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Special Issue on Allergic Rhinitis Volume V, Issue III July-August 2015 Chest Research Foundation Bulletin, Pune - India Allergic Rhinitis: Diagnostic and Therapeutic Implications A llergic rhinitis (AR) is a potentially debilitating condition that globally affects individuals from all age groups. As recently reported by the World Allergy Organization, AR prevalence rates are increasing worldwide, and this condition affects an estimated 10-30% of the global population. Recent data published by Kubavat and also by the International Study of Asthma and Allergies in Childhood (ISAAC) suggest that AR has an estimated prevalence between 10-13% in India. Since AR is an independent risk factor for developing asthma, it is extremely important to raise physician awareness regarding AR, especially the need to promptly diagnose and effectively manage this condition. In order to recognize and effectively manage the heterogeneous clinical manifestations of AR, we must first understand the complex pathophysiology underlying this condition. AR pathophysiologic mechanisms revolve around allergen-induced sensitization and the associated pro-inflammatory responses mediated by Th2 cytokines as well as key effectors cells (e.g. mast cells, basophils, T cells, eosinophils). Allergens are taken up and processed by antigen presenting cells (APCs), which are found on the nasal mucosal surface. Peptides from the allergens are presented by the APCs through major histocompatibility complex (MHC) class II molecules. MHC class II molecules, in combination with the antigen complex, serve as a ligand for T-cell receptors on CD4+ T cells. Once stimulated, CD4+ T cells differentiate into allergen-specific Th2 cells, which may produce pro-allergic (IL-4, IL5, IL-13) cytokines. These cytokines collectively enhance IgE production by B cells as well as eosinophil activation and recruitment. Antigen-specific IgE binds to high-affinity FcεR1 receptors on mast cells and/or basophils. Antigen cross-linking of bound IgE results in mast cell and/or basophil degranulation and the release of inflammatory mediators (e.g. histamine), thereby contributing to the clinical symptoms associated with AR. The clinical evaluation of AR is primarily based on detailed history taking, physical examination, and allergy testing. A thorough medical history can help to identify symptoms that are likely due to AR and to ascertain potential triggers. In considering a diagnosis of AR, clinicians should consider the development/onset/temporality of symptoms Sunit P. Jariwala Director of Allergy/Immunology Research, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA (especially seasonal versus perennial), precipitating and/or aggravating factors, medication history, family history, social and occupational history, and the impact of AR on the patient’s quality of life. AR commonly presents with nonspecific symptoms including sneezing, nasal congestion, nasal pruritus, anosmia, and/or rhinorrhea. A history of seasonal (i.e. during specific seasons) or perennial (i.e. year round) symptoms may help elucidate potential environmental triggers. For example, common seasonal allergens may include mold spores as well as pollens from weeds, grass, and trees. Perennial allergens include cockroaches, dust mites, pet dander, and mold spores (can persist year round in unusually warm climates). Physical examination may identify “allergic shiners”, the “nasal crease”, pale and swollen blue-gray nasal mucosa, and/or Dennie-Morgan lines. Clinicians must also note findings that reflect systemic diseases associated with rhinitis and/ or conditions that may mimic AR. In evaluating patients with suspected AR, clinicians must consider other possible diagnoses that may have similar clinical findings. For example, one must consider anatomic abnormalities, ciliary dysfunction, nasal polyps (commonly co-exist in the setting of AR), nasal septal deviation, tumors, nasal turbinate or adenoidal hypertrophy, systemic conditions (e.g. vasculitis, sarcoidosis), and cerebrospinal fluid (CSF) rhinorrhea. Clinicians must also consider nonallergic (i.e. not IgE-mediated) rhinitis, which may present similarly to AR. Examples of nonallergic rhinitis include vasomotor rhinitis, gustatory rhinitis, infectious rhinitis, nonallergic rhinitis with eosinophilia syndrome (NARES), occupational rhinitis, hormonal rhinitis (e.g. hypothyroidism-induced), drug-induced rhinitis (including rhinitis medicamentosa), and atrophic rhinitis. In order to determine specific allergic triggers and to confirm the diagnosis of AR, clinicians may perform allergy testing. The most commonly utilized methods to evaluate for allergies in the setting of suspected AR include allergy skin testing (immediate hypersensitivity testing) in vivo and specific IgE testing in vitro. Since allergenic pollen types vary between ecozones, physicians in a given region must be aware of the predominant allergy-causing pollen in that area. For each geographic location, allergy testing panels and immunotherapy can be tailored based on the main pollen types. In light of the wide geographic diversity in India, predominant allergenic pollen types have been extensively characterized for each region. Based on the allergy test results, environmental control measures can be performed and allergen immunotherapy may be considered. Patients with negative allergy testing and a clinical history strongly suggestive of AR might be evaluated for local allergic rhinitis (LAR), which is characterized by the local production of specific IgE and the absence of systemic atopy. To accurately diagnose LAR, a nasal allergen provocation test can help to identify the allergens causing the symptoms. In patients that are refractory to standard medical therapy, specialized testing such as imaging and endoscopy may be considered. For example, radiographic studies may help to evaluate for structural abnormalities and/or >>Continued on page 2 |Volume V, Issue III, July-August 2015|RespiMirror 1 >>Continued from page 1 Allergic Rhinitis: Diagnostic...... comorbid conditions (e.g. adenoid hypertrophy, sinusitis). A computed tomography (CT) scan of the sinuses is more sensitive and specific than conventional radiography in the evaluation of sinusitis. Sinus CT may also help to identify septal abnormalities and nasal polyps. In the setting of complicated sinusitis and/or suspected comorbid conditions, rhinolaryngoscopy may be performed. AR management strategies include environmental control, pharmacotherapy, and allergen immunotherapy. Once potential environmental triggers are identified following history taking and/or allergy testing, patients may be advised to avoid allergens such as dust mites or pet dander. For example, recommended dust mite avoidance strategies may include dust mite encasings for bedding, humidity control, and high-efficiency particulate air (HEPA) vacuuming of carpet; multiple interventions are recommended over isolated interventions. Possible medication options include oral antihistamines (secondgeneration are preferred over first-generation), oral antihistamines used in combination with decongestants, intranasal mast cell stabilizers (e.g. cromolyn), intranasal antihistamines, intranasal corticosteroids, intranasal anticholinergics (may reduce rhinorrhea, but are usually not effective for other nasal symptoms) intranasal antihistamine combined with intranasal corticosteroid, leukotriene receptor antagonists, and nasal saline. In most cases of AR, intranasal steroids are typically considered as first-line therapy and are not typically associated with systemic side effects. However, intranasal steroids must be used with extreme caution in the setting of epistaxis and glaucoma (in this setting, intraocular pressure must be monitored by an ophthalmologist). A brief course of oral corticosteroid therapy may be prescribed in the setting of severe nasal symptoms and/or when nasal polyps are present. Omalizumab has been shown to be effective in allergic rhinitis, but in the United States is presently only approved for allergic asthma and chronic urticaria. With increasing worldwide prevalence rates, AR is often under diagnosed and undertreated. AR and its comorbid conditions may significantly impact an individual’s quality of life, school/work performance, and social interactions. In order to prevent the potentially devastating complications of AR, effective management strategies must include patient education, targeted environmental control measures, pharmacotherapy, and considering allergen immunotherapy in the appropriate setting. Refractory AR cases must be further investigated for potential masquerading conditions with prompt referrals for imaging and/or specialized evaluations (e.g. endoscopy) when indicated. Further AR research is necessary in order to enhance the available diagnostic and treatment modalities with hopes of improving disease-related quality of life and offering cost-effective medical care. Red Blood Cells RBCs are the most abundant blood cells which are produced in the bone marrow by hemocytoblasts. They have a unique biconcave shape which helps them to accommodate more hemoglobin and therefore, transport oxygen more efficiently. Due to absence of nuclei(because they want to utilize that space for packing hemoglobin)RBCs do not replicate andtheir life span is around 120 days after which they are degraded in the spleen. RBC’s comprise 99% of the circulating blood cells. RBC production is regulated by the kidneys. When the level of oxygen in the blood is reduced, kidneys secrete the hormone erythropoietin (EPO). EPO travels from the kidney to the bone marrow where, it binds to its receptors on the stem cells (hemocytoblast) and stimulate them to produce RBC’s. Prenatally the liver is the primary site of EPO synthesis and the production is switched to the kidneys around birth. People with kidney failure become anemic because the kidneys no longer make enough EPO to stimulate red blood cell production. Secondary polycythemia is mostly due to increased erythropoietin (EPO) production either in response to chronic hypoxia or from an erythropoietin secreting tumor. Polycythemia in COPD is the body’s attempt to adjust to decreased levels of blood oxygen by increasing the production of red blood cells. While this may be useful in the short term, overproduction eventually clogs small blood vessels. Apart from their role in transporting oxygen, RBC’s are also a major storage site for glucose in the body, which is circulating all the time. It stores more glucose than the liver. 2 RespiMirror|Volume V, Issue III, July-August 2015| CAT About 93% of the glucose is located in plasma and 7% of the glucose in the red blood cells Mr. Nitin Vanjare DOG About 87.5 % of the glucose is located in plasma and 12.5% of the glucose in the red blood cells HUMAN About 58 % of the glucose is located in plasma and 42 % of the glucose in the red blood cells The human body produces ~2.4 million red blood cells per second. Under stress this number can increase by 7 times The cumulative surface area of all the RBC’s in the human body is roughly around 2,000 times as that of the body’s exterior surface. One drop of blood consists of around 500,000 RBC’s RBC’s contain Hemoglobin as the main transporter of oxygen. The total amount of Hb present in the RBC’s is 750 gms (3/4th of a Kg) RBC’s travel from the heart through the body and back to the heart in merely 20 to 60 seconds. Each red blood cell contains about 280 million hemoglobin molecules Nose and nasal physiology & Rhino Manometry Dr Rahul Kodgule Chest Research Foundation, Pune Himesh Reshamiya – “The nose does matter” Listening to the famous hindi song “O Bavariya” by Himesh Reshamiya makes one realize how much a nose can affect our lives. Nasal physiology and anatomy plays a big role in the respiratory and olfactory function. Nasal symptoms are highly prevalent and by themselves can hamper our daily activities. Knowledge of nasal physiology and anatomy can be helpful in understanding the contribution of nose in effective and defective functioning of respiration. Nasal Cycle Eye sockets Upper turbinate Middle turbinate Shaded areas of congestion Maxillary sinus Lower turbinate Nasal septum Protection: Performing the role of door-keeper, the nose provides a “gate-pass” for air entry in the lungs. In order to ensure proper functioning of the muco-ciliary system and gas transfer in the lower airways, the air is required to be clean, warm and humid. Particles larger than 3µm which largely included particulate pollutants are trapped by nasal vibrissae. Particles between 0.5µm to 3µm usually consist of pathogens that are dealt mainly by the muco-ciliary system. The goblet cells in nasal mucosa secrete a mucus blanket which is moved backwards towards nasopharynx like a conveyer belt by the cilia. Proteins secreted in the mucus further ensure destruction of the pathogens. Particles <0.5µm can travel all the way towards smaller airways and alveoli. Thermo-regulation: Nose is also called as “the air-conditioner” for the lungs. The surface area of the nasal mucosa is large particularly in the region of middle and inferior turbinates and the adjacent parts of the septum and is highly vascular with cavernous venous spaces. This creates an effective “radiator” effect leading to warming up of cold air. The nose has an unbelievable Turbinates (Shelves) Tip of Nose Adenoid Area Nostril Tongue Throat Palate Teeth Decongeated Side Congeated Side capacity to warm inhaled air from subzero temperature to near body temperature in just 0.25 seconds. Interestingly hot air is also cooled to body temperature. Humidification: The typical aero-dynamics of the nose leads to crowding of air in the narrow portion of the upper airway ensuring close contact between the airstream and mucosal surfaces. Rich blood supply keeps the mucosal surface extremely moist. Evaporation of the mucosal moisture leads to rapid humidification of inhaled air up to 75-80%. Adults condition more than 14,000 litres of air every day, using approximately 20% of our daily water intake. Nasal cycle, why do we have two nostrils?: Like the shifts of factory workers, each side of the nose shifts functioning with the other. The autonomic nerve supply creates cyclical congestion and decongestion of each nasal side leading to periodic turbinate hypertrophy and unilateral nasal obstruction. This obstruction lasts for about 2-4 hours. Nasal resistance: 50% of the total airway resistance is contributed by nasal resistance. Nasal resistance plays an important role in maintaining the elasticity of the lungs. Prolonged mouth breathing may lead to areas of atelectasis and poor ventilation. Increased nasal resistance can also be conducive to emphysema. Common factors that can reduce nasal resistance are exercise, sympathomimetics, rebreathing, atrophic rhinitis and erect posture. On the other hand, nasal resistance can be increased by causes like infective/allergic rhinitis, vasomotor rhinitis, hyperventilation, supine posture, alcohol, aspirin and cold air. Measuring nasal obstruction: Nasal obstruction can be measured and monitored using several methods. Nasal inspiratory peak flow measurements are quite useful for home monitoring of nasal obstruction. The inspiratory peak flow meter is relatively inexpensive, portable and easy to use. The most sensitive method is rhinomanometry and is specific for nasal measurements. However, rhinomanometer is relatively expensive, requires technician training and patient co-operation and hence, can be conducted only in the clinics. Acoustic rhinomanometry is relatively easier for the patients to perform and is quite repeatable. Rhinomanometry: Rhinomanometry measures the pressure and flow of inspired or expired air through the nose and estimates nasal resistance. The measurements can be made for one nostril (anterior rhinomanometry) or both the nostrils (posterior rhinomanometry). Anterior rhinomanometry is relatively easy to perform and is hence most widely used. The pressure sensing tube is placed in one nostril and the other one is left open. The subject then blows through the nose in the rhinomanometer and nasal resistance is measured. It can be repeated after a decongestant spray. If the spray significantly reduces the resistance, that suggests nasal congestion as cause of symptoms. However, if the decongestant does not reduce the resistance, anatomical abnormality like nasal deformity or bone or cartilage within nasal cavity is suspected. |Volume V, Issue III, July-August 2015|RespiMirror 3 Management of Allergic Rhinitis – Does surgery have a role? Prof. Mohan Kameswaran Senior Consultant ENT Surgeon, Madras ENT Research Foundation, Chennai Allergic rhinitis (AR) results from an IgE mediated hypersensitivity reaction of the nasal mucosa to inhaled allergens and represents a global health issue affecting between 10% to 25% of the world population. Allergic rhinitis is characterized by nasal obstruction, watery nasal discharge, itching and sneezing. Additional associated symptoms include headache, impairment of smell and eye irritation. The prevalence of AR is increasing, resulting in multiple co-morbidities, causing a significant impact on quality of life. Management guidelines include avoidance of relevant allergens and triggers (house dust, dust mites, cigarette smoke, air pollution and seasonal pollens), pharmacotherapy such as topical nasal steroids, systemic antihistamines, topical antihistamines, decongestants, leukotriene receptor antagonists and nasal saline formulations. However, in some patients, these medications are not effective or may result in significant side effects. Immunotherapy can be recommended in recalcitrant cases. Pharmacotherapy still remains the mainstay of treatment of AR. Not all patients with moderate/severe allergic rhinitis are controlled despite optimal pharmacotherapy. Many surgical options exist for the treatment of allergic rhinitis, directed primarily at the underlying nasal obstructive component. Surgery does not cure Allergic Rhinitis. Surgical intervention is indicated for complicating conditions such as rhinosinusitis, severe septal deviation, nasal polyps or other anatomical abnormalities. The indication for nasal and sinus surgery should always be based on a lack of effect of adequate drug treatment and the functional and clinical relevance of the anatomical variation or disease. Indications for surgery for allergic rhinitis include pharmacotherapy resistant turbinate hypertrophy, cartilaginous or bony obstruction of the nasal airways (septum, bony pyramid) which can make AR harder to treat, sinonasal polyps, allergic fungal rhinosinusitis, enlarged adenoids and otitis media with effusion. rhinitis. In long-standing allergic rhinitis, a severe drug-resistant hypertrophy of the inferior turbinates may develop, which leads to constant nasal obstruction & watery secretion due to an increase in glandular structures. (Fig. 1) Turbinoplasty induces scar tissue and fibrosis within the submucosal layer, while Inferior Turbinate excellent relief with regards to symptoms of nasal obstruction but less satisfactory in rhinorrhoea. Advances in technology has resulted in new tools which can produce fibrosis and shrinkage of the inferior turbinate while helping preserve mucosa. Laser surgery using CO2 laser, KTP 532 laser, or diode laser is simple and effective surgical treatment that can be used to reduce the size of the swollen nasal turbinate while preserving the surface epithelium and ciliary function. (Fig. 3) Complications of laser treatment are not common, but include crusting, synechiae formation, and bony exposure of nasal structures. Fig.1: Hypertrophied inferior turbinate in AR destroying glandular and vascular structures. The surgical reduction of the inferior turbinate body and mucosal surface, which should always be limited, increases the cross-sectional area of the nasal valve, reduces nasal resistance and increases nasal airflow. Reduction in nasal obstruction and secretions results in significant symptom relief. Traditionally, submucus diathermy of inferior turbinate which involves passing a probe just below the mucosal surface lining of the turbinate bones and cauterizing using heat energy was used to shrink the size of the turbinates. (Fig.2) Cryosurgery to freeze and debulk the hypertrophied inferior turbinates has also been used. Cryosurgery has shown to provide Fig. 3: Laser surgery of the inferior turbinate Radio Frequency ablation (RFA) utilizes a probe that is inserted directly into the inferior turbinate and is used to deliver a low-frequency ionic energy causing shrinkage of the turbinate. Coblation turbinoplasty uses RF energy between electrodes in a saline medium to create a field of ionized sodium molecules capable of ablating turbinate tissue. (Fig.4) Turbinate Hypertrophy This is the commonest indication for surgery in allergic rhinitis. Although no single modality has evolved as the gold standard treatment of allergic rhinitis, the mainstay of surgical intervention targets the inferior turbinate. The inferior turbinate, being the initial deposit point for allergens, has proven to be the most important contributor to nasal obstruction and dynamic compliance of the nasal cavity. This is due to vaso-reactive engorgement of turbinate tissue and associated inflammation of mucosal lining in allergic 4 RespiMirror|Volume V, Issue III, July-August 2015| Fig. 4: Coblation turbinoplasty Fig.2: Submucus diathermy of the inferior turbinate RFA and coblation are well tolerated with minimal adverse effects and coblation in particular, is associated with less pain, which may have expanded implications for the pediatric population. Microdebrider-assisted >>Continued on page 5 >>Continued from page 4 Management of Allergic Rhinitis surgery has demonstrated superior results in improving nasal volume and blockage. Concha Bullosa Concha Bullosa is essentially pneuma tization of the anterior aspect of the middle turbinate. (Fig. 5) Surgical treatment of concha bullosa gives good symptom relief in AR. (Fig.6) (CRS) continue to experience bothersome symptoms despite adequate medical treatment. This group represents a therapeutic challenge. Functional Endoscopic Sinus Surgery allows adequate ventilation and drainage of the involved sinuses. Co-morbid allergy has to be treated with pharmacotherapy in patients with sinusitis. Treatment of the allergy before surgery may improve the success of ESS. Balloon Sinuplasty involves using a balloon catheter device and is another surgical treatment option available for allergic rhinosinusitis. (Fig. 8) This system is based on a flexible catheter and wire technology to restructure the blocked ostium allowing the return of normal sinus drainage and function with little or no disruption of the mucosal lining. (Fig. 9, 10) Fig. 5: Left concha bullosa Fig. 8: Pre-op CT scan showing left maxillary sinusitis in a patient with AR adequate sinus aeration and assist with medical and topical therapies. (Fig. 11) Microde briders which are surgical shaver systems have greatly enhanced the ease of surgical management of polyps. Fig. 11: Microdebrider surgery for nasal polyposis in AR Allergic fungal sinusitis is a cause of chronic sinusitis. It is a noninvasive disease caused by mucosal hypersensitivity directed against fungal antigens deposited on sinus mucosa. (Fig.12) The diagnostic criteria for AFS include the presence of chronic sinusitis usually with chronic mucosal thickening on sinus radiographs, (Fig.13) the presence of “allergic mucin” and fungal hyphae within the allergic mucin with large numbers of eosinophils. A positive fungal culture of the allergic mucin helps to confirm the diagnosis. Management comprises of endoscopic sinus surgery with pharmacotherapy. Complete removal of allergic mucin & fungal debris (antigenic reduction), drainage and ventilation of the sinuses with preservation of underlying mucosa should be achieved. (Fig. 14, 15) Fig.6: Laser surgery for concha bullosa Sinusitis, Sinonasal polyposis and Allergic fungal sinusitis Endoscopic Sinus Surgery (ESS) is of indirect benefit in allergic rhinitis patients who present with concomitant chronic rhinosinusitis (CRS), sinonasal polyposis, or allergic fungal sinusitis. Nasal allergy may cause recurrent sinusitis because of the obstruction to the sinus ostia and sinusitis is the most frequent comorbidity of uncontrolled AR. (Fig. 7) A significant percentage of patients with AR and chronic rhinosinusitis Fig.9: Balloon Sinuplasty device Fig 12: Endoscopic picture of a case of AFRS with polyps and mucin Fig 10: Balloon Sinuplasty – Intra-op Fig.7: CT scans showing sinusitis in a patient with AR Nasal polyps are considered as a chronic inflammatory disease of the sinonasal mucosa, being part of the spectrum of chronic sinus pathology and implicates an IgE type hypersensitivity. The goal of endoscopic sinus surgery is to remove diseased tissue, provide Fig. 13: CT scans in Allergic Fungal Rhinosinusitis. The heterogeneous density is pathognomonic Adenoid hypertrophy Nasal obstruction, secretions or rhinorrhoea become bothersome in children with AR and adenoid hypertrophy. The incidence of >>Continued on page 11 |Volume V, Issue III, July-August 2015|RespiMirror 5 ALLERGIC RHINITIS AND IT’S IMPACT ON ASTHMA Dr. Sitesh Roy Dr Roy Health Solutions Clinic, Mumbai Asthma and allergic rhinitis are both diseases of airway inflammation and often coexist as a spectrum of the same disease entity i.e. one airway hypothesis or united airways disease. Some experts even propose that it is reasonable to consider patients with asthma as a subgroup of the larger population of patients with allergic rhinitis, since allergic rhinitis is highly prevalent in patients with asthma. Allergic rhinitis (AR) is defined clinically by the symptoms caused by immunologically mediated (most often IgE-dependent) inflammation after the exposure of the nasal mucous membranes to offending allergens to which the individual is sensitised. Symptoms of allergic rhinitis include rhinorrhea, nasal obstruction or blockage, nasal itching, sneezing, and postnasal drip that reverse spontaneously or after treatment. Allergic conjunctivitis often accompanies allergic rhinitis. Patients with perennial symptoms of AR, which are often associated with sensitisation to indoor allergens (eg, dust mites, pet dander, fungi/mould), tend to have prominent nasal congestion and posterior nasal drainage, suggesting greater sinus involvement. Patients with asthma are also more likely to have rhinosinusitis, which describes disorders affecting both the nasal passages and paranasal sinuses causing nasal congestion, posterior nasal drainage, facial pressure and pain, headache, fatigue, and reduced sense of smell. Allergic rhinitis was previously classified into seasonal, perennial, and occupational. Perennial allergic rhinitis is usually caused by indoor allergens such as dust mites, moulds/ fungus, insects (cockroaches) and animal dander. Seasonal allergic rhinitis is usually related to a wide variety of outdoor allergens such as tree, grass, weed pollens or moulds/ fungus. However, from a diagnostic and therapeutic point of view, it is often difficult to differentiate between seasonal and perennial symptoms. Some seasonal allergens cause perennial symptoms, while some perennial allergens may cause seasonal symptoms only, and the majority of patients in India are polysensitized to seasonal and perennial allergens. Introduction The incidence of allergic diseases such as allergic rhinitis and asthma are increasing rapidly (allergic rhinitis: 10-40%; and asthma: 5-15%), both in the developed and the developing world, leading to reduced quality of life of the patients, reduced productivity and increasing medical costs. 6 RespiMirror|Volume V, Issue III, July-August 2015| Epidemiologically, up to 40% of patients with allergic rhinitis also have asthma, and up to 80% of patients with asthma experience nasal symptoms. The rising evidence on the links between allergic rhinitis and asthma comes from epidemiological, immunological and clinical studies. Furthermore, patients with allergic rhinitis are at three times the risk of developing asthma compared with those without allergic rhinitis. In children who develop rhinitis within the first year of life, their chances of developing asthma are twice as great as in those who develop rhinitis later in life. There is also a strong link between asthma and bacterial rhinosinusitis, viral upper respiratory infections (acute viral rhinosinusitis), and nasal polyposis seen too. Indeed, rhinitis frequently precedes asthma in the atopic march, and treating allergic rhinitis with pharmacotherapy and immunotherapy has beneficial effects on asthma control, suggesting that upper airway disease is closely linked to and a risk factor for asthma. The WHO Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines suggested the currently accepted classification for allergic rhinitis as mild or moderate-severe and as intermittent or persistent to mirror the now well-accepted longer standing classification of asthma as intermittent, mild, moderate or severe as per several international guidelines. Pathophysiological Links between Allergic Rhinitis and Asthma Interestingly, anatomically the respiratory epithelium is substantially the same from the nasal passage to the bronchioles. Also, the nose and the bronchi share the same adrenergic and cholinergic innervations. Both AR and asthma cause airflow limitation as a key feature. Bronchial inflammation evidenced by increased eosinophils and increased basement membrane thickness has been seen in patients with isolated allergic rhinitis compared to healthy controls. Allergic rhinitis patients without asthma, who underwent bronchoprovocation challenges in and out of their sensitised pollen seasons, had a significant lower PC20 values i.e. greater bronchial hyperreactivity noted in-season compared to out-of-season suggesting a link between upper and lower airway inflammation and reactivity. Similarly, the inflammatory cell counts in the bronchi of these isolated allergic rhinitis patients was greater in pollen season vs. out-of-season. Allergic rhinitis patients also tend to show greater forced expiratory value in 1st second (FEV1) rise after bronchodilator therapy compared to healthy controls, which is a feature typically seen in asthma patients. Two-thirds of allergic rhinitis patients in one study demonstrated >12% increase in FEV1 after bronchodilator therapy without having a pre-existing diagnosis of asthma. Epidemiological Links for Allergic Rhinitis with Asthma Individuals with AR have a 3-fold risk of developing asthma in the future. On the basis of the WHO ARIA classification, a retrospective study in 9 countries showed that intermittent rhinitis was observed in less than 20% of patients, whereas patients with persistent rhinitis comprised approximately 80%. Although 25-30% of allergic rhinitis patients had mild allergic rhinitis, 60-70% had moderate-severe rhinitis. Furthermore, approximately 40-60% of allergic rhinitis patients had co-existent asthma, and their asthma symptoms worsened in their allergy season. In the Tasmanian Asthma Study, childhood allergic rhinitis raised the consequent risk of developing asthma between 7-12 years of age by 7-fold, between12-20 years of age by 4-fold and between 20-44 years of age by 2 fold compared to non-allergic children. An international survey called the ‘One Airway Survey’ carried out in four Asian countries in patients or parents of patients, a significant proportion of the patients reported that having allergic rhinitis with asthma had a negative effect on their ability to enjoy social activities (64%) and eight out of 10 patients felt a disruption in daily activities including their ability to get a good night’s sleep (84%), participation in leisure and sports activities (81%), and concentration at work or school (80%). Thus the personal and social impact of these two epidemiologically linked entities together is really significant. Immunological Links for Allergic Rhinitis with Asthma Both allergic rhinitis and asthma are inflammatory respiratory diseases, and their inflammatory mechanisms are similar in that they are characterized by an inflammatory infiltrate made up of eosinophils, T-cells, and mast cells that release several mediators, chemokines and cytokines, local and systemic specific IgE synthesis, and a systemic link via the bone marrow. A typical early phase >>Continued on page 7 >>Continued from page 6 ALLERGIC RHINITIS AND IT’S IMPACT and late phase response are also common to both rhinitis and asthma. Several studies have shown that patients with allergic rhinitis exhibit bronchial hyperresponsiveness and an increase in inflammatory cells in the lower airway, and that nasal allergen challenge further increases this hyperreactivity. Similarly, isolated segmental bronchial allergen challenges have been demonstrated to increase nasal inflammatory markers within hours suggesting an immunological cross-talk that is intrinsically built into our upper and lower airways. Eosinophils have been demonstrated in the nasal mucosa of patients with asthma, even in the absence of symptoms of rhinitis. In addition, patients with allergic rhinitis have increased numbers of inflammatory cells in their bronchial mucosa. Also, in patients with severe asthma, sinus mucosal thickening on computed tomography correlates with the severity of lower airway disease indicated by sputum eosinophilia, exhaled nitrous oxide, functional residual capacity, and diffusing capacity. Therapeutic links for Allergic Rhinitis with Asthma The therapeutic outcomes of treating allergic rhinitis on asthma has shown that allergic rhinitis treatment improves asthma symptoms and lowers the overall costs and even reduces emergency room visit and hospitalizations. This parallel relationship is influenced by many interactions between the upper and the lower airways. One such interaction is based on the fact that the nasal passages play a major homeostatic role by conditioning inhaled air, but other and perhaps even more important is the bidirectional cross-talk that results from the systemic inflammation that is produced after local allergic reactions in the upper or lower airways. Even in the 1900’s ENT surgeons noted improvement in asthma control after nasal and sinus surgery in selected patients. As allergic rhinitis severity increases in those patients with co-morbid asthma, the severity of asthma also is found to increase. Difficult to control asthma might be associated with moderate to severe allergic rhinitis in some cases too. Several therapeutic strategies that can treat both rhinitis and asthma are either available in the market today or are in development. Among them are leukotriene receptor antagonists (LTRAs), anti-IgE monoclonal antibodies (omalizumab), immunotherapy, DNA vaccines, anti-IL-4R, anti-IL-5, anti-VLA-4, anti-CCR antibodies. The IgE antibody plays a central role in allergic immune responses. Recent studies have also shown the local production of IgE in allergic airway diseases. Targeting IgE is therefore an important strategy in the treatment of allergic diseases. Omalizumab (a humanized monoclonal antibody) has the ability to Mechanisms by which Allergic rhinitis may lead to Asthma 1. Vagal reflex/rhinobronchial reflex 2. Per continuum passage of allergic inflammation from the nose to the bronchi 3. Irritant mechanis caused by postnasal drip 4.The oral respiration caused by nasal obstruction, which promotes bronchial hyperresponsiveness as dry and cold air penetrates into the bronchi 5. The systemic release of mediators and cytokines involving even the bone marrow. reduce circulating IgE and represents a unique therapeutic approach for the treatment of IgE-mediated allergic diseases. The anti-IgE monoclonal antibody (omalizumab) has demonstrated efficacy in attenuating both the early and late-phase bronchial responses to inhaled aeroallergens. Therapy with omalizumab reduces the frequency of asthma exacerbations and the need for inhaled corticosteroids (ICS), improves asthma symptoms, lung function, and quality of life but also simultaneously for those patients with allergic rhinitis too, their nasal and ocular symptoms are also significantly reduced, and their quality of life is significantly improved. Anti-IgE therapy for concomitant upper and lower airway allergic diseases by targeting a central common component driving the allergic inflammatory response is another proof of concept for the “one airway hypothesis”.Cysteinyl leukotrienes are important mediators in the pathophysiology of both asthma and allergic rhinitis, released in both the early and late phase of the allergic reaction, further linking the ‘one airway’ concept of upper and lower airway disease. LTRAs, which block the actions of cysteinyl leukotrienes, have proved to be effective and well tolerated therapies in the treatment of asthma and allergic rhinitis.Both histamine and cysteinyl leukotrienes are elevated in the nasal secretions of patients with allergic rhinitis. Histamine induces several of the responses that typify allergic rhinitis (e.g. itching and sneezing), but other mediators such as cysteinyl leukotrienes are manifold more potent than histamine in causing nasal congestion. Both newer generation nonsedating anti-histamines and anti-leukotriene therapies have been shown to have beneficial effects on both allergic rhinitis and asthma symptoms. In a study by Price et al. in patients with asthma and co-morbid allergic rhinitis, the use of montelukast with budesonide as a combination therapy was shown to be superior to doubling the dose of budesonide, both with or without the use of concomitant allergic rhinitis medications. Nasal steroids have been shown to reduce the bronchial hyperresponsiveness of asthma patients with seasonal allergic rhinitis. In another case-control study evaluating data on the risk of emergency room visits or hospitalisations for asthma, those patients who were on intranasal corticosteroids for their AR, had a significantly reduced risk for both the above mentioned outcomes. Therapeutic strategies such as LTRAs or LTRAs plus non-sedating anti-histamines, represent a good option of therapy for the considerable numbers of patients with mild asthma and coexisting allergic rhinitis by increasing patient compliance and improving the quality of life. Immunotherapy and its impact on Allergic rhinitis and Asthma Allergen exposure in clinically relevant sensitised cases is a known trigger for both allergic rhinitis and asthma symptoms. Those patients with concomitant AR and asthma show significant improvement in symptoms, medication scores, and reduced exacerbations for both conditions after appropriate AIT. Carefully selected, 3-5 years of allergen immunotherapy (AIT) designed to de-sensitise the patient to their major clinically relevant aeroallergens is a wellestablished efficacious therapy for such patients. Indeed timely allergen immunotherapy utilising standardized, reliable aeroallergen extracts either sublingually or subcutaneously can prevent the future development of asthma in several paediatric studies. Conclusions Much of the above epidemiological, pathophysiological, immunological and therapeutic evidences linking allergic rhinitis and asthma in a variety of indisputable ways have been summarised wonderfully by the World Health Organization initiative Allergic Rhinitis and its Impact on Asthma (ARIA). Evaluating every patient with allergic rhinitis for clinical or subclinical asthma via careful history, spirometry and other investigative tools as well as evaluating every patient with asthma for evidence of allergen sensitisation with prick skin testing or blood tests for specific IgE towards selected aeroallergens would indeed be worthwhile and highly recommended given the strength of current clinical data relating these two conditions. Thus, optimally comanaging allergic rhinitis and asthma, when present in the same patient together using allergen avoidance, pharmacotherapy and immunotherapy ultimately leads to the best clinical outcomes for our patients. |Volume V, Issue III, July-August 2015|RespiMirror 7 Allergen Specific Immunotherapy for Allergic Rhinitis M T Krishna Consultant Allergist and Immunologist and Honorary Reader in Medicine Heart of England NHS Foundation Trust Birmingham, UK Dr. Anjali Ekbote Consultant Immunologist, Background Allergic rhinitis (AR) is defined as presence of at least two nasal symptoms (rhinorrhoea, itching, sneezing or blockage) associated with an IgE mediated immune response to common aero-allergens such as pollens, house dust mite, animal dander and rarely moulds. Allergic rhinitis is the most common form of non-infectious rhinitis and is usually associated with conjunctivitis, i.e., allergic rhinoconjunctivitis (ARC). The incidenceof AR/ARC has been steadily increasing since the 19th century and is estimated to affect 500 million individuals worldwide. Whilst the physical symptoms of AR are well recognised, its impact on health related quality of life (HRQoL) is often underestimated. Diagnosis of AR involves obtaining a detailed clinical history in conjunction with demonstration of sensitisation to relevant allergen(s) by skin prick testing and/or serum specific IgE. First line treatment for AR/ARC involves a combination of H1-receptor antagonists(oral and/or intranasal), intranasal corticosteroids, leukotriene receptor antagonists and cromones (nasal and ocular). Whilst most patients show a good therapeutic response, some benefit only partially. A common cause of treatment failure is poor compliance and/or suboptimal nasal spray technique. The Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines defined allergen specific immunotherapy (AIT) as “the practice of administering gradually increasing quantities of an allergen extract to an allergic subject to ameliorate the symptoms associated with the subsequent exposure to the causative allergen”. Allergen specific immunotherapy modulates the immunological response to an allergen from an atopic T-helper 2 (Th2) state to a tolerant T-helper 1 (Th1) or T-regulatory (Treg) response thereby providing lasting benefit. Historical perspective The allergy community worldwide celebrated 100 years of AIT in 2011. In 1911, Noon and his colleague Freeman from St. Mary’s Hospital, London, UK described a therapeutic process recognisable today as AIT. Briefly, they reported that in subjects with symptoms suggestive of grass pollen-related AR/ARC, sensitisation was demonstrable by conjunctival exposure to pollen extract. Following subcutaneous (SC) injections of grass pollen extract (referred to as pollen toxin in 1911) administered at incremental doses over an initial (short interval between doses) and 8 RespiMirror|Volume V, Issue III, July-August 2015| maintenance (longer interval between doses) phase, subjects experienced clinical benefit. Whilst the basic principles underpinning AIT remains the unchanged after a century, current vaccines are superior in terms of their standardisation and immunogenicity with several preparations available via the subcutaneous (SC) and increasingly, sublingual (SL) routes. Considerable evidence demonstrating the efficacy and safety of these modalities are available. Current practice Patient selection criteria Robust patient selection criteria are critical to the success of AIT. Candidates for treatment display symptoms of AR which are consistently attributable to allergen exposure. Investigation to confirm IgE sensitisation to the causative allergen is required. However, a positive test alone does not make the diagnosis of an allergy. Challenge testing can be used to demonstrate an allergy but is impractical and seldom used in routine clinical practice. AIT is absolutely contraindicated in patients with moderate-severe asthma and brittle asthma. It should not be initiated in patients with significant cardiac (e.g. ischaemic heart disease, cardiac failure) or chronic respiratory disease with poor respiratory reserve. Betablockers and ACE-inhibitors should be discontinued prior to commencement of AIT. It should not be initiated in pregnancy, although can be continued after a careful risk-benefit analysis provided treatment has been well tolerated and in maintenance phase. However, the general consensus is to discontinue therapy as far as possible in view of the rare but real possibility of anaphylaxis that may potentially compromise the wellbeing of the foetus. Systemic autoimmune conditions, immunodeficiency and concurrent immunosuppressive or immunomodulatory therapy are relative contraindications and each patient is assessed on individual merits. In the UK, patients selected for AIT typically have markedly impaired HRQoL due to AR/ ARC with a sub-optimal response or those In patients with co-existent mild asthma and rhinitis, adequate control of asthma must be documented by spirometry and diary record of stable peak expiratory flow rate (PEFR) prior to enrolment into the AIT. who have experienced an adverse reaction to first line agent(s) (H1-antihistamines, intranasal corticosteroids, leukotriene receptor antagonists). In contrast, AIT may be offered to patients with relatively milder symptoms in other parts of the world. There is some evidence in the literature that early use of AIT in patients with house dust mite related-AR (monosensitised) reduces the risk of progression to asthma and onset of newer sensitisation(s). This requires further confirmation in larger clinical trials. Patient selection criteria are identical regardless of the AIT product employed. Choice of treatments Allergen specific immunotherapy preparations used in the UK are standardised for allergen content. Preparations may utilise adjuvants, for example aluminium hydroxide is used in some SC preparations to delay the release of allergen and enhance immunogenicity. Other preparations may use modified allergens (termed “allergoids”) which are less allergenic but maintain their immunogenicity thereby theoretically reducing the risk of systemic reactions.Whilst single AIT is used in the UK, multiple allergen mixes are employed in the USA based on the patient’s sensitisation profile. However, evidence for the use of multi-allergen mixesis lacking at the present time.The two main modalities of AIT employed in routine clinical practice are subcutaneous injection immunotherapy and sublingual immunotherapy as described in the following sections. Subcutaneous Immunotherapy (SCIT) Standard SCIT protocols involve administration of gradually increasing doses of standardised allergen extract, usually administered once a week until the target maintenance dose is reached. The conventional protocol involves a 12 week up dosing protocol (induction phase). The maintenance dose is then continued at 4-6 weekly intervals for 3-5 years. Accelerated induction protocols have been described -“clustered”(7 weeks) or “rush”(2-4 days) or “ultra-rush”(24 hrs) have been employed, although the latter two are associated with higher rate of systemic allergic reactions. Dose modifications may be required for missed injections, following large local or systemic reactions and during pollen season. All SCIT treatments are administered in a hospital out-patients department setting. >>Continued on page 9 Dr. Monica Barne Chest Research Foundation, Pune How to use The Nasal Spray WHILE USING THE NASAL SPRAY Using an INCS Spray: 1. Blow your nose until your nostrils are clear. 2. Shake the bottle gently and remove the dust cover. 3. Hold the bottle firmly with your forefinger and middle finger on either side of the spray tip while supporting the base of the bottle with your thumb. 4. Hold one nostril closed with your index finger. 5. Lean your head slightly forward and carefully put the tip of the nasal applicator into your open nostril keeping the bottle upright. 1. If you are using the pump for the first time, point the bottle away from your body and press down and release the pump eight times. If you have used the pump before but not within the last 4 days, press down and release the pump one time or until you see a fine spray. Caution The nozzle should not be pointed medially towards the nasal septum as this may damage the Little’s area and cause epistaxis. The nozzle should be pointed slightly laterally. >>Continued from page 8 Allergen Specific Immunotherapy Pre-SCIT injection checks include questions relating to general health, adverse events, changes in medication and PEFR. Patients are monitored for an hour post-injection, although delayed systemic reactions may rarely occur. Common adverse reactions to SCIT are swelling and itching at the ingestion site and fatigue. Less commonly systemic reactions ranging from rhinitis symptoms to anaphylaxis may also occur. Long term efficacy up to 8-10 years following a 3 year course of treatment has been reported in SCIT clinical trials for grass pollen-related hay fever. Sublingual Immunotherapy (SLIT) Sublingual immunotherapy is available as tablets (no up-dosing needed) and liquid formulations (up-dosing is required). In contrast to SCIT, SLIT is initiated under medical supervision in the hospital setting but continued daily by patients at home. Regular 3-6 monthly follow-up in clinic helps to ensure compliance with treatment, advice regarding adverse events and dose adjustments if required. Side effects include short-lived local itching, irritation and swelling affecting oropharyngeal mucosa. These reactions typically reduce as patients become accustomed to treatment. Less commonly heart burn, abdominal discomfort, diarrhoea and systemic reactions have been reported in clinical trials. The optimal treatment duration in the UK is three years. Recent studies have shown long term efficacy with SLIT to grass pollen with patients maintaining clinical benefit and 6. Begin to breathe through your nose. 7. While you are breathing in, use your forefinger and middle finger to press quickly and firmly down on the applicator and release a spray. Continue to breathe in. 8.Breathe out through your mouth. 9. Repeat steps 4-8 for the other nostril. 10.If you are advised to take two squirts repeat steps from 4-8. 11.Wipe the applicator tip with a clean tissue and replace the dust cover. Image Courtesy : Cipla sustained immunological responses at year 5 following a 3 year course of treatment. Further data from long term follow up are awaited. Practical aspects Allergen specific immunotherapy must only be undertaken by specialists with adequate knowledge and experience in this field. Due to the risk of an immediate systemic allergic reaction including anaphylaxis, particularly with SCIT, treatment should only be administered in centres where facilities for cardiopulmonary resuscitation are readily available. Accelerated protocols are seldom indicated for AR, but if undertaken, should be administered in a high dependency unit setting. Following SCIT injection (or initial SLIT treatment), patients must be monitored for 60 minutes. Previous surveys have shown that common causes of near fatal or fatal anaphylaxis during SCIT are related to misidentification of the patient, administration of the incorrect allergen, dosage errors and poorly controlled asthma. However, with robust patient selection criteria and stringent standard operating protocols AIT remains a safe treatment. There no reliable biomarkers that can accurately predict treatment response. Efficacy is evaluated in routine clinical practice using HRQoL questionnaires pre and post AIT. Allergen challenges are employed in a research setting and these have shown that AIT induces higher threshold for clinical reactivity and reduces the area under the curve for early and late phase allergic responses. Future directions Clinical trials involving new products and novel routes of administration to improve tolerability and efficacy of AIT are underway. Allergoids or allergenic epitopes recognised by T cells may be utilised to enhance Th1 reactivity. Recombinant allergens also hold promise for the future. New adjuvants such as bacterial DNA and monophosphoryl lipid A (MPL) enhance immunogenicity by potentiating the Th1 response A recent study has shown that an intralymphatic route of administration of grass pollen extract is an effective and safe modality of treatment for patients with seasonal allergic rhinitis. There is also interest in intradermal and epicutaneous routes of administration of allergen but these need confirmation in large randomised control trials (RCT). Concurrent administration of monoclonal anti-IgE antibody (omalizumab) with SCIT has shown to enhance efficacy and safety and this also requires large RCTs for confirmation and investigation into health economics. Summary statement In conclusion, AIT is a safe and effective treatment for AR/ARC and alters the natural course of the disease. It is a relatively expensive and time consuming treatment and currently offered only to patients with moderate-severe disease not showing adequate therapeutic response to first line pharmacotherapy. It is likely that newer immunomodulatory therapies will be available over the next decade for treatment of AR/ARC. |Volume V, Issue III, July-August 2015|RespiMirror 9 ADVANCES IN ALLERGIC RHINITIS Dr. Mahesh PA, Professor, Department of Pulmonary Medicine, JSS Medical College & University, Mysore Epidemiology Allergic Rhinitis is a very common disease affecting a large proportion of patients across the globe (10-30%) and is associated with severe impairment of quality of Life. In the US, it is the most common chronic condition in children and in the top 6 chronic conditions in adulthood. The cost of allergic rhinitis runs into billions of dollars in direct and indirect health care costs. The prevalence of allergic rhinitis continues to increase in most countries in the world. Allergic rhinitis can be classified as seasonal or perennial, with symptoms being intermittent or persistent. Intermittent allergic rhinitis is said to be present when the frequency of the symptoms are <4 days/ week or <4 weeks/year. Persistent Allergic rhinitis is said to be present when the frequency of >4 days/week and >4 weeks /year. Another term has been introduced recently as Episodic allergic rhinitis when the symptoms can occur due to an individual’s exposure to an environment that is not normally part of his environment; example, exposed to a cat in a friend’s house. Rhinitis is said to be mild when it has not affected the sleep and the quality of life of the patient or moderatesevere when these are affected. Recent advances in pathogenesis Role of Dendritic Cells: Dendritic cells along with the nasal epithelial cells are critical players in the regulation of the immune system in the nasal mucosa of patients with allergic rhinitis. The Dendritic Cells and the Epithelial cells have receptors called the pathogen recognition receptors (PRR’s) that recognize the various Pathogen Associated Molecular Patterns (PAMP’s). At the time of the allergic inflammation, Dendritic cells would be activated by various cytokines such as Thymic Stromal Lymphopoietin(TSLP), IL-1 and IL-33. Once epithelial DCs are triggered, they are activated and migrate to the draining lymph node via lymphatics, controlled by CCR7. Activated DC’s respond to various allergens as well as bacterial products such as Staphylococcal super antigens. Role of IL-33: Recently, studies have demonstrated the role of cytokines such as IL33 in allergic inflammation. IL-33 is a nuclear cytokine, which is expressed normally during homeostasis but is not found extracellulary in significant quantities. During tissue damage such as an allergic reaction, these are released and are potent mediators and immune stimulators of the Th2 cells leading to large productions of IL-5 and IL-13, important mediators of allergic inflammation. IL-33 is very important in allergic rhinitis as evidenced by studies on IL-33 deficient mice. Role of IL-32: A recent addition to the cytokines that are important for allergic 10 RespiMirror|Volume V, Issue III, July-August 2015| ARIA Guidelines : Recommendations for Management of Allergic Rhinitis Mild intermittent Moderate severe intermittent Mild persistent Moderate severe persistent Intra-nasal steriod Local cromone Leukotriene receptor antagonists Second-generation nonsedating H1 antihistamine Intranasal decongestant (<10 days) or oral decongestant Allergen and irritant avoidance Immunotherapy rhinitis is the IL-32, a cytokine produced by immune cells, such as T lymphocytes, natural killer cells, epithelial cells, mast cells, keratinocytes, eosinophils. IL-32 contributes to pro-inflammatory cytokine synthesis and is involved in several inflammatory pathways such as phosphatidylinositide 3-kinase (PI3K)/Akt pathway, nuclear factor (NF)-κB/AP-1 pathway, p38 mitogen-activated protein kinase (MAPK) and caspase-1 pathways. Role of TSLP: TSLP is an important regulator of innate and adaptive immune responses associated with the Th2 cytokine-mediated inflammation, such as Allergic Rhinitis. IL-32 has been shown to significantly increase TSLP production from monocytes. TSLP is expressed in epithelial cells, fibroblasts, endothelial cells and smooth muscle cells at nasal mucosa. TSLP is also expressed in activated mast cells and TSLP from filaggrin deficient keratinocytes in patients with atopic dermatitis (AD) is critical for the progression of AD to Allergic Rhinitis and Asthma. Role of Caspase 1 pathway: Caspase-1 is critical for innate immunity and plays an important role in several important inflammatory diseases. Activation of Caspase-1 pathway is associated withnasal inflammation in mouse models of AR with an increase in IL-1β, IL-18, histamine and IgE. Important inflammatory regulators such as IL-32 and TSLP are increased by the activation of caspase-1 which also promotes COX-2-dependent inflammation. Clinical features Clinicians should consider a diagnosis of Allergic rhinitis, when patients present with a history and clinical examination that is consistent with an allergy and one or more of the symptoms associated with allergic rhinitis: nasal congestion, runny nose, itchy nose, or sneezing. Findings of AR consistent with an allergic cause include, but are not limited to, clear rhinorrhea, nasal congestion, pale discoloration of the nasal mucosa, and red and watery eyes. Diagnosis: Role of Allergy testing: Allergy testing is recommended by the guidelines to identify the causative allergen and to plan specific avoidance measures. These data also helps to plan for immunotherapy in selected patients who are unable to avoid these allergens. Role of Regular Sinonasal Imaging: Regular CT scans are not recommended for all patients with allergic rhinitis alone. Role of Nasal Smears: Demonstration of high eosinophilia in the nasal smears in the absence of atopy can suggest Non-allergic rhinitis with eosinophilia syndrome (NARES). Management Pharmacotherapy: Inhaled nasal steroids form the cornerstone of the management of allergic rhinitis especially moderate-severe persistent allergic rhinitis. The myth that long-term use of intra-nasal corticoids (INCS) can lead to mucosal atrophy was evaluated in a systematic review, which concluded that there is no evidence of mucosal atrophy on long-term use of INCS. It may be useful to use intranasal saline douching which will help to remove the mucus and inflammatory secretions and help in the absorption of INCS and thus improve efficacy. In symptomatic patients use of second generation non-sedating antihistamines are recommended. Clinicians may offer intranasal anti-histamines such as azelastine for patients with allergic rhinitis. Clinicians should not offer leukotriene receptor antagonists >>Continued on page 11 >>Continued from page 10 ADVANCES IN ALLERGIC RHINITIS as a first line therapy for patients with allergic rhinitis. Combinations of different pharmacotherapeutic agents can be given to patients who do not respond to monotherapy. Decongestants should not be used for children less than 4 years. Allergy Avoidance: Environmental avoidance measures such as removal of carpets from the living room and bedroom, removal of pets that the patient is sensitized to, exposure to strong sun for at least 3 hours twice a week for reduction of dust mites in the bedding, pillow and blankets, house dust mite allergen barrier bed and pillow covers and air filtration systems are recommended. Though many studies have demonstrated a reduction in levels of allergens, studies that have evaluated the correlation of reduced allergen levels to reduced symptoms clinically are limited. It would probably be useful to use more than one environmental control measures for added benefit. It is also advisable to avoid mosquito coils and burning of incense sticks at home. Immunotherapy: Patients who do not respond adequately to pharmacotherapy with or without environmental controls should be referred for immunotherapy either subcutaneous or sublingual. There is a large body of evidence in the form of Randomized Control Trials for both subcutaneous and sublingual immunotherapy in the management of allergic rhinitis and is given a Grade Level ‘A’. The various benefits include an altered natural history of allergic rhinitis and prevention of progression, better symptom control, reduced need for pharmacotherapy, improves asthma and even prevents asthma or other comorbidities in a significant proportion of patients, and may prevent new sensitizations to other aeroallergens. Cost-effective analysis has confirmed long-term benefits in costs on use of immunotherapy. Some of the problems associated with use of subcutaneous immunotherapy include pain at site of injection, local reactions, rarely systemic reactions are noted and there is an increased frequency of visits to the clinic/hospital for injections and an increased initial cost. Most of these are addressed by the use of Sublingual immunotherapy, which is approved by the WHO for home use. Surgery: Surgical reduction of the inferior turbinates’ in patients with allergic rhinitis who have nasal obstruction that is not responding to medical therapy is recommended. Surgery has been shown to improve nasal airflow, quality of life, better sleep and reduced medicine requirement and better reach of the medicines into the nose after the surgery. Advances in Pharmacotherapy There is a need for newer drugs in the management of the allergic rhinitis. The current armamentarium is sufficient in the management of most cases with mild and intermittent allergic rhinitis but is insufficient to manage severe persistent rhinitis or refractory rhinitis. Studies have continued on improving the delivery and optimizing the dose of intranasal steroids. The ideal dose of beclomethasone has been identified as 320 microgram/day. A newer formulation of ciclesonide dry powder nasal inhaler has been approved in the USA. Ciclesonide is a pro-drug that is activated by local esterases. The other prodrug that is studied to have equal efficacy to other inhaled steroids is rofleponidepalmitate. Antihistamines currently in development include H3 receptor antagonists such as JNJ-39220675 and H4 receptor antagonists GSK835726 and H1/ H3 receptor antagonists GSK835726. Another >>Continued on page 12 >>Continued from page 5 Management of Allergic Rhinitis Fig. 16: Adenoid hypertrophy Fig. 14: AFRS - Endoscopic sinus surgery Fig. 18: Grommet in a patient with OME & AR may be a useful adjunct when combined with other procedures, such as turbinate reduction or endoscopic surgery. Conclusion Fig. 17: Coblation Adenoidectomy Fig. 15: Post-op endoscopic picture in AFRS adult adenoid hypertrophy is increasing because of allergy. (Fig. 16) Surgery is indicated in adenoids causing significant embarrassment to the airway. (Fig. 17) Otitis media with effusion (OME) Observed prevalence of allergic rhinitis in patients with chronic or recurrent OME ranges from 24% to 89%. OME not responding to medical management may require myringotomy and insertion of ventilation tube. (Fig. 18) Deviated Nasal Septum Anatomic deformities of the nasal septum, such as bony spurs or cartilaginous deviation, may affect laminar airflow and worsen subjective nasal obstruction in allergic rhinitis patients. Septoplasty may help in reducing nasal obstructive complaints. Septoplasty Allergic rhinitis can develop into chronic rhinosinusitis or have associated complications, such as nasal polyps, chronic sinusitis or middle-ear disease. When allergen avoidance and pharmacotherapy fail to control symptoms, surgical intervention can be considered. Although there is no gold standard surgical treatment for allergic rhinitis, advancements in technology and surgical technique have made surgery safer and more effective. The mainstay of surgery in AR is the conservative reduction of the inferior turbinate. Septoplasty and endoscopic sinus surgery alone have little role in the treatment of allergic rhinitis, but may be useful adjuncts when fixed anatomic deformities, chronic rhinosinusitis, or sinonasal polyposis are present. An understanding of the underlying pathophysiology of allergic rhinitis is crucial and a tailored approach is needed for each individual patient. |Volume V, Issue III, July-August 2015|RespiMirror 11 >>Continued from page 11 ADVANCES IN ALLERGIC RHINITIS molecule under investigation is the R926112, which is a mast cell inhibitor that prevents release of histamine from mast cells and could be useful in the management of allergic rhinitis. Some of the most exciting work in newer drugs in Allergic Rhinitis is in the development of Toll-like receptor (TLR) agonists. The TLR’s are present on the innate immune cells and recognize various Pathogen Associated Molecular Patterns (PAMP’s). TLR-4 recognizes bacterial lipopolysaccharides such as endotoxin, TLR-7 recognizes viral single strand DNA and TLR-9 recognizes bacterial DNA. Various TLR agonists are shown to be useful in the treatment of allergic rhinitis. Already in clinical trials are TLR-4 agonists called CRX675, which is used as an intranasal aqueous preparation that can stimulate a Th1 immune response. Studies are also being evaluated with intranasal AZD8848, a TLR-7 agonist that is likely to be useful in managing allergic rhinitis by changing the immune balance towards Th1 from the Th2 immune profiles. A TLR-8 agonist, VTX-1463, is being evaluated in a randomized double blind placebo controlled trial via intra-nasal route and found to be clinically effective in reducing nasal symptom scores. VTX – 1463 is a potent drug that reduces the nasal inflammation by regulating monocytes, macrophages and myeloid dendritic cells. In patients with perennial allergic rhinitis, CYT003-QbG10, a TLR-9 agonist is used via injections, once a week for 6 weeks and was found to reduce nasal symptom scores and was found to be safe and well tolerated.Other inflammatory mediators are also responsible for the inflammation in allergic rhinitis. The CRTH2 is a receptor present on the Th2 cells, basophils and eosinophils and is stimulated by PGD2. CRTH2 antagonist, BI 671800 has been used as a oral tablet at 200 mg twice daily and has been found to be clinically useful. Another 5 CRTH2 antagonists are being evaluated at present. Phosphoinositide 3-kinase (PI3K) is a key enzyme in the signaling pathway in the intracellular environment in various inflammatory cells such as T and B-lymphocytes. It is important in cell survival, response to stimuli such as antigens and proliferation. The PI3K isoforms are of 4 classes; PI3K a, PI3K b, PI3K g and PI3K l. P110d, the isoform of PI3K l is an important regulator of immune function. An oral P110d antagonist has been tested in clinical trials and could be useful in the management of allergic rhinitis. Advances in Immunotherapy Subcutaneous (SCIT): One of the key important advances is the use of recombinant allergens, which have been already produced for house dust mites and a few pollens. They have prepared whole allergens, which mimic the exact wild type allergen, or only modified allergenic epitopes that have higher immune-stimulatory effects but reduced chance of eliciting a clinical allergic reaction. Peptide fragment of allergenic proteins 13-17 amino acids in length, either alone or as a fusion protein attached to an unrelated non-allergenic carriers have been developed and are under investigation for improved safety and efficacy as compared to conventional immunotherapy. Sublingual (SLIT): A large number of studies have been conducted on the role of sublingual immunotherapy for clinical use. The newer forms include Dissolvable sublingual tablets (SLIT- tablet), sublingual aqueous allergen extracts (SLIT-aqueous) and enteric microencapsulated preparations. Intralymphatic: The other novel route being studied is the intralymphatic route where the antigen solutions are directly injected into the lymph nodes. In both SCIT and SLIT the processing of the antigens happens at the draining lymph nodes. This route needs almost 1000 times less antigens than SCIT and less frequent injections and has been shown to have the same efficacy as SCIT with less adverse events. More studies are required before a final conclusion can be drawn. Epicutaneous: This is recently being investigated and involves the regular applications of antigens in a base of petroleum jelly as a patch to the skin. This is probably safer than SCIT but needs a large number of studies before any conclusion can be drawn. Advances in Biologic therapy Some studies are being conducted in subjects with refractory allergic rhinitis to evaluate the response to various biologic therapies that have been found to be useful in the management of asthma. Omalizumab, in the same dose as is used in the management of asthma has been found to be useful. A IL-13 monoclonal antibody QAX576, important in propagating the Th2 pathway has been studied. Imatinib, a drug used in the management of leukemia has been evaluated in the management of allergic rhinitis. Its main action is on c-kit an antigen on the surface of the dendritic cells that is related to the activation of the T cells. By inhibiting this c-kit axis, inflammation mediated by both Th2 and Th17 can be controlled. - CRF’s training programmes - - To read the previous issues of Respimirror visit www.crfindia.com - Chest Research Foundation Marigold Premises, Survey No 15, Kalyaninagar, Pune 411014, Maharashtra, INDIA. Phone: +91 20 27035361/66208053 Fax: : +91 20 27035371. Website: www.crfindia.com For your feedback / queries write to [email protected] Do you want to conduct a training programme in your city? Please write to Ms. Simi Raghavan at [email protected] NOTE : FOR PRIVATE CIRCULATION ONLY. Edited by : Ms. Simi Raghavan Published by : Chest Research Foundation, Pune n Printed by : Bookmark I Print Division, Pune 12 RespiMirror|Volume V, Issue III, July-August 2015|