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.

The practice of allergology

The practice of allergy involves the diagnosis and care of patients with:

• Rhino-conjunctivitis, along with nonallergic rhinopathy

• Sinusitis, both acute and chronic, alone or complicated with nasal polyps 

• Otitis and Eustachian tube disorders 

• Asthma and all its forms including cough-variant asthma and exercise-induced asthma 

• Cough from all causes 

• Bronchitis, chronic obstructive pulmonary disease (COPD) and emphysema 

• Hypersensitivity pneumonitis 

• Alveolitis 

• Atopic dermatitis/eczema 

• Contact dermatitis 

• Urticaria and angioedema 

• Drug allergy 

• Food allergy 

• Latex allergy 

• Insect allergy and stinging-insect hypersensitivity 

• Gastrointestinal reactions resulting from allergy, including eosinophilic esophagitis and gastroenteritis 

• Anaphylactic shock

• Immunodeficencies, both congenital and acquired 

• Occupational allergic diseases 

• Identifying and managing risk factors for progression of allergic diseases — the «allergic march» 

• Other specific organ reactions resulting from allergy

• Conditions that may mimic or overlap with allergic disease 

• An expert knowledge of the epidemiology and genetics of allergic diseases Immunodeficencies and autoimmune diseases, with special knowledge of regional and local allergens

As part of the practice of allergy, the allergist should be capable of ordering and interpreting allergy-and immunology-related laboratory tests:

• Evaluating total IgE and allergen specific IgE measurements

• Carrying out appropriate provocation testing for allergic and immunologic disease 

• Providing analysis and advice regarding local environmental/airborne allergens and irritants, as well as the analysis and advice regarding ingested allergens/ irritants

• Conducting and/or evaluating tests of pulmonary function and tests of inflammatory markers

• Conducting and/or evaluating tests of nasal function; this may include examination of nose and throat via fiberoptic rhinoscopy and nasal endoscopy 

• Specific allergen and venom immunotherapy 

• Providing pharmacotherapy of allergic disorders and related diseases including aero-allergens, drugs, venoms, occupational allergens, and food allergens 

Because of the highly specialized training, the allergist can advise both patients and other members of the medical community on:

 The role of effector cells involved in allergic disease (stem cells, • lymphocytes, mast cells, basophils, eosinophils, neutrophils, • monocytes, macrophages, dendritic cells) 

• The molecules involved in the immunological response (both innate and acquired) including chemical mediators; immunoglobulins; antibodies; complement; cytokines;interleukins; chemokines and their receptors; human leukocyte antigen/major histocompatibility complex (HLA/MHC) antigens • The main hypersensitivity reactions 

• Cell-to-cell interactions 

• The scientific in vitro laboratory diagnostic tests for allergy and 

• their selection and interpretation, including allergenspecific in vitro assays; enzyme-linked immunosorbent assays (ELISAs); Western blotting; tests for inflammatory markers, protein and cellular antigen stimulation tests; histamine release assays

The allergist is especially competent in performing/interpreting the following: 

• Allergic history and physical examination 

• Skin testing 

• Where necessary, investigating alternative diagnoses 

• Environmental modification strategies to reduce allergen exposure 

• Specific immunotherapy (allergen vaccines; both oral and injective)

• Immunomodulatory therapy 

• Drug desensitization 

• Evaluation and treatment of allergic and immunologic competence 

• Management and treatment of anaphylactic shock 

• Education for patients, caregivers and primary care physicians 

Allergy Education for Patients and Families

• The provision of appropriate training and education for patients and families is fundamental to the management of allergic disease.

• The evidence base for the efficacy of education and training is relatively weak but it is effective in asthma and, to a lesser extent, eczema and anaphylaxis. 

• Different age and ethnicity populations require different educational approaches. 

• Modern information technology is valuable, especially to educate younger subjects. 

• Education and training programs should contain a written self management action plan

Allergen Avoidance

• Effective allergen avoidance leads to an improvement of symptoms in allergic patients. 

• Several studies of comprehensive environmental interventions in asthmatic children report benefits. 

• There is little evidence to support the use of a simple single intervention, e.g., only covering bedding, to control dust mite allergen levels. 

• Similarly, in mite allergic patients with rhinitis, single mite avoidance measures are not beneficial. 

• The following is a guide for a pragmatic approach to allergen avoidance:

– Use a comprehensive environmental intervention to achieve the greatest possible reduction in allergen exposure; 

– Tailor the intervention to the patient’s allergen sensitization and exposure status;

 – If unable to assess the level of allergen exposure, use the level of allergen-specific IgE antibodies or the size of skin test wheal as an indicator;

 – Start the intervention as early as possible in the natural course of the disease;

 – Primary prevention strategies aimed at eliminating or reducing exposure to potentially sensitizing agents should be developed and evaluated. 

PREVENTION OF ALLERGIC DISEASES

• The rise in prevalence of allergic diseases has continued in the industrialized world for more than 50 years. 

• Sensitization rates to one or more common allergens among school children are currently approaching 40%-50%. 

• Strategies used to tackle these problems are thus far ineffective. 

• Primary prevention is difficult because the reasons for increased sensitization rates are unknown. Also, the mechanisms involved in the progression of sensitization in increasing numbers of individuals resulting in allergic diseases are incompletely understood. Asthma and allergies may have their origin early in life, even in-utero.

• Reliable early markers of IgE-mediated diseases are unavailable. 

• Novel research indicates that tolerance is the key to prevention. More research about the mechanisms involved in the development of tolerance should be encouraged. Inadequate or lack of tolerance in allergic individuals appears to link with immune regulatory network deficiencies. 

• National asthma and allergy plans (e.g. The Finnish Asthma Programme 1994-2004) have concluded that the burden of these community health problems can be reduced. The change for the better is achieved as governments, communities, physicians and other health care professionals, and patient organizations commit to an educational plan to implement best practices for prevention and treatment of allergic diseases. 

Pharmacotherapy of Allergic Diseases

• Subjects from all countries, ethnic and socio-economic groups, and ages suffer from allergies.

• Asthma and allergic rhinitis are common health problems that cause major illnesses and disability worldwide.

• The strategy to treat allergic diseases is based on: (i) patient education, (ii) environmental control and allergen avoidance, (iii) pharmacotherapy, and (iv) immunotherapy. 

• Pharmacotherapy is the mainstay of treatment for allergic diseases because it not only controls symptoms but improves the quality of life.

• Primary care physicians play an important role in first line management of allergies. They have to make the initial clinical diagnosis, begin treatment, and monitor the patient. 

• Allergy specialists are trained to make a specific diagnosis and treat patients with allergies, particularly those with moderate/severe disease.

• The chronic nature of allergies makes it essential to propose and explain long-term management strategies to patients, health care policy makers, and government authorities. 

• In recent decades, a substantial improvement has been made in the efficacy and safety of allergy pharmacotherapy. 

• Disease management using evidenced-based practice guidelines has been shown to yield better patient outcomes.

Allergen Specific Immunotherapy

• Allergen specific immunotherapy is recognized as an effective treatment for respiratory allergy and Hymenoptera venom allergy. 

• Subcutaneous Immunotherapy (SCIT) represents the standard modality of treatment. Sublingual Immunotherapy (SLIT) which is now accepted as an alternative to injection immunotherapy, has recently been introduced into clinical practice. 

• The additional effects of allergen specific immunotherapy, that are lacking with pharmacological treatment, are the long-lasting clinical effects and the alteration of the natural course of the disease. This prevents the new onset of asthma in patients with allergic rhinitis and prevents the onset of new sensitizations. 

• The mechanisms of action of specific immunotherapy are multiple and complex, and result in a modification of the immunological responses to allergens, with subsequent reduction of the allergic inflammatory reaction. The mechanisms of action of SCIT and SLIT are similar.

• SCIT maintains its beneficial effects for years after it has been discontinued. This long-term or carry over effect also occurs with SLIT. 

• SCIT indications, contraindications, limits and practical aspects are defined in numerous guidelines. 

• SLIT is considered a viable alternative to SCIT and is used in clinical practice in many countries. A 2009 World Allergy Organization Position Paper further details the indications, contraindications, and methodology of using SLIT.

• New forms of immunotherapy, allergen products, and approaches to food allergy and atopic eczema are under investigation.

Biological Agents 

• Research in allergy and immunology has led to a variety of novel therapeutic approaches; some agents are already utilized in clinical practice and more are in clinical trials. 

• New therapeutic approaches include toll-like receptor agonists, cytokine blockers, specific cytokine receptor antagonists and transcription factor modulators targeting syk kinase, peroxisome proliferator-activated receptor gamma, and nuclear factor kappa B. 

• The anti-IgE mAb omalizumab is effective to treat allergic asthma, but the criteria to select patients for this type of therapy are not well-defined.

Socio-economic Factors and Environmental Justice

• The global prevalence, morbidity, mortality and economic burden of asthma have increased over the last 40 years.

• However, the growth and burden of the disease is not uniform. Disparities in asthma morbidity and mortality, with an inverse relationship to social and economic status, are increasingly documented around the world. 

• Asthma and other atopic disorders may be more concentrated among those of lower socio-economic status because they also bear a disproportionate burden of exposure to suboptimal, unhealthy environmental conditions (e.g. physical, social, and psychological conditions).

• Future research needs to pay increased attention to the social, political, and economic forces that result in marginalization of certain populations in disadvantaged areas of the world which may increase exposure to known environmental risk factors contributing to the rising asthma burden.

Climate Change, Migration and Allergy 

• The Earth’s temperature is increasing as illustrated by rising sea levels, glaciers melting, warming of the oceans and diminished snow cover in the northern hemisphere. 

• Climate change coupled with air pollutant exposures may have potentially serious adverse consequences especially for human health in urban and polluted regions. 

• High summer temperatures have an impact on rates of acute exacerbation and hospital admission for elderly patients with breathing problems and may cause unexpected death. 

• Pollen allergy is frequently used to study the interrelationship between air pollution and respiratory allergy. Climatic factors (temperature, wind speed, humidity, thunderstorms, etc.) can affect both biological and chemical components of this interaction.

• Changes in the weather such as thunderstorms during pollen seasons may induce hydration of pollen grains and their fragmentation which generates atmospheric biological aerosols carrying allergens. As a consequence asthma outbreaks can be observed in pollinosis patients. 

• Migration from one country to another involves exposure to a new set of pollutants and allergens as well as changes in housing conditions, diet and accessibility to medical services which may affect migrants’ health.

• Atopy and asthma are more prevalent in developed and industrialized countries compared with undeveloped and less affluent countries. 

• Migration studies provide information on the role of environmental factors on the development of atopy and asthma. 

• Physicians should be aware that environmental and climate changes may enhance the development of allergic diseases and asthma.

 • Physicians should be aware that migrants, especially from developing to more developed countries, are at increased risk to acquire allergic diseases and asthma and that the effect is age and time-dependent. Early age and longer time increase the likelihood of developing atopy and asthma.

EVIDENCE BASED APPROACHES TO DIAGNOSIS AND MANAGEMENT

Diagnosis and Identification of Causative Allergens

• Confirmation of allergy and identification of causative allergens are crucial to correctly manage allergic diseases. 

• Precise diagnosis allows the implementation of therapies oriented to the etiologic factors of allergic diseases, such as environmental measures and immunotherapy. 

• Diagnosis begins with a detailed medical history and physical examination. 

• The identification of a temporal association between symptoms and allergen exposure constitutes the basis for further testing.

• Clinical suspicion is confirmed by means of investigation of IgE antibodies in vivo (skin tests) or in vitro. 

• Skin tests should include relevant allergens and the use of standardized allergen extracts.

• In vitro testing is especially useful when skin test results do not correlate with the history or cannot be performed.

• In vitro tests can be applied to “probability of disease” prediction in food allergy.

• There is a need for increased accessibility to allergy diagnosis and therapies and improved diagnostic methodologies that can substitute in vivo provocation tests for drug and food allergy. 

• The use of unproven tests increases the unnecessary costs of allergy diagnosis

RISK FACTORS FOR ALLERGIC DISEASE

Sports and Allergies

• Moderate and controlled exercise is beneficial for allergic subjects and should be part of their management.

• Vigorous exercise may trigger or exacerbate several allergy syndromes such as bronchospasm, rhinitis, urticaria-angioedema and anaphylaxis. 

• Allergy diagnosis should be part of the routine medical examination in all professional and amateur athletes, in order to adopt adequate preventative and therapeutic measures for controlling the disease, while avoiding potential symptoms occurring on exercise.

The Potential of Genetics in Allergic Diseases 

• Allergic disorders are heterogeneous and involve important gene-environmental interactions. 

• Human genetics has a role to play in understanding susceptibility for disease onset, phenotypes and subphenotypes, severity, response to treatments and natural history. 

• Although candidate gene association studies have provided some insight into the role of genes in disease susceptibility, most new information is emerging from hypothesis-free approaches such as genome-wide association studies. 

• Many early gene association studies were under-powered and the results have not been confirmed in different populations. 

• Genetic factors that influence the expression of atopy are different from those that influence disease manifestations or its severity in specific organs. 

• Poymorphism of a single gene usually accounts for only a small proportion of the disease phenotype. 

• Epigenetic influences involving multiple mechanisms, including methylation of CpG islands in gene promoters, histone acetylation, phosphorylation and methylation and a large number of micro RNAs, explain a proportion of the gene-environmental interactions and trans-generational effects. 

• The genetic epidemiological observations for specific candidate genes in atopy and allergic disease require careful replication, enhanced by international collaboration and the availability of large, well-characterized casecontrol populations for genotyping. The only way to achieve this is to promote greater cooperation among researchers and create multidisciplinary teams including researchers from academia, industry and clinical practice.

Allergens as Risk Factors for Allergic Diseases

• Sensitization (IgE antibodies) to foreign proteins in the environment is present in up to 40% of the population.

• Such sensitization is strongly associated with exposure for proteins derived from pollens, molds, dust mites and cockroaches. 

• For asthma, rhinitis and atopic eczema there is a strong and consistent association between disease and sensitization. 

• The association between sensitization to grass pollens and symptoms of hay fever occurring during the grass pollen season provides strong evidence for a causal role of grass pollen in the disease.

Environmental Risk Factors: Indoor and Outdoor Pollution 

• Epidemiological studies show that indoor and outdoor pollution affects respiratory health, including an increased prevalence of asthma and allergic diseases. 

• Outdoor pollution is associated with substantial mortality; for example in China, outdoor pollution is associated with more than 300,000 deaths annually. 

• Conservative estimates show that exposure to indoor air pollution may be responsible for almost 2 million deaths per annum in developing countries. 

• Exposure to outdoor/indoor pollutants is associated with new onset of asthma, asthma exacerbations, rhinitis, rhinoconjunctivitis, acute respiratory infections, increase of anti-asthmatic drug use, and hospital admissions for respiratory symptoms. 

• Abatement of the main risk factors for respiratory disease and, in particular, environmental tobacco smoke, indoor biomass fuels and outdoor air pollution, will achieve huge health benefits.

Allergy to Drugs and Biological Agents

• Adverse drug reactions (ADR) may affect up to 1/10 of the world’s population and affect up to 20% of all hospitalized patients. 

• More than 10% of all ADR are unpredictable drug hypersensitivity reactions (DHR). 

• Both under-diagnosis and over-diagnosis are common. 

• The most common DHR involve antibiotics such as penicillins, cephalosporins, and sulfonamides, and aspirin and other non steroidal anti-inflammatory drugs.

• The clinical spectrum of DHR involves various organs, timing and severity. 

• DHR can be severe, even life threatening, and are associated with significant mortality rates. Drugs may be responsible for up to 20% of fatalities due to anaphylaxis. 

• DHR have a significant socio-economic impact on both direct costs (management of reactions and hospitalizations) and indirect costs (missed work/school days; alternative drugs). 

• Diagnostic procedures for DHR should also attempt to identify the underlying mechanisms causing the DHR. 

• Diagnosis is critical for DHR management and prevention. Selection of an alternative drug and desensitization is necessary in some cases

Insect Allergy 

• Hymenoptera venom allergy (HVA) is a common global medical problem and refers to subjects who have a sting-induced large local (LL) or systemic allergic reaction (anaphylaxis). A LL reaction is defined as a reaction larger than 10 cm in diameter which lasts over 24 hours in which the signs and symptoms are confined to tissues contiguous with the sting site. Systemic reactions cause generalized signs and symptoms and include a spectrum of manifestations, ranging from mild to life-threatening. Mild systemic reactions may be limited only to the skin and consist of flushing, urticaria, and angioedema. More severe systemic reactions can involve bronchospasm, laryngeal edema, and hypotension. HVA can cause fatal anaphylaxis. 

• The morbidity rate is underestimated; fatal reactions may not be appropriately recorded, accounting for this underestimation. 

• The incidence of positive specific IgE antibodies to venom is high in the general population, but only a fraction of such individuals develop a systemic reaction. 

• Fatal reactions occur in up to 50% of individuals who have no documented history of a previous systemic reaction. 

• HVA impairs long-term quality of life (QOL) and is the cause of substantial socio-economic problems. 

• A subject’s QOL is negatively affected when appropriate diagnosis and education are not achieved and when venom immunotherapy (VIT) (a series of injections of the venom to which the subject is allergic and which essentially cures their disease) is not utilized. 

• HVA can be effectively treated with VIT and appropriate venom therapies.

• HVA poses a problem in occupational settings, especially in bee keepers and greenhouse workers. 

• HVA has important adverse consequences in terms of employment, earning capacity and leisure and sporting activities. 

• HVA has a substantial adverse financial impact on healthcare costs.

Occupational Allergy 

• Occupational allergic diseases represent an important public health issue due to their high prevalence and their socio-economic burden. 

• Occupational asthma (OA) contributes significantly to the global burden of asthma, since the condition accounts for approximately 15% of asthma amongst adults. 

• Allergic contact dermatitis (ACD) is one of the most common occupational diseases. 

• Occupational allergic diseases remain largely underrecognized by physicians, patients, and occupational health policy makers. 

• Occupational allergic diseases can result in long-term health impairment, especially when the diagnostic and avoidance measures are delayed. 

• Occupational allergic diseases lead to important adverse consequences in terms of healthcare resources, employment, earning capacity and quality of life. 

• Occupational allergic diseases are associated with a substantial adverse financial impact for affected workers, insurance or compensation schemes, health services, and employers. 

• Occupational allergic diseases are, by definition, preventable diseases and their burden should be minimized by appropriate preventative strategies.

White Book on Allergy

Atopic Eczema

•  An increase in the worldwide prevalence of atopic eczema has been observed. 

• Atopic eczema is the most common chronic inflammatory skin disease with a varied clinical spectrum. 

• Atopic eczema is often the first manifestation of the atopic patient and early intervention may offer an opportunity to impede or stop the atopic march. 

• Atopic eczema represents an important public health issue due to its impact on quality of life and its socio-economic burden.

Anaphylaxis 

• Epinephrine, at appropriate doses, is the drug of choice to treat anaphylaxis. 

• There is lack of consensus about the definition of anaphylaxis and this lack of consensus in definition contributes to the variability in its identification, treatment and the use of epinephrine. 

• The variability and severity of anaphylaxis is somewhat dependent on the route by which the allergen or inciting agent is delivered, i.e. parenteral versus oral administration; the former is commonly associated with more severe reactions. 

• There is a variety of other terms which describe anaphylaxis which cause confusion, especially with its definition and treatment. These include: generalized systemic reaction; systemic allergic reaction; constitutional reaction; and serious hypersensitivity reaction. 

• Anaphylaxis includes both allergic and non-allergic etiologies.

• The term “anaphylactoid” is outdated

Food Allergy 

• Globally, 220 – 250 million people may suffer from food allergy. 

• Food allergy significantly affects the quality of life of sufferers (mainly children). 

• Stakeholders must be prepared to meet the needs of patients by enhancing the diagnostic process, the traceability of responsible foods, and the availability of substitute foods, assisting hospitalized patients, and preventing mortality. 

• Large areas in the world lack legislation on food labelling.

• As diagnostic and therapeutic decision strategies are not clear-cut, evidence-based guidelines are necessary for clinicians, patients, governments and industry to deal with the challenge of food allergy. Such guidelines, eg, the WAO recommendation on the Diagnosis and Rationale Against Cow’s Milk Allergy (DRACMA) are available and are ready to be implemented. 

• Epidemiologic studies are necessary, in particular, in less developed areas of the world. 

• Oral desensitization represents a promising approach to reduce the burden of disease caused by food allergy.

Urticaria and Angioedema 

• Urticaria is a heterogeneous group of disease sub-types characterised by wheals (fleeting elevations of the skin lasting approximately 24 hours) and/or angioedema (deeper swellings of skin and mucus membranes). 

• Three major categories exist: a) spontaneous occurrence of wheals, associated with acute and chronic urticaria; b) wheals and angioedema elicited by particular stimuli, and in particular physical urticarias: and c) other urticarial disorders such as exercise-induced urticaria. 

• Urticaria occurs frequently with a lifetime prevalence above 20%.

• Except for acute urticaria, diagnostic and therapeutic procedures can be complex and referral to a specialist is often required.

• Untreated, chronic urticaria has a severe impact on quality of life and impairs productivity by up to 30%.

• The socio-economic impact of urticaria is great, since it is a disease which primarily occurs in people of working age. 

• Moderate to severe urticaria requires specialist treatment. In many health care systems worldwide, access to specialty care is insufficient.