;56:813–824. [2] International Rhinitis Management Working Group. International Consensus Report on the Diagnosis and management of Rhinitis. Allergy 1994;49:1–34. [3] Mygind N, Dahl R. Epidemiology of allergic rhinitis. Pediatr Allergy Immunol 1996;7(Suppl 9):57–62. [4] Quah BS, Rassan MH, Razak AR. Prevalence of asthma, rhinitis and eczema among schoolchildren in Kelantan, Malaysia. Acta Paediatric Jpn 1997;39:329– 335. [5] ARIA: Allergic Rhinitis and its impact on Asthma, Workshop report, 2001. [6] Wright AL, Holberg CJ, Martinez FD. Epidemiology of physician-diagnosed allergic rhinitis in childhood. Pediatrics 1994;94:895–901. [7] Sly RM. Changing prevalence of allergic rhinitis and asthma. Ann Allergy Asthma Immunol 1999;82:233–248. [8] Ray NF, Baraniuk JN, Thamer M, Rinehart CS, Gergen PJ, Kaliner M. Direct expenditures for the treatment of allergic rhinoconjunctivitis in 1996, including the contributions of related airways illnesses. J Allergy Clin Immunol 1999;103:401–407. [9] Saval P, Fuglsang G, Madsen C, Osterballe O. Prevalence of atopic disease among Danish schoolchildren. Pediatr Allergy Immunol 1993;4:117–122. [10] Wutfhuch B, Ackermann Liebrich U, Leunberger P, Schindler C. Prevalence of atopy and pollinosis in the adult population of Switzerland (SAPALDIA Study). Swiss Study on Air pollution and Lung Diseases in Adults. Int Arch Allergy Immunol. 1995;106:149–156. [11] Dotterund LK, Kvammen B, Bolle R, Falk ES. A survey of atopic diseases among schoolchildren in Sor Varanger community. Possible effects of subarctic climate and industrial pollution from Russia. Acta Derm Venereol 1994;74:124–128. [12] Salmun N, Cerqueiro C, Kohan M, Neffen H. Rhinitis incidence and risk factors in argentine children. J allergy Clin Immunol 1997;99:1–39. [13] Okuda M, Passàli D. Epidemiological Surgery on Allergic Rhinitis Worldwide. IFOS Newsletter, Summer, 1998. [14] Leung R, Lai CK, Douglass C. Prevalence of asthma and allergy in Hong Kong schoolchildren: an ISAAC study. Eur Respir J. 1997;10:354–360. [15] Goh DY, Lee BW, Quek SC, Cbew FT. Prevalence and severity of asthma, rhinitis, and eczema in Singapore schoolchildren. Arch Dis Child 1996;74:131– 135. [16] Selcuk ZT, Topal T, Enunlu T, Caglar T. The prevalence of allergic disease in primary schoolchildren in Edirme, Turkey. Clin Exp Allergy 1997;27:262–269. [17] Bener A, Abdulrazzaq M, Debuse P, Al Mutawwa J. Prevalence of asthma among Emirates schoolchildren. Eur J Epidemiol 1994;10:271–278. [18] Bousquet J, Duchateau J, Pignat JC, et al. Improvement of quality of life by treatment with cetirizine in patients with allergic rhinitis as determined a French version of the SF-36 questionnaire. J Allergy Clin Immunol. 1996;98:309–316. [19] Juniper EF, Guyatt GH. Development and testing of a new measure of health status for clinical trials in rhinoconjunctivitis. Clin Exp Allergy 1991;21:77–83. [20] Juniper EF. Impact of upper respiratory allergic diseases on quality of life. J Allergy Clin Immunol 1998;101:S386–S391. [21] Blaiss MS. Quality of life in allergic rhinitis. Ann Allergy Asthma Immunol 1999;83:449–454. [22] Shapiro GC. The role of nasal airway obstruction in sinus disease and facial development. J Allergy Clin Immunol 1988;82:935–940. [23] Newman LJ, Platts-Mills TAE, Phillips CD, Hazen KC, Gross CW. Chronic sinusitis: relationship of computed tomography finding to allergy, asthma and eosinophilia. JAMA 1994;271:363–367. [24] McNally PA, White MV, Kaliner MA. Sinusitis in an allergist’s office: analysis of 200 consecutive cases. Allergy Astham Proc 1997;18(3):169–175. [25] Pelikan Z. The role of allergy in sinus disease. Children and adults. Clin Rev Allergy Immunol 1998;16(1–2):55–156. [26] Georgitis JW, Matthews BL, Stone B. Chronic sinusitis: characterization of cellular influx and inflammatory mediators in sinus lavage fluid. Int Arch Allergy Immunol 1995;106(4):416–421. [27] Passàli D, Damiani V, Passàli FM, Mora R, Passali GC, Bellussi L. Natural history of allergic rhinitis: our experience in Italy. Clin Exp All Rev 2003;3:28–32. [28] Alho OP, Karttunen R, Juokko H, Koskela M, Suramo L, Uhari M. Subjects with allergic rhinitis show signs of more severely impaired paranasal sinus functioning during viral cold than nonallergic subjects. Allergy 2003;58(8):767– 771.
G. Caruso et al. / International Journal of Pediatric Otorhinolaryngology 73S (2009) S19–S25
[29] Passàli D, Bellussi L, Damiani V, Passali GC, Passali FM, Celestino D. Allergic rhinitis in Italy: epidemiology and definition of most commonly used diagnostic and therapeutic modalities. Acta Otorhinolaryngol Ital 2003;23(4):257–264. [30] Bluestone CD, Doyle WJ. Anatomy and physiology of the Eustachian tube and middle ear related to otitis media. J Allergy Clin Immunol 1998;81:997–1003. [31] Alles R, Parikh A, Hawk L, Darby Y, Romero JN, Scadding G. The prevalence of atopic disorders in children with chronic otitis media with effusion. Pediatr Allergy Imnmunol 2001;12:102–106. [32] Bernstein JM. Role of IgB-mediated hypersensitivity in otitis media with effusion: pathophysiologic considerations. Ann Otol Rhinol Laryngol Suppl 1994;163:15–19. [33] Meltzer EO et al. Histamine levels and nasal cytology in children with chronic otitis media and rhinitis. Ann Allergy Asthma Immunol 1995;74:406–410. [34] Bernstein JM. Role of allergy in Eustachian tube blockage and otitis media with effusion: a review. Otolaryngol Head Neck Surg 1996;114:562–568. [35] Passàli D, Bellussi L. IgE and secretory otitis media. In: Mogi G, et al., editors. Recent advanced of Otitis Media. Amsterdam/New York: 1994;543–545. [36] Ebert CS, Pollock HW, Dubin MG, Scharer SS, Prazma J, McQueen CT, Pillsbury HC. Effect of intranasal histamine challenge on Eustachian tube function. Int J Pediatr Otorhinolaryngol 2002;63:189–198. [37] Nagahime H, Lino Y, Kojima C, Miyazawa T, Lida T. Clinical characteristic of so called eosinophilic otitis media. Auris Nasus Larynx 2002;29:19–28. [38] Wright ED, Hurst D, Miotto D, Giguere C, Hamid Q. Increased expression of major basic protein (MBP) and interleukin-5 in middle ear biopsy specimens from atopic patients with persistent otitis media with effusion. Otolaryngol Head Neck Surg 2000;123:533–538. [39] Jang CH., Kim YH. Demonstration of RANTES and eosinophil cationic protein in otitis media with effusion with allergy. Int J Pediatr Otorhinolaryngol 2003;67:531–533. [40] Passàli D, Damiani V, Passàli GC, Passàli FM, Bellussi L. The impact of persistent allergic rhinitis on the middle ear. Data from the observation of 100 children. Allergy Clin Immunol Int – J World Allergy Org 2005;17:114–116. [41] Moses P. The Voice of Neurosis. New York: Grune & Stratton, 1954;121. [42] Wolf IJ. Allergic factors in the etiology of spasmodic croup and laryngotracheitis. Am Allergy 1966;24:79–82. [43] Williams AJ, Baghat MS, De Stableforth, Cayton RM, Shenoi PM, Skinner C. Dysphonia caused by inhaled steroids: recognition of a characteristc laryngeal abnormality. Thorax 1983;38:813–821. [44] Portman M. La Dysphonie. Paris: Laboratoires du Dr. E. Buchara, 1982. [45] Weiss ST, Tager IB, Munoz A, Speizer FE. The relationship of respiratory infections in early childhood to the occurrence of increased levels of bronchial responsiveness and atotpy. Am Rev Respir Dis 1985;131(4):573–578. [46] Pearlman DS. The relationship between allergy and croup. Allergy Proc 1989;10(3):227–231. [47] Litmanovitch M, Kivity S, Soferman R, Topilsky M. Relation between recurrent croup and airway hyperreactivity. Ann Allergy 1990;65(3):239–241. [48] Zach M. Air pollution and pediatric respiratory disease: croup. Lung 1990;168 (Suppl):353–357.
S25
[49] Castro-Rodriguez JA, Holberg CJ, Morgan WJ, Wright AL, Alonen M, Taussig LM, Martinez FD. Relation of two subtypes of croup before age of three to wheezing, atopy, and pulmonary function during childhood: a prospective study. Pediatrics 2001;107(3):512–518. [50] Grane B. The mast cell count in the subepithelial tissue of the larynx, trachea and bronchi of human embryos. Acta Path Microbiol Scand 1959;46(131):1– 64. [51] Haapanen ML. Provoked laryngeal dysfunction. Folia Phoniatr 1990;42:157– 169. [52] Corren J. The relationship between allergic rhinitis and bronchial asthma. Curr Opin Pulm Med 1999;5(1):35–37. [53] Passàli D, Kern EB, Bellussi L, Damiani V, Galli J, Lauriello M, Passali GC, Passali FM, Salerni L. Acute, recurrent and chronic rhinosinusitis. Collana di Aggiornamento AUORL 2007;5:1–140. [54] Doroszewska G, Winiarski P, Bartuzi Z. Oral allergy syndrome-problem. Otolaryngol Pol 2006;60:917–922. [55] Czarnecka-Operacz M, Jenerowicz D, Silny W. Oral allergy syndrome in patients with airborne pollen allergy treated with specific immunotherapy. Acta Dermatovenerol Croat 2008;16:19–24. [56] Tatachar P, Kumar S. Food-induced Anaphylaxis and Oral Allergy Syndrome. Pediatr Rev 2008,4:24–27. [57] Clement PAR. Committee report on standardization of rhinomanometry. Rhinology 1984;22:151–155. [58] Hilberg O, Jackson AC, Swift DL. Acoustic rhinometry: evaluation of nasal cavity geometry by acoustic reflection. J Appl Physiol 1989;66:295–303. [59] Passàli D, Bellussi L, Bianchini-Ciampoli M, De Seta E. Our experiences in nasal mucociliary transport time determination. Acta Otolaryngol (Stockh) 1984;97:319–323. [60] Collins-Williams C, Nirami RM, Lamenza C, Chin. Nasal provocative testing with molds in the diagnosis of perennial allergic rhinitis. Ann Allergy 1972;30:557–561. [61] Passàli D, Anselmi M, Bellussi L, Passàli FM, Passali GC. Storia delle metodiche utilizzate quali test di provocazione nasale aspecifica (TPNA) alla luce di esperienze personali. Riv Orl Aud Fon 1999;3-4:121–130. [62] Lloyd GAS, Lund VJ, Scadding GK. CT of the paranasal sinuses and bronchial endoscopic surgery: a critical analysis of 100 symptomatic patients. J Laryngol Otol 1991;105:181–185. [63] Howarth PH. Assessment of antihistamine efficacy and potency. Clin Exp Allergy 1999;86:87–97. [64] Brannan MD, Herron JM, Affrime MB. Safety and tolerability of once-daily mometasone furoate aqueous nasal spray in children. Clin Ther 1986;65:449– 456. [65] Passàli D, Fokkens WJ, van Cawenberge P, Ferrara A, Scadding GK. Allergy in children. Int J Pediatr Otorhinolaryngol 1995;32:S81–S86. [66] EAACI working group on immunotherapy. Local immunotherapy. Allergy 1998;53:933–944.