Adenotonsillar Disease

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Recent Patents on Inflammation & Allergy Drug Discovery 2012, 6, 121-129

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Adenotonsillar Disease Andreas E. Zautner* Universitätsmedizin Göttingen, Abteilung für Medizinische Mikrobiologie, Kreuzbergring 57, D-37075 Göttingen, Germany Received: August 27, 2011; Accepted: January 31, 2012; Revised: February 1, 2012

Abstract: Adenotonsillar disease (adenoiditis and recurrent tonsillitis) is a prevalent otolaryngologic disorder aetiologically based on chronic inflammation triggered by a persistent bacterial infection. These bacteria, mostly Staphylococcus aureus, Haemophilus sp., and Streptococcus sp., persist predominantly intracellular and within mucosal biofilms. The recurrent or chronic inflammation of the adenoids and faucial tonsils leads to chronic activation of the cell-mediated and humoral immune response, resulting in hypertrophy of the lymphoid tonsillar tissue. This hypertrophic tissue is the cause for the prominent clinical symptoms: obstruction of the upper airways, snoring, and sleep apnea for adenoiditis or sore throat, dysphagia and halitosis for recurrent tonsillitis. Treatment strategies should target the persisting bacteria within their biofilm or intracellular shelter. Macrolide antibiotics like clarithromycin are able to modulate the immune system and to interfere in bacterial signaling within biofilms. Clindamycin, quinupristin-dalfopristin, and oritavancin are intracellular high active compounds. Surgical removal of the hypertrophic tissue by modern procedures like laser tonsil ablation, eliminates not only a mechanical obstacle of the airways, it removes also the basis for the aetiologic cause, the “biofilm carrier”. This review summarizes the role of bacterial persistence in mucosal biofilms for the aetiology, diagnosis and treatment of adenotonsillar disease and relevant patents.

Keywords: Adenoiditis, mucosal biofilm, recurrent tonsillitis, Staphylococcus aureus. INTRODUCTION Biofilm formation is an evolutionary ancient strategy for a large number of bacteria and fungi to persist and survive under suboptimal, sometimes even hostile conditions [1]. Pathogens living in biofilms resist antimicrobials, the host immune response as well as physical and chemical stressors. In general, biofilms are defined as surface-attached microbial communities, consisting of the aggregated bacterial cells and an extracellular polymeric substance matrix (EPS) [2]. Thus, classical biofilms can be found on inorganic surfaces like venous catheters, orthopedic prostheses, heart pacemakers, at the dental surface, and on otolaryngologic devices [3]. Another form of biofilms, assembling on or inside mucosal environments are so-called “mucosal biofilms”. This biofilm type could be associated with a large number of chronic infectious diseases amongst others in otolaryngological infections like chronic otitis media, chronic rhinosinusitis, and adenotonsillar disease [2]. Biofilms are complex threedimensional structures with internal compartments, channels, and bacterial microcolonies. They are professionalized bacterial subpopulations according to metabolic performance, antimicrobial resistance, EPS-matrix production, surface molecules, and virulence-associated factors. Bacteria in biofilms communicate with each other by a process called quorum sensing (QS) - a kind of cell density sense. Biofilm formation is characteristically linked to chronic diseases, *Address correspondence to this author at the Universitätsmedizin Göttingen, Abteilung für Medizinische Mikrobiologie, Kreuzbergring 57, D-37075 Göttingen, Germany; Tel: +49-551-395857; Fax: +49-551-395861; E-mail: [email protected]

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which do not respond to conservative antimicrobial treatment. Examples include recurrent urinary tract infections with Escherichia coli, Klebsiella oxytoca or Pseudomonas aeruginosa, Streptococcus pneumoniae in otitis of the middle ear, P. aeruginosa infections in cystic fibrosis and Staphylococcus aureus in chronic rhinosinusitis, and adenotonsillar disease [2]. The pharyngeal lymphoid ring, also known as Waldeyer's-Pirogov tonsillar ring, consists of the pharyngeal (adenoids), the tubal, the palatine (the faucial tonsils or simply tonsils) and the lingual tonsils [4]. Chronic recurrent inflammation of this area has two prominent aspects, which were linked to each other, and both lead to prevalent clinical symptoms: chronic infection on the one hand and consecutive hypertrophy of the tonsillar tissue on the other hand leading to obstruction of the upper airways. This review intends to highlight the role of bacterial persistence in biofilms besides intracellular hideaways for the aetiology of adenotonsillar disease and recurrent tonsillitis. Moreover, the major topics of pathogenesis, diagnosis and treatment will be demonstrated. New insights in in vivo biofilm formation, new developments in diagnostics and medical and surgical treatment will be discussed. GENERAL ASPECTS OF BIOFILMS ON INERT SURFACES Naturally, bacteria organize themselves in mono- or multispecies, multicellular collectives termed biofilms. Only a small fraction of bacteria exists solely planktonic. By interacting and living with each other, bacteria achieve a lot of © 2012 Bentham Science Publishers

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benefits like shelter from fluctuations in temperature, pH, humidity, DNA damage by radiation, the host’s cellular and humoral immune factors, as well as from antibiotics and other toxic compounds [3]. Compared to planktonic bacteria, biofilm bacteria show an altered gene expression pattern. This altered gene expression pattern results in a distinct bacterial phenotype. Two crucial aspects are in contrast to planktonic cells greatly reduced in biofilms. First, the bacterial metabolism and second the reproduction by division. In consequence, antibiotics targeting mostly proliferating and high metabolic active bacterial cells show a much lower efficacy against the ones residing in biofilms [5-7]. It could be shown that dead bacteria in the periphery of a biofilm wall their viable cohabiters and form a nidus for regrowth from inside [3]. Planktonic bacteria adhere in a first step to an inert surface, get sessile and start proliferation by division. Aggregated bacterial cells form microcolonies that grow and mature. The biofilms growth-form depends mainly on the surrounding fluid conditions: In quiescent fluids, biofilms tend to grow in mushroom-like or mound-like structures surrounded by channels, in fast moving streams they tend to form streamers [1]. The biofilm disperses by detachment into the overlying fluid or spreading over the solid surface [8]. Another characteristic of bacteria in biofilms is the production of EPS-matrix. The EPS-matrix is mainly composed of polysaccharide-biopolymers in which the bacteria are embedded, but it also contains proteins, glycoproteins, (glyco)lipids and extracellular DNA (e-DNA) [9]. Highly hydrated EPS biopolymers form a matrix that holds the bacteria in the biofilm together. Thus, the EPS-matrix provides mechanical stability and mediates adhesion to surfaces. Additionally, it keeps extracellular enzymes close to the secreting bacterial producers and acts in this way as a superordinate digestive system that protects from phagocytosis and reduces the accessibility for immunoglobulins [10]. Intense intercellular communication of biofilm bacteria is another important characteristic to sustain function and structure, especially the sense for cell density called quorum sensing. In general, quorum sensing coordinates processes, which would be insufficient, if only single bacterial cells would perform them. If the quorum - the threshold number is reached, the bacteria start such processes like the production of EPS-matrix components. The mediators of quorum sensing, named autoinducers, act as “bacterial pheromones” and are secreted into the environment. N-Acetyl-L-homoserine lactones (AHL), also known as autoinducer-1, are responsible for intra-species communication [11, 12], whereas furanosyl-borat-diesters, known as autoinducer-2, are used for inter-species communication [13]. Moreover, biofilms are a place of intensive exchange of genetic material. Due to the close proximity of bacterial cells, the conjugation rate is much higher than in suspensions of planktonic cells [14]. In that way, biofilm bacteria maintain a large and accessible gene pool. Biofilm formation can be easily recognized on inert surfaces. The most familiar surface associated biofilm is the dental plaque [15]. Other biofilm infections known from clinical routine are colonized venous or arterial catheters,

Andreas E. Zautner

artificial heart valves, pacemakers, orthopedic prostheses, [16] and otolaryngologic devices like endotracheal tubes, tracheostomy tubes, voice prostheses, and tympanostomy tubes [3]. Once coated by a biofilm, such device-associated infections are hardly to treat without removal of the “biofilm carrier”. In irregular time intervals, planktonic bacteria or whole emboli are shed from the infected device causing systemic infections [17-19]. Without sufficient antibiotic or surgical treatment to efface the mother biofilm, therapeutic success is not likely to achieve. MUCOSAL BIOFILMS IN OTOLARYNGOLOGIC INFECTIONS In recent research, biofilm formation was identified to play a pivotal role in the aetiology of numerous causal and anatomical associated chronic otolaryngologic infections like chronic rhinosinusitis, chronic otitis media, and adenotonsillar disease [2]. Naturally, there is no inorganic footplate for planktonic bacteria to attach on the epithelium of naso- and oropharynx. Thus, the difficulty to identify in vivo biofilms associated with diseases has led to a panel of specific criteria to diagnose biofilm infections [2, 20, 21]. These include: a)

Association of bacteria with a surface or aggregation with each other,

b) Examination of the infected tissue proves the presence of bacterial cell aggregation embedded in an extracellular matrix of bacterial and/or host components, c)

Demarcation of the infection to a circumscribed location,

d) In spite of proven susceptibility of planktonic bacteria, failure of antibiotic treatment or detection of intrabiofilm viable bacteria by in situ Live/Dead-staining or reverse transcription polymerase chain reaction in the absence of positive culture, e)

Lack of bacterial growth in cultures despite reasonable suspicion of infection,

f)

Insufficient immune clearance, demonstrated by the presence of bacterial cell clusters in the host tissue and inflammatory cells adjacent to the macrocolonies.

The terminus “mucosal biofilms” was coined by Garth Ehrlich [1] for bacterial aggregations on or in a mucosal environment. The significant difference between mucosal biofilms and “classic” biofilms on inert surfaces are that the EPS matrix of mucosal biofilms is composed besides the bacterial components to a larger extent of host proteins and cells [1]. Mucosal biofilms could be directly pictured by scanning electron microscopy, confocal laser scanning microscopy combined with fluorescence in situ hybridization (FISH), immunostaining and nucleic acid labeling in faucial tonsils [3, 22, 23], adenoids [24, 25], chronic otitis media [26] and cholesteatoma [3]. Chole and Faddis demonstrated the presence of mucosal biofilms mostly in tonsillar crypts with the help of light and transmission electron microscopy in 73.7 % (14 of 19) of tonsil specimen from patients with recurrent tonsillitis (RT) [22]. These mucosal biofilms may explain the chronicity of

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some forms of tonsillitis. But it should be noted that bacteria of the normal flora could also form these biofilms. Characteristic for mucosal biofilms are aggregated bacteria surrounded by a carbohydrate containing matrix on or within the adenotonsillar epithelium [24, 25]. Biofilms in the adenoids may act as reservoir for chronic otitis media and chronic rhinosinusitis [26]. Thus, adenoidectomy was shown to be a sufficient therapy for the two diseases [27,28]. Hypertrophy of the pharyngeal (adenoids) and/or the tubal tonsils itself may lead to a blockage of the pharyngeal opening of the Eustachian tube and in consequence to a hypoventilated middle ear. This promotes the formation of mucosal biofilms, which were shown to be responsible for the emergence of chronic otitis media with effusion [3, 29]. Placement of tympanostomy tubes increase the oxygen tension in the middle ear space, endorsing the clearance of the biofilm by promoting the regrowth of ciliated epithelium and are therefore a sufficient treatment for chronic otitis media. [30]. Cholesteatoma, a destructive and expanding growth of keratinizing squamous epithelium in the middle ear was also shown to be associated with mucosal biofilms [31]. Pseudomonas aeruginosa, Haemophilus influenza, Streptococcus pneumonia and Staphylococcus aureus are typical pathogenic bacterial species found in biofilms from otolaryngologic patients [3]. TONSILLOLITHES Tonsillolithes are according to their structure a special feature in this respect. They form within tonsillar crypts by the release of volatile sulfur compounds produced in the sulfur metabolism of anaerobic bacteria [32, 33] and were associated with chronic recurrent tonsillitis. In contrast to the mucosal biofilms found by Chole and Faddis [22], tonsillolithes share a common structure with dental biofilms and are similar in their arrangement to surface associated biofilms. One typical bacterial species found in tonsillolithes is Fusobacterium nucelatum [23, 33]. CLINICAL MANIFESTATION AND PATHOGENESIS Acute Tonsillitis and Peritonsillar Abscess (PTA) Acute tonsillitis is the consequence of an acute viral or bacterial infection. If the bacterial infection spreads from the pharynx to the connective tissue in the peritonsillar area, a PTA (quinsy) may arise as a complication of an untreated acute tonsillitis. The predominant bacterial species isolated from PTA-cavities are streptococci, primarily Streptococcus pyogenes (group-A-Streptococci), and anaerobes, mainly Fusobacterium sp., often accompanying each other [34-41]. One severe but very rare complication of acute tonsillitis is the Lemierre's syndrome, also known as postanginal sepsis [42, 43]. It is typically caused by the anaerobe bacterium Fusobacterium necrophorum or related species of the genus Fusobacterium. They are part of the resident oropharyngeal flora and may reside in the biofilms of tonsillolithes [23, 33]. In the interior of a formed abscess cavity, anaerobic bacteria like F. necrophorum can thrive and penetrate the connective tissue around the internal jugular vein [44], where they induce a septic thrombophlebitis. From the infected thrombus,

bacteria and blood clots disseminate by the bloodstream to other parts of the body, leading to emboli, abscesses, sepsis and septic infarctions [45, 46]. The most frequent involved sites of septic metastases are the lungs and the joints [47]. Pulmonary microemboli hinder the blood oxygenation, causing shortness of breath, cough, pleuritic chest pain, hemoptysis, crepitations and severe pneumonia [48]. Involvement of joints leads to arthalgia and arthritis. Other symptoms could be headache, muscle pain, jaundice, trismus and extreme lethargia. Usually, a few days after occurrence of the initial symptoms, Lemierre's syndrome is associated with gastrointestinal syndromes like abdominal pain, diarrhea, nausea and vomiting. Hepato- and splenomegaly can be found as a result of abscesses in these organs [44, 49]. The production of bacterial toxins such as lipopolysaccharide (LPS) may cause severe sequelae and every severity degree of sepsis and septic shock with its typical symptoms: hypotension, tachycardia, oliguria, tachypnea, diffuse intravascular coagulation and thrombocytopenia [50]. Due to molecular mimicry, A-streptococci-tonsillitis can cause postinfectious complications like secondary damage to heart valves (rheumatic fever), joints (arthritis) and kidneys (glomerulonephritis). Other prevalent causes of acute tonsillitis are respiratory viruses. The leading pathogens in the field of viral tonsillitis are the common cold viruses like the influenza-A/B-viruses, adenoviruses, rhinoviruses, coronaviruses, and the respiratory syncytial virus. Also herpes viruses like the EpsteinBarr virus, the cause of acute mononucleosis (glandular fever, Pfeiffer's disease, kissing disease), herpes simplex virus and cytomegalovirus can lead to acute tonsillitis [51]. Adenotonsillar Disease and Chronic Recurrent Tonsillitis In contrast to PTA, the most prevalent pathogen associated with RT is S. aureus followed by Haemophilus influenzae, Haemophilus parainfluenzae and several betahaemolytic streptococci [35]. S. aureus is accompanied in many cases by Haemophilus spp. and Streptococcus spp. In rare cases, nonfermenter species like Burkholderia cenocepacia or Enterobacteria can be cultured from tonsil specimen [52]. The spectrum of bacterial pathogens associated with RT leads to the conclusion that only a minority of adenoiditis or RT cases is the consequence of recurrent infections with new pathogens. The most probable mechanism is the endogen reactivation of either intracellular persisting bacteria [34, 35] or pathogens within biofilms [3, 22-26, 53]. According to spa gene sequencing or multi locus sequence typing (MLST) data, the S. aureus strains associated with RT originate from the colonizing residual flora of the skin, nose and pharynx [35]. Nearly, all S. aureus isolates cultured from the intracellular space were also able to form biofilms, at least on fibronectin coated surfaces. The reactivation from intracellular and a consecutive forming of biofilms or the persistence followed by invasion of tonsillar cells is assumable. The tonsils are physically the inductive sites for both, cell-mediated and humoral immune response against ingested and inhaled pathogens [54]. Thus, recurrent or chronic infection of the adenoids and/or the faucial tonsils may lead to a recurrent activation and in consequence to hy-

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pertrophy of lymphoid tonsillar tissue. In this respect, hypertrophy is part of the physiological immunological reaction. The adenoid and tonsillar hypertrophy is mainly due to an increase of B-cells, helper T-cells and regulatory T-cells (Treg) [55]. In the majority of hyperplastic tonsils, dense infiltrates of S-100+ dendritic cells could be shown [56]. Comparison of histological specimen from RT patients with hypertrophy and patients suffering from recurrent acute tonsillitis without hypertrophy demonstrated that tonsil hypertrophy is associated with increased tonsil weight, follicle number, follicular area and circumference, S-100+ cell density in crypt and surface epithelium, and CD20+ cell number in crypt epithelium [57]. In contrast to that, CD45RO + cell density in central and peripheral extrafollicular areas, CD20+ cell density in surface epithelium, cyclin D1+follicular and central extrafollicular areas, cell density in surface epithelium, follicles, and lymphocyte as well as plasma cells in crypts were lower compared to non-hypertrophic recurrent acute tonsillitis patients [57]. Parenchymal fibrosis and keratinous material in the crypt epithelium were present in both groups [54]. In patients with adenoid vegetations, follicular area and circumference, CD20+ cell number in the extrafollicular tissue and in the surface epithelium, S-100+ cell density in surface epithelium and cyclin D1+ cell density in follicles was even higher than in patients with RT with hypertrophy and patients suffering from recurrent acute tonsillitis without hypertrophy [57]. The mechanical obstruction of the upper airways has even further physiological consequences. Enlarged adenoids can obstruct the nasopharynx in a way that breathing through the nose becomes very uncomfortable and inhalation occurs instead through the open mouth. Adenoid enlargement can also affect the sound of the voice without stopping nasal airflow altogether. Thus, the patient starts to twang. A longterm adenoid hypertrophy causes obstruction of the nasopharynx resulting in a dentofacial growth anomaly that was coined as adenoid facies (Facies adenoidae) [58]. Very large adenoids obstruct the airflow in the nose and in the Eustachian tube, as well. This can lead to sinusitis and otitis media with middle ear effusions. The adenoids function in these cases as a reservoir for pathogenic provoking recurrent infections. Excessive "drip" from infected adenoids might even irritate the mucosa of the vocal cords and might cause an irresistible urge to cough. Finally, adenotonsillar disease leading to obstruction of the upper airways is one well known reason for snoring and obstructive sleep apnea (OSA), which is characterized by repetitive pauses in breathing during sleep, reduction in blood oxygenation, sleep disturbance and fatigue. Furthermore, immunological parameters and genetic predispositions for tonsillar hypertrophy should be taken into consideration. It was also suggested that a local lymphocyte dysfunction may play a pivotal role in the aetiology of RT and tonsillar hypertrophy [59]. Persistent local inflammatory reactions triggered by persisting bacteria effect the histomorphological changes and the resulting functional deficiencies in adenotonsillitis and RT [60].

Andreas E. Zautner

Diagnosis The diagnostic measures with respect to RT and PTA divide up into two branches. One branch is the clinical diagnosis, estimating the degree of hypertrophy and the associated upper airway obstruction. The other branch is the cultural detection of bacteria persisting either intracellularly or in biofilms (which is not a generally established part in the diagnosis of adenotonsillar disease). Both branches contribute to the decision between conservative antibiotic treatment of RT and PTA or surgical intervention. Furthermore, the development of symptoms over a certain time period should be considered to estimate the chronicity of this disease. The degree of adenotonsillar or tonsillar hypertrophy can be easily assessed by observation of the naso- or oropharynx. A very clear indication for adenoidectomy is the obstruction of nasopharynx associated with impaired breathing through the nose and recurrent respiratory infections, as well as obstruction of the pharyngeal opening of Eustachian tube following recurrent otitis media. The clinical criteria for RT or RT-indicated tonsillectomy, respectively, include at least seven episodes in the past year or at least five episodes per year for two years or at least three episodes per year suffering from a sore throat with odynophagia and one of the secondary criteria. The secondary criteria are an increased body temperature >38.3°C, cervical adenopathia (tender cervical lymph nodes), tonsillar exsudate or positive tests for group A beta-hemolytic streptococci in anamnestic reports in the last year(s) before tonsillectomy. The indication for tonsillectomy includes additionally sleep-disordered breathing, abnormal polysomnography, signs of tonsillar sclerosis, obstruction of tonsillar crypts and scar tissue on the tonsils [61-64]. The diagnosis of PTA includes in combination with unilateral persistent pain in the peritonsillar area, tonsillar bulge, and optional trismus and the aspiration of pus. The abscess in the peritonsillar area can be visualized by magnetic resonance tomography (MRT) or X-ray computed tomography (CT) with contrast solution. Diagnosis of Lemierre's syndrome bases also on tomography imaging, bacterial culture but depends largely on the patient history, signs and symptoms. Thrombosis of the internal jugular vein can be relatively easily displayed with Doppler sonography, but a CT scan or an MRT scan is more sensitive. There are lots of studies comparing the efficiency of different material collection methods for bacterial culture including superficial swabs, fine needle aspiration or multiple consecutive lavage samples (for otitis media) [35, 65]. The bacterial spectrum of RT, adenoiditis and otitis media is well known and generally polymicrobial ,a calculated antibiotic treatment should be sufficient. In the case of Lemierre's syndrome, bacterial cultures taken from the blood or joint aspirates can also contribute to identify the causative agent. A very common used but questionable method estimating the need for tonsillectomy or tonsillotomy are serological tests for group A beta-hemolytic streptococci (GAS). Frequently considered are serological titers for anti-streptolysin

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O (ASO) [66-68] and anti-deoxyribonuclease B (ADN-B) [69, 70], whereas anti-hyaluronidase (AH) [71, 72], antinicotineamide adenine dinucleotidase (ANAD), and antistreptokinase (ASL) [73, 74] are less often included in test panels [75]. ASO and ADN-B elect a rapid IgG3 response, which reaches 2-3 week post infection its maximum and declines continuously after that [76]. Because of the common high GAS-prevalence it is necessary to estimate upper limits of normal (ULN) ASO and ADN-B titers since recent GAS-infections should cause above ULN serum titers and can be identified thereby. ULN titers of ASO are 195 IU for adults and 239 IU - 305 IU for children [77-79]. ADN-B ULN were found to be 200 IU - 640 IU for children as well as for adults [77, 78]. Here arises the first problem because these ULN values show a very large range according to study population and region. The sensitivity of significantly increased ASO and/or ADN-B titers is about 65% and the specificity is about 96% compared to bacterial throat swabs [80] the value of these tests decreases for the assessment of the indication for tonsillectomy/tonsillotomy or antibiotic therapy primarily due to the relatively low prevalence of GAS caused tonsillitis compared to viruses and other bacterial species [35, 81]. Thus, some studies could not demonstrate significant differences in antibody levels between patients with RT and those without relapsing throat infections [82, 83] whereas others could described elevated titers [84, 85]. SYMPTOMATIC TREATMENT Symptomatic treatment of RT or pharyngitis in general includes saline gargles, a soft diet, a lot of drinking, analgetics and antipyretics. “Traditional chinese” [86-88] or ayurvedic treatment [89] include herbal gargle solutions. Other pharmaceutical solid lozenge compositions containing icelandic moss (Lichen islandicus) [90]. Anti-inflammatory, analgesic, antiviral and antianginal effects were shown or at least attributed for these herbal solutions. Another way to relieve the symptoms of tonsillitis, laryngitis and pharyngitis is the application of a local anaesthetic in a viscous solution, covering the inflamed area [91]. An alternative approach is the restoration of the normal resident bacterial flora of the pharynx with a suspension containing three different Streptococcus sanguis II strains and one Streptococcus mitis strain. This should help to treat and to prevent A-streptococcal tonsillitis [92]. Furthermore, the recurrence of tonsil infections can be suppressed by the application of pharmaceutic lactic acid [93]. Finally, it should be mentioned that snoring and sleep apnea associated with hypertrophic adenoids can be treated with inhalative corticosteroids like Budesonide [94] or leukotriene antagonists [95]. The mechanism behind these therapies is the inhibition of the inflammatory proliferation stimuli and thereby the reduction of the adenotonsillar tissue size.

infections of tonsils are in particular S. aureus but also H. influnezae and several Streptococcal species. Usually, penicillin V, ampicillin or oral cephalosporines are prescribed to treat acute as well as intermittent episodes of RT. Beta-lactames have only low effects against nonproliferating bacteria in biofilms and factual no effects against intracellular bacteria because of their inability to pass the cell membrane. However, a 30-day course of amoxicillin/clavulanate reduced the need for tonsillectomy significantly from 67.2% down to 37.5% of patients [96]. Clindamycin is an intracellular high active compound. Recently, it was shown that all S. aureus isolates from 254 patients with RT or PTA were sensitive for clindamycin [35]. The superiority of clindamycin over penicillin in the treatment of non-streptococcal RT has already been demonstrated in 1989 and therefore it was recommended [97]. Furthermore, this antimicrobial was effectively used in the eradication of recurrent infections caused by S. pyogenes [98, 99]. Additionally, the antibiotics quinupristin-dalfopristinand oritavancin, launched commercially only a few years ago, have been demonstrated as sufficient therapy against intracellular S. aureus [100]. It has been shown that macrolide antibiotics like clarithromycin are able to modulate infections irrespective from their antimicrobial effects. Additionally to their immunomodulatory effects, they can hinder bacterial signaling [101, 102]. Clarithromycin treatment was shown to reduce the EPS-matrix of P. aeruginosa as well as S. epidermidis biofilms, although the bacteria themselves were clarithromycin resistant [103, 104]. Subinhibitory concentrations of clindamycin were also demonstrated to inhibit the transcription of S. aureus exoproteins [105] what might suggest that clindamycin could inhibit S. aureus biofilm formation or maintenance. Another aspect that has to be considered is the way of application of the antimicrobial agent. Usullay, antibiotics are given per os to treat RT. Serious cases of PTA and Lemierre's syndrome are primarily treated with antibiotics given intravenously. Fusobacterium necrophorum is generally highly susceptible to beta-lactam antibiotics, metronidazole, clindamycin and third generation cephalosporins [48]. Due to the possibility of co-infections by another bacterial species, it is often advised not to use a monotherapy in treating Lemierre's syndrome. Thus, penicillin-derived antibiotics in combination with a beta-lactamase inhibitor such as clavulanic acid or a combination with metronidazole are recommended [44, 106, 107]. Clindamycin can be also given as monotherapy. Besides oral and intravenous application, there exists other more unconventional ways to apply antibiotics. There are approaches for the lymphotropic administration of antibiotics and immunocorrective agents [108] as well as injection of antibiotics at the sternocleidomastoid muscle [109].

Antibiotic Treatment It has to be taken into account in the treatment strategy of adenotonsillar disease that bacteria persist in biofilms as well as in the intracellular space. In addition, it has to be considered that the major bacterial species associated with chronic

Surgical Treatment The general aim of surgical removal of the hypertrophic and infected adenoid and the tonsils tissue is the circumventive reconstitution of the free passage of the upper airways.

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The removal of the hypertrophic tissue is not only the elimination of a mechanical obstacle. It destroys also the habitat of the bacteria, which persist either intracellular or in biofilms and provoke the process of chronic infection and consecutive proliferation of the lymphatic tissue. Thus, it is both a symptomatic and causal therapy. The method of choice to treat adenotonsillar disease is the surgical removal of the adenoids by adenoidectomy. The Danish physician Wilhelm Meyer was the first who performed adenoidectomy already in 1868 [110]. Indications for adenoidectomy are nasal obstruction and recurrent otitis media, caused by the adenoids blocking the Eustachian tube. The procedure of adenoidectomy is carried out under general anaesthesia. The hypertrophic adenoid tissue is ablated through the mouth by the use of special adenoid curettes [111] and bleedings are staunched by cauterisation. There are also other methods using lasers, rotating shavers, radiofrequency current or the harmonic scalpel. After removal of the adenoids, the nasopharynx is temporarily packed with sterile gauze for hemostasis. Adenoidectomy is often carried out in combination with tonsillectomy, simply because the otolaryngologist has a clear view on the adenoids after removal of the faucial tonsils. Thus, both procedures can be assessed at the same time. In general, two different surgical procedures with wide variety of methods are common for the treatment of RT: complete extracapsular tonsillectomy and intracapsular partial tonsilar removal (tonsillotomy) [112]. Because of the high risks associated with tonsillectomy especially posttonsillectomy hemorrhage, children below the age of six years should generally undergo only partial tonsillectomy (tonsillotomy) [113, 114]. Whereas extracapsular tonsillectomy is mostly done by “traditional” cold dissection but also by using electrodissection [115], intracapsular partial tonsillectomy is more and more performed using carbon dioxide lasers [116] or an endoscopic microdebrider [117]. Analogous to that, the method of choice for the treatment of PTA is “a chaud” bilateral tonsillectomy [118, 119]. The standard procedure for tonsillectomy includes the separation and the removal of the tonsils from the subcapsular plane. This is preferably done by the use of a scissor and blunt dissection. Tonsillectomy is carried out on a flat lying patient lying with a hyperextended neck (Rose’s position). A single tonsil is removed by holding it by the upper part, pulling it slightly medially, and making a cut over the anterior faucial pillar. After that, a snare can be used to make a small cut on the lower portion prior to the final removal of the tonsil. Bleedings are usually stilled by compression, with electrocautery, ligation of sutures, and the topical application of thrombin [120]. Alternatively, other procedures and instruments are applicable like harmonic scalpels, electrocautery, (bipolar) radiofrequency ablation, the dissection and snare method, laser tonsil ablation, microdebrider as well as thermal welding and lasers. ALTERNATIVE TREATMENT PROCEDURES Besides the antibiotic and surgical methods of choice, there is a panel of further therapeutical approaches to treat adenoiditis, RT and associated diseases or disorders.

Andreas E. Zautner

Light therapy with noncoherent polarized light might stimulate the immune response in the treatment of adenoiditis and tonsillitis [121]. Sublingual administration of the immunostimulatory drug Imudon in patients with immunodefiency might help to cure RT [122] or improve the outcome after tonsillectomy [123]. Imudon is a mixture of bacterial lysates containing LPS and other bacterial immunogens. It stimulates the proliferation of immunocompetent cells, activates phagocytes and stimulates the secretion of lysozyme and immunoglobulin A [124]. Photodynamic therapy (PDT), which is rarely used in the treatment of chronic peridontitis [125] as well as head and neck carcinomas, is another method to treat chronic tonsillitis [126-129]. In a first step, the lacunae of the palatine tonsils are rinsed with physiological saline using a Hartmann cannula. In a second step, a solution with a photosensitizer, water-soluble porphyrin, methylene blue or chlorophylite, absorbing optic radiation in a spectral range within 625-700 nm or 840-1270 nm is applied. Then the tonsils are irradiated with help of a light-diode [130] or a laser [131]. Photodynamic therapy should reduce the hypertrophic tissue and decreases the number of relapses. Animal Model Up to now there are no well-standardized animal models for recurrent tonsillitis. As mentioned above, the most prevalent bacterium and therefore the most likely reason for inducing proliferation of the tonsillar tissue resulting in hypertrophic adenoids and tonsils are intracellular persisting S. aureus [35]. To simulate S. aureus induced RT Golonev and coworkers developed a chinchilla (Chinchilla langier) animal model. In this model, RT is induced by injection of a S. aureus suspension with 3x106 cfu/mL in physiological saline into the peritonsillar fiber above the upper pole of the palatine tonsil [132]. With this model, the efficacy of benzylpenicillin in the experimental treatment of RT was demonstrated as proof of principle. However, there are no scientific publications using this model so far, except for the patent itself. Leroy and coworkers developed a comparable chinchilla model for H. influenzae induced otitis media [65]. Animals were inoculated either directly into the middle ear cavity or nasopharyngeally with bacteria harvested in the mid-log phase and suspended in sterile Hank’s solution. CURRENT & FUTURE DEVELOPMENTS Mucosal biofilms and host cell invasion are the two major strategies of bacteria to persist in the hostile environment of the human pharyngeal lymphoid ring. Both strategies provide safeguard from antibiotics and the human immune system. Chronic persistence of bacteria triggers recurrent episodes of inflammation and hypertrophy of the tonsillar tissue. Thus, periodic episodes of fever and upper airway obstruction are the major symptoms of adenoiditis and recurrent tonsillitis. The estimation of anti-streptolysin O and anti-deoxyribonuclease B might be removed completely from the criteria for RT due to recent epidemiological data. The treatments of choice are further on surgical measures eliminating the airway obstacles and the persisting biofilm or intracellular bacteria within the tissue. Because of the relatively high risk of post-tonsillectomy hemorrhage, especially

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in younger children, partial tonsillectomy/tonsillotomy using CO2 or kalium titanyl phosphate LASER technique [133, 134] might be used more often in future. Further advanced technologies applicable to cure RT are the endoscopic microdebrider [135] and thermal tissue welding [136] promising less post-operative pain and post-operative bleedings. Conservative treatment of moderate hypertrophy grades with antimicrobial compounds have to consider these bacterial persistence strategies and should therefore be efficient in mucosal biofilms as well as in the intracellular space. CONFLICT OF INTEREST

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The author declared no potential conflicts of interests with respect to the authorship and/or publication of this article.

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ACKNOWLEDGEMENTS

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The author’s work is supported by the Deutsche Forschungsgemeinschaft and the Forschungsförderungsprogramm of the Universitätsmedizin Göttingen, Germany. I am grateful to Jasmin Corso for revising the text of the manuscript.

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