Rhinosinusitis

Introduction

RS affects about 31 million subjects in the US per year and is about midway between rhinitis and asthma in frequency. The annual costs are about the same as for asthma, making RS one of the 10 most costly conditions. The underlying causes of RS are shown in Table 1. Allergic rhinitis and non-allergic rhinopathy are the most common underlying causes, but anatomical abnormalities, sensitivity to nonsteroidal anti-inflammatory drugs (NSAID’s) and immune deficiencies are also frequently found.

Symptoms and Severity 

The most common symptoms of acute and chronic RS are shown in Table 5. Patients complaining about these symptoms who are found to have purulent drainage in the nasal cavities or pharynx should be considered as possibly having RS. In most cases, a good history and physical examination, possibly including a rhinoscopic examination, leads the discerning physician to consider RS and initiate empiric treatment. A Computerized Tomography (CT) scan of the sinuses is the “gold standard” for confirming the diagnosis of RS.

The evaluation of RS is quite similar to the approach taken for rhinitis: determining whether the symptoms are acute or chronic; whether the disease involves the nose alone or both the nose and sinuses; whether the patient is allergic or not; whether there is an active infection or an on-going immune inflammatory response; whether to treat empirically or to take cultures from the nose, perform rhinoscopy, order a CT scan, do an immune evaluation, or consult with a surgeon about the need for sinus surgery. These complex evaluations are standard for allergists/ immunologists and are the type of analytic decisions for which the allergist is specifically trained.

Therapeutic Considerations

 If the conclusion is that the patient does have chronic or recurrent RS, the overwhelming majority of patients do very well with careful medical management. The principles of management include medically reducing swelling in the nose, sinus irrigation, topical corticosteroids in the nose and sinuses, appropriate antibiotics, and careful education about the chronic nature of the disease and need for on-going treatment. 

In many instances, medical treatment is chronic and on-going, and aimed at controlling symptoms, but is not curative. Thus, some patients prefer the option of a surgical procedure that might eliminate an anatomical obstruction that could be the cause of RS, in the hope of a definitive cure. The current surgical  approach to RS is functional endoscopic sinus surgery where the functional ostia which drain the sinuses are identified and enlarged. This approach has an impressive 1-2 year incidence of symptom improvement. However, patients with predisposing diseases that originally led to RS still suffer from these processes and often develop RS again at a later date. Medical management is usually required for on-going symptom relief.

Symptoms and Severity

Although some symptoms are similar in all forms (itching – which is typical of allergic conjunctivitis, distinguishing it from other forms of a red eye – redness, tearing and photophobia), the pathophysiology, disease associations, and clinical presentation can differ, for example, the giant papillae in VKC and CLC. The disease severity and management are different in these phenotypes of ocular allergy (Figure 2). While SAC and PAC (very often associated with rhinitis) impair a patient’s quality of life they are mild diseases and are easily controlled by adequate anti-allergic treatment. On the other hand, VKC (occurring alone or more frequently associated with asthma, particularly in young boys before puberty and in some geographical regions with intense natural light) and AKC (typically associated with atopic eczema) are rare but severe clinical entities, in which the involvement of the cornea (vernal and atopic keratoconjunctivitis) is difficult to treat and may eventually cause impairment of visual function.

The allergist has a central role in the diagnosis of allergic conjunctivitis. Patients with bilateral red itching eyes should always be referred to the allergist not only for skin testing and IgE determination, which may be negative, particularly in some cases of VKC and AKC, but also to evaluate general and ocular clinical symptoms. The allergist can also arrange for more sophisticated tests such as the detection of eosinophils in tears, which is typical of VKC and AKC, or of SAC and PAC during the acute phase. The age of the subject, the clinical association with asthma or eczema, the presence of ocular pain or of an intense photophobia, and a poor response to common anti-allergic treatments should prompt the allergist to consult an ophthalmologist to evaluate the presence of a possible corneal involvement.

Therapeutic Considerations

 An adequate treatment of rhinitis with topical steroids, immunotherapy when indicated, systemic and topical antihistamines (or more recent molecules with a dual antihistaminic and anti-inflammatory action) may easily control SAC and PAC. The corneal involvement in VKC and AKC often requires the use of steroids, with the potential for severe iatrogenic side effects of these drugs in the eye (glaucoma, ulcers).

Future Research Needs 

Research efforts in allergic conjunctivitis should mainly be devoted to the most severe forms of ocular allergy (SOA), in an attempt to clarify their pathophysiology better, to standardize diagnosis, and to suggest new forms of treatment. 

Rhinosinusitis

Key Statements 

• Rhinosinusitis (RS) is one of the most common and expensive medical conditions. 

• RS occurs in a number of forms, the most common of which are either acute or chronic. 

• Initial treatment of RS is usually by a primary care physician (PCP) and if unsuccessful, the PCP should refer either to a surgeon or to an allergist for specialized care. 

• In the vast majority of cases, RS is controlled by proper medical management without the need for surgery. 

• Surgery should be considered only in those patients who are properly managed but in whom a number of medical treatment programs fail. 

• The Allergist, who is trained in allergy, immunology, microbiology, internal medicine and/or pediatrics combined with an expert knowledge of nasal and sinus anatomy and appropriate pharmacology, is best suited to manage RS.

Therapeutic considerations

Treatment modalities recommended for patients with AR. According to the ARIA guidelines, the management strategies include four components: 

1) Patient education; 

2) Prevention of exposure to environmental allergens and irritants; 3) Pharmacological therapies; and 

4) Immunotherapy.

The effective first line drugs for AR are non-sedating antihistamines and intranasal corticosteroids. Other drugs with favorable efficacy and safety profiles include leukotriene receptor antagonists, chromones, and topical and oral decongestants. Subcutaneous immunotherapy and sublingual immunotherapy are effective and have preventative as well as long lasting effects on the disease.

In developing countries, there are limitations for the adequate treatment of AR, such as little access to specialized diagnosis and treatment, the small number of allergists, lack of confirmatory in vivo and in vitro diagnostic tests, and the cost of medications or immunotherapy

Co-morbidities, and especially asthma, must be treated concomitantly with AR. The ARIA guidelines strongly recommend that patients with AR be evaluated for asthma, and that patients with asthma be assessed for AR.

Unmet Needs 

• To define control of AR. 

• To define severe AR. 

• To define phenotypes and disease heterogeneity. 

• Additional therapies for unresponsive patients. 

• Pharmaco-economic studies. 

• Increased access to diagnosis and treatment, including allergen-specific immunotherapy, in developing countries.

Allergic Conjunctivitis

Key Statements 

• Allergic conjunctivitis is an increasingly prevalent allergic disease, with the same clinical gravity as allergic asthma and allergic rhinitis. 

• The umbrella term “allergic conjunctivitis” includes distinct clinical entities, from mild but disturbing forms due to IgE sensitization to aeroallergens, to forms of keratoconjunctivitis where the severe allergic inflammation, with corneal involvement, is more difficult to diagnose and treat, and may lead to permanent ocular damage and even loss of vision.

Introduction 

Allergic conjunctivitis is the most common cause of a red eye, affecting more than one billion people globally. There are several clinical forms of allergic conjunctivitis; intermittent or seasonal (SAC), persistent or perennial (PAC), vernal (VKC), atopic (AKC) and induced by contact lenses (CLC).  

Inflammation

The clinical spectrum of asthma is highly variable, and different cellular patterns have been observed, but the presence of airway inflammation remains a consistent feature. The histopathologic features of asthma include inflammatory cell infiltration consisting of eosinophils, lymphocytes, activated mast cells and evidence of injury to epithelial cells. A notable feature of asthma is the presence of mast cells within the bundles of airway smooth muscle. Neutrophils predominate in a subset of patients with asthma including some patients with occupational asthma, those with severe asthma, and patients who smoke, but predominantly neutrophilic inflammation is also found in some patients with none of these characteristics. Based on careful pathology studies in well phenotyped patients, their response to treatment, and overall natural history, asthma is now considered to comprise different subtypes or endotypes in which different aspects of the underlying pathology may dominate the clinical expression of the disease.

Airway Remodeling 

In some patients with asthma persistent changes in airway structure occur, including epithelial goblet cell and submucous gland meta- and hyperplasia, sub-epithelial fibrosis, proliferation of nerves and blood vessels and most importantly, smooth muscle hypertrophy. These changes are not prevented nor completely reversed by currently available therapies, including inhaled corticosteroids. Some patients with asthma develop a phenotype in which airflow obstruction is not completely reversible and is favored by increased severity and duration of asthma and tobacco smoking. It is assumed that this reflects the results of airway remodeling. 

Increasing Prevalence 

There was a sharp increase in the prevalence, morbidity, and mortality associated with asthma beginning in the 1960’s and 1970’s in the so-called “Westernized” countries of the world. A study from Finland indicated a sharp rise in asthma in young adults beginning about 1960, while in Scotland the prevalence of wheezing in school children doubled from 10% to 20% between 1965 and 1989. In the United States, hospitalizations for asthma began to increase in 1972, deaths attributed to asthma began to rise in 1978, while from 1980 to 1994 the prevalence of individuals reporting physician diagnosed asthma increased from 3% to 5.4%, the increase occurring in all age groups, but greater in children.

The best information on the prevalence of asthma throughout the world was obtained by the International Study of Asthma and Allergies in Childhood (ISAAC). Questionnaires were completed primarily in 1994 and 1995 by 463,801 children aged 13-14 years from 56 countries, and by parents of 257,800 children aged 6-7 years from 38 countries. Asthma was considered to be present if there was a positive response to the question “Have you had wheezing or whistling in the chest in the last 12 months”, translated into the appropriate local language. In the 13-14 year old age group, the indicated prevalence varied more than 15-fold between countries, ranging from 2.1%-4.4% in Albania, China, Greece, Georgia, Indonesia, Romania and Russia to 29.1%-32.2% in Australia, New Zealand, Republic of Ireland and the United Kingdom. Other countries with low prevalence were mostly in Asia, Northern Africa, Eastern Europe and the Eastern Mediterranean regions, and others with high prevalence were in South East Asia, North America and Latin America. Trends for prevalence in the 6-7 year olds was similar to those in the older children with prevalence of wheezing varying from 4.1%-32.1%. 

The same survey was conducted 5-10 years later in 56 countries in children 13-14 years of age and 37 countries in children 6-7 years of age. This study, termed ISAAC III, was primarily intended to assess changes in asthma prevalence over time. Overall, there was only a slight increase in asthma prevalence from 13.2% to 13.7% in the 13-14 year olds and from 11.1% to 11.6% in the 6-7 year olds. The most striking change was a decline in prevalence of asthma in the English speaking counties which formerly had had the highest prevalence. Other areas such as Latin American, Eastern Europe and North Africa that already had high to intermediate prevalence continued to show an increase and, with the exception of India, all countries with low prevalence rates in ISAAC I reported increased prevalence in ISAAC III. Thus, overall, the disparity in asthma prevalence found in ISAAC I was found to have diminished, perhaps due to increasing urbanization in developing countries  

An international assessment of the prevalence of asthma in adults (the European Community Respiratory Health Survey or ECRHS) was conducted between 1991 and 1994. Data were obtained on asthma prevalence in 138,565 subjects 20- 44 years of age from 22 countries mostly in Europe, but also Oceania and North America.

There were 15 countries in which both ISAAC and ECRHS data were available and in these countries there was a strong correlation between the two surveys in the finding for current wheeze. Similar to ISAAC, the ECRHS found a high prevalence of reported asthma symptoms in English-speaking countries, and a high prevalence in Western Europe, with a lower prevalence in Eastern and Southern Europe. Overall, the prevalence of reported wheezing in the adults varied from 4.1% to 32%. Factors considered to underlie the increase in asthma are poorly understood even though connections with the Western-type lifestyle seem to be a common factor. Possibilities include diet, air pollution, exposure to certain environmental chemicals and drugs, virus infection, maternal tobacco smoking and changes in housing type and indoor environment. Most likely multiple factors will interact and these may differ in different countries. An important cause of lateonset asthma is chemical exposure in the workplace. 

Severity of Allergic Rhinitis

The severity and duration of symptoms of AR varies in different patients. The classification of AR into mild and moderate/ severe is useful for therapeutic purposes. Severe persistent rhinitis sufferers are those patients whose symptoms are inadequately controlled despite adequate (i.e., effective, safe, and acceptable) pharmacologic treatment based on guidelines. 

Bousquet et al have reported that current treatment and allergy diagnosis have no effect on the patient’s assessment of rhinitis severity and that the severity, rather than the duration, had a greater impact on Visual Analogue Scale levels. Therefore, we should consider control of the disease as the main target of management. It is likely that a large proportion of this group of patients may benefit from allergen specific immunotherapy

The Burden of Allergic Rhinitis

AR has a significant socio-economic impact on the patient, the patient’s family and society. It affects multiple parameters including quality of life, physical, psychological and social functioning and has financial consequences.

Physical Symptoms: Allergies in America, a survey conducted by telephone involving 2,500 adults with AR, showed that the most common symptoms are congestion, rhinorrhea, nasal and ocular itching, tearing, sneezing, headache, facial and ear pain

Psychological effects: Fatigue, irritability, anxiety, depression, frustration, self-consciousness and lower energy, motivation, alertness, and ability to concentrate, are commonly present in patients with AR 

Decreased quality of life: Investigators have used health status questionnaires to assess the quality of life of patients with asthma or rhinitis. While physical functioning was slightly higher in patients with AR compared with patients with asthma, social functioning was lower in the AR group.

Sleep disturbances: Nasal congestion is often associated with sleep-disordered breathing. Up to 57% of adult patients and up to 88% of children with AR have sleep problems, including micro-arousals, leading to daytime fatigue and somnolence, and decreased cognitive functioning. These are accompanied by disorders of learning performance, behaviour and attention in children.

Interference with social interaction: Social isolation, activity limitations, limited visits to friends and family, and an inability to visit open spaces such as parks and closed spaces (restaurants, cinemas), are frequent consequences of AR. Patients are forced to carry handkerchiefs or tissues, and need to rub and blow the nose repeatedly

Use of medications: On average, patients with AR usually use two or more medicines to treat their AR. Self-medication with over the counter sedating antihistamines results in drowsiness and further impairment of cognitive and motor functions.

Financial burden: It has been demonstrated that patients with AR support two-fold increases in medication costs and 1.8 times the number of visits to health practitioners when compared with matched controls. Expenses for AR include direct and indirect costs 

In the United States of America, direct costs for AR increased from $ 2.7 billion in 1995 to $7.3 billion in 2002. Indirect costs in 2002 were estimated at $4.28 billion, with a total amount of $11.58 billion for that year. Additionally 3.5 million lost work days and 2 million lost school-days occur annually. On any given day, about ten thousand children are absent from school in the USA because of AR.

The burden of allergic diseases

Allergic Rhinitis

Key statements 

• Allergic rhinitis (AR) results from an IgE-mediated inflammation of the nasal mucosa. 

• The disease currently affects between 10% and 30 % of the population. 

• Studies indicate that prevalence rates are increasing worldwide. 

• The classification proposed in the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines is useful for the implementation of treatment. 

• AR is a risk factor for asthma. 

• Other co-morbidities of AR include: sinusitis, nasal polyposis, conjunctivitis, otitis media with effusion, upper respiratory infections, breathing through the mouth, and sleep disorders. 

• AR has a significant impact on patients based on the degree of the severity of their symptoms. It has psychological effects, interferes with social interactions, and creates an economic burden not only for the affected subject, but for the family and for the society at large. 

• Management is based on patient education, environmental control measures, pharmacotherapy and specific immunotherapy

Introduction

Allergic rhinitis is defined by the presence of nasal congestion, anterior and posterior rhinorrhea, sneezing, and nasal itching secondary to IgE-mediated inflammation of the nasal mucosa. It must be differentiated from other non allergic forms of rhinitis with a similar clinical picture

Risk factors for the development of AR include a family history of atopic diseases, increased total serum IgE before 6 years of age, higher socio-economic class, and the presence of positive immediate-type hypersensitivity skin tests. The most common causative allergens include pollens, dust mites, molds, and insects.

Atopic subjects inherit a predisposition to produce specific IgE antibodies that bind to high-affinity receptors on mast cells. In the nose, IgE-bound mast cells recognize the allergen and degranulate, releasing preformed mediators (histamine, tryptase, chymase, kininogenase, heparin, and other enzymes). Newly formed mediators including prostaglandin D2 and cysteinyl leukotrienes are released by mast cells, eosinophils, basophils, and macrophages and produce edema, rhinorrhea, mucosal hypertrophy, mucus secretion, and vasodilation leading to nasal obstruction. Stimulation of sensory nerves results in nasal itch, sneezing, and increased congestion. This early allergic response is followed by a late-phase response starting 4 - 8 hours after allergen exposure, which is characterized by congestion, postnasal mucous discharge, hyposmia, and nasal hyperreactivity to non specific environmental stimuli. Repeated mucosal exposure to allergens results in a priming mechanism by which the amount of allergen required to induce an immediate response decreases as a consequence of the influx of inflammatory cells

Prevalence

Allergic rhinitis is the most common form of non-infectious rhinitis, affecting between 10% and 30% of all adults and as many as 40% of children. Epidemiologic studies show that the prevalence of AR continues to increase worldwide. The World Health Organization has estimated that 400 million people in the world suffer from AR, and 300 million from asthma.

In the United States of America, the prevalence of AR ranges from 3% to 19%. According to the Centers for Disease Control and Prevention, 23.7 million cases were reported in 1996. Overall, it affects 30 to 60 million individuals annually. In childhood, affected boys outnumber girls, but the sex ratio is about equal in adults. AR develops before the age of 20 years in 80% of cases. Increased prevalence is observed in non whites, in some polluted urban areas, and in first-born children. AR accounts for 16.7 million physician office visits annually.

In Europe, the European Community Respiratory Health Survey established the prevalence of AR as being from 4% to 32%. The International Study on Asthma and Allergies in Childhood (ISAAC) reported the prevalence of allergic rhinitis in Latin America.

The practice of allergology

The allergist is especially competent in appropriately providing the following treatments:

• Antihistamines 

• Mast cell stabilizers

 • Bronchodilators

• Nasal, oral, ocular, topical, and inhaled glucocorticosteroids 

• Decongestants 

• Leukotriene modifiers 

• Phosphodiesterase modifiers, including theophylline 

• Adrenergic agonists 

• Anticholinergics (oral, topical and inhaled) 

• Mucolytics 

• Antibiotics 

• Adrenaline, epinephrine 

• All other pharmacologic and immunologic agents used to treat allergic and immunologic diseases The allergist is uniquely aware of the pharmacologic properties of the treatments, their limitations and side effects. He/she is also keenly aware of how other medications may affect allergic processes and cause allergic conditions, for example, coughing and angioedema (ACE inhibitors).

Allergists treat a variety of skin conditions and are expert in the use of: 

• Emollients 

• Antibiotics 

• Topical glucocorticosteroids 

• Immune modulators and all other agents and techniques used to manage eczema and other allergic skin disorders

Part of the current therapeutic arsenal includes: 

• Use of immune modulators, such as specific allergen immunotherapy (oral and injective) 

• Immunoglobulin replacement used to treat allergic and immunologic disorders 

• Monoclonal antibodies, including anti-IgE

Part of the education of patients involves: 

• Instruction on the methods and value of allergen avoidance techniques 

• Avoidance diets and nutritional implications of dietary modification 

In particular for pediatric patients the allergist should be able to educate the parents, relatives and teachers about ways to optimize the prevention and treatment of allergies in children. 

In order to apply all these treatments properly, the allergist must have current and ongoing knowledge of national and international guidelines for the management of allergic and immunologic disorders in adults and children, with particular emphasis on safety and efficacy of all therapies. 

The membership of WAO is approximately 35,000 allergists worldwide representing the bulk of the trained allergists globally. In some developed countries such as Japan, Germany and the US, there are 4,000-8,000 trained allergists per country, representing about 1 allergist per 25,000 to 75,000 patients. It is estimated that ideal care would be provided by about 1 allergist per 20,000-50,000 patients, provided that the medical community was trained and competent to provide first and second level care by primary care physicians and other organrelated specialists. On the other hand, there are countries such as Costa Rica with less than 10 allergists and others with even fewer. Thus, the huge number, diversity and importance of patients with allergic diseases is overwhelmed by the inadequacy of the training of the medical community to provide care to these sick and needy patients. It is in part from this pressing need that this White Book on allergy was developed.