History of Allergy

The concept of allergy is relatively recent in the history of clinical medicine. Until the late 19th century allergy was not considered to be a medical discipline. In fact, the concept of hypersensitivity reactions to generally innocuous substances present in the environment had not yet been developed. Seasonal catarrh or “hay fever” was seen as toxic reactions to various plant products, and therapies were developed to neutralize these “toxins.”

In the early 20th century, scientific interest in allergy blossomed. Researchers began to explore the clinical reactions and mechanisms through which exposure to various substances in the environment produced symptoms. Challenge models were developed in which crude antigens from plant extracts were placed onto mucosal surfaces such as the nasal mucosa or conjunctiva, and responses were assessed related to these specific exposures. Researchers such as Noon began to quantify these responses and assess the degree of reactivity generated by various exposures. He related the degree of response to the robustness of the allergic sensitivity, and developed a rudimentary quantification scheme for measurement. He then applied this scheme to a specific treatment algorithm, and demonstrated in the 1920s that immunotherapy for inhalant allergy could be successfully implemented using these quantitative data.

Clinical interest in allergy developed steadily over the first half of the 20th century. Allergy practice flourished both in internal medicine and in otolaryngology, and numerous practice modalities were recommended during this time. Many papers and texts were written to promulgate treatment based on these various approaches. In addition, professional societies were founded within both medical specialties to further the practice of allergy and to foster communication of techniques and outcomes. These societies continue to the present day, and are very active and influential in the coordination of allergy care.

Despite a strong clinical interest in allergy and an active system of clinical practice, the causes of allergy were not well understood until the 1960s. During that period of time Johannson and Ishizaka independently isolated immunoglobulin E from the serum of allergy patients and demonstrated its primary role in clinical allergy. This development demonstrated the molecular basis of allergy and allowed both a rapid progression of the science related to allergy practice as well as the growth of standardized in vitro serum tests for specific IgE. These developments continued to foster a growth in clinical allergy practice, and led to the rapid influx of clinical and scientific research in the field of allergy-related immunology. These interests continue to the present day.

Allergy continues to be a prominent area of practice within clinical medicine, although the number of trained practitioners within medicine, pediatrics, and otolaryngology is relatively small in comparison to the number of physicians practicing other areas of medicine. In fact, practitioners of allergy account for only about 1% of the physicians practicing clinical medicine in the developed world, with a lesser number active in the developing world. Despite the large prevalence and impact of allergic diseases such as rhinitis, asthma, eczema, and urticaria, a small force of trained physicians is charged with care of the allergic patient.

It is the purpose of this textbook to review clinical allergy as it affects the diagnosis and treatment of the patient with allergic diseases. The text is meant to be clinically practical and of direct application for physicians and allied health personnel across medical specialties, both within the fields related to clinical allergy and in the primary care disciplines. It will provide the user with practical information on the assessment and management of patients with various allergic diseases, and will also discuss the pathophysiological and mechanistic bases for clinical practice. Allergic diseases remain a challenge for physicians and other health care professionals, and this textbook will attempt to address that clinical challenge in a practical and straightforward manner.

Prevalence of Allergic Diseases

In general, studies have suggested that allergic diseases, both respiratory and nonrespiratory, are steadily increasing in prevalence. This rise has been seen around the globe, not only in the west but also throughout the developing world. It has been estimated that 25% to 30% of the population in the western world are affected by allergic illnesses on a yearly basis, with a somewhat lower prevalence in the developing world. By a variety of indicators, the prevalence of allergic diseases such as rhinitis and asthma continue to grow steadily.¹

In order for patients to develop allergic hypersensitivity, and therefore to express allergic symptoms, they must have the genetic predisposition to respond in this manner. This predisposition to develop allergy is referred to as atopy. Individuals who are able to develop these allergic responses are said to be atopic. Atopy is genetically determined, with children of allergic parents more likely to develop allergy than children whose parents are not allergic. In fact, if both parents are allergic, the likelihood of an individual developing clinical allergy is greater than 50%.

Allergic diseases occur throughout the lifespan, but often have their origins in childhood. Infants and young children are often sensitized to foods and other macromolecules absorbed through the gut, and develop a variety of hypersensitization symptoms such as colic and eczema. These sensitivities can be enhanced by maternal food allergies, and these allergies have been demonstrated to be transmitted placentally. Among these atopic children, exposure to aeroallergens over the first few years of life often causes additional sensitization, resulting in the development of upper respiratory allergy and the condition known as allergic rhinitis. Allergic rhinitis also has a very strong genetic predisposition, with up to two-thirds of children with both parents suffering from allergic rhinitis also demonstrating symptoms of this disease. Concurrent with the development of allergic rhinitis is a rise in IgE levels in children. As will be discussed later in this chapter, IgE is the immunoglobulin involved in the immune response, and levels of IgE become significant in allergic children after the age of 2 years. Allergic rhinitis is quite common in childhood, with studies suggesting that up to 40% of children may be diagnosed by their physician with allergic rhinitis by the age of 6 years.

In many children with allergic rhinitis, respiratory inflammation continues to worsen over time, not only affecting the upper airway but beginning to cause disease in the lower airway as well. Lower airway inflammation, referred to as asthma, is a common disease of both childhood and adulthood, with prevalence rates in the population of about 8% worldwide. Asthma is more common among patients with allergic rhinitis than among the general population, with allergic rhinitis patients demonstrating a threefold increase in the development of asthma over time. While not all asthma is atopic, and while early childhood asthma is associated with infectious causes such as respiratory syncitial virus, the major identifiable predisposing cause for asthma is allergic disease. In fact, some studies suggest that allergy may be present in most, if not all, patients with significant asthma.

This progression of allergic disease from food-mediated colic and eczema, to allergic rhinitis, and finally to asthma has been referred to as the allergic march, implying that allergic disease will continue to progress in a steady manner from early childhood into adulthood.² It is unclear at this time whether early aggressive intervention can prevent or blunt this progression of disease. It is clear, however, that this allergic march is common in many children with atopic disease.

Burden of Allergic Diseases

Allergic rhinitis, asthma, and other atopic diseases are not only characterized by bothersome symptoms, they also carry a significant burden to patient function and quality of life. While diseases such as allergic rhinitis are sometimes considered trivial by physicians and other health providers, they have great impact on the daily activities of the individuals who are symptomatic. In addition, other atopic diseases such as asthma not only impact quality of life and daytime function, but can be life threatening if not appropriately recognized and managed. For that reason, atopic diseases should be suspected given characteristic signs and symptoms and should be managed actively and effectively.

For example, allergic rhinitis has been demonstrated to affect a daytime function in both children and adults.^3,4 These studies suggest that over 90% of children and adults have noted disruption in their abilities to work productively in the workplace or in the school when their rhinitis is symptomatic. Nearly one in four of these adults and children have missed work or school due to their symptoms. These findings demonstrate that allergic rhinitis is not only bothersome in terms of its adverse symptoms, it will impact the ability of adults and children to perform the general activities of their daily living, such as work and school attendance. Similar findings have been reported in a number of studies.

In addition, in patients with allergic rhinitis, the presence of the disease impacts on other aspects of function. Children with allergic rhinitis learn less effectively than those without the disease.⁵ Adults and children with allergic rhinitis have difficulty falling asleep and staying asleep.⁶ Furthermore, many of the older treatments for allergic rhinitis, particularly the first-generation antihistamines such as diphenhydramine, further adversely affect quality of life and function through their sedating and anticholinergic side effects.⁷

While the effects of upper airway allergy on function and quality of life can be significant, the adverse effects of asthma are even more dramatic. Asthma is a disease that is often poorly treated, due to a variety of factors including poverty, delay in diagnosis, inappropriate treatment, and patient nonadherence. It affects sleep, learning, daytime function, and has a significant negative impact on quality of life. Asthma deaths continue to number around 180000 annually on a worldwide basis, with delay in diagnosis and inadequate treatment being primary driving factors.⁸

The impact of these chronic diseases is substantial in the population around the world. Awareness of the signs and symptoms of atopic diseases and knowledge about effective treatment methodologies for managing these diseases is often lacking. Only through continued vigilance and sensitivity to the role of atopy in chronic disease will intervention strategies improve and effective management of these illnesses be possible.

Comorbidities of Allergic Diseases

Allergic diseases can be expressed in many different organ systems. While respiratory allergies are the most common group of allergic illnesses, allergic reactions can affect the eyes, the skin, and the gastrointestinal tract. These various allergic responses can be triggered by a wide variety of substances, which can be inhaled, ingested, injected, or contacted directly onto a mucosal surface. In addition, these allergic responses can be immediate in onset or delayed, and can be brief in duration or prolonged.

The majority of allergic diseases affect the upper and lower respiratory tracts. Respiratory illnesses that have a very direct allergic pathogenesis include allergic rhinitis and asthma. Other respiratory illnesses such as otitis media and acute and chronic rhinosinusitis have significant elements of allergy, at least in the expression of their symptoms, and perhaps in their pathogenesis as well (Figure 1.1). Among patients with allergic rhinitis, both adults and children, there is a greater prevalence of these other allergic illnesses than in the nonallergic population. In addition, among patients with allergic rhinitis, there is a higher likelihood of the development of rhinosinusitis, asthma, and otitis media than in patients who do not have allergic rhinitis. For that reason, the presence of allergy must be considered in any individual who presents with chronic respiratory symptoms, either upper or lower.

Figure 1.1 Comorbid allergic diseases.

Over the past decade, an awareness of the close interrelationship between upper and lower airway inflammatory diseases has been appreciated. Due to similarities in epithelial cells and membranes, inflammatory mediators, and pathophysiological mechanisms, the entire airway has been conceptualized as a unified system. It has been observed that diseases that affect one portion of this airway system will often affect other respiratory sites as well. This observation has led to a model described as the “unified airway model,” also known as the model of “one airway, one disease.”^9,10 Allergic rhinitis and asthma, therefore, are considered diseases along a pathophysiological spectrum, whose mechanisms exert similar influences in discrete portions of a unified airway system. This model has been useful conceptually, in explaining many observations of concurrent inflammation in both the upper and lower airway.

In 2000, the World Health Organization brought together an international panel of experts to examine the association between upper and lower airway inflammatory diseases. This panel issued a consensus document known as the ARIA document (Allergic Rhinitis and its Impact on Asthma). In the ARIA guidelines, the close association between allergic rhinitis and asthma was detailed, with specific recommendations for treatment of these coexisting diseases. The document stated “The upper and lower airways may be considered as a unique entity influenced by a common, evolving inflammatory process, which may be sustained and amplified by interconnected mechanisms.” In addition, it went on to argue that “When considering a diagnosis of rhinitis or asthma, an evaluation of both the upper and lower airways should be made.”¹¹

Despite this common existence of allergic diseases, both in allergic rhinitis and asthma as well as in related illnesses, the diagnosis of allergy is seldom entertained. Many clinicians fail to consider a diagnosis of allergy among patients with chronic respiratory illnesses or other types of chronic inflammation. Patients will rarely present to the clinician with the complaint of “allergies,” unless they have what are considered classic seasonal allergic symptoms such as sneezing. In order for clinicians to diagnosis a patient with an allergic disease, and for them to initiate appropriate treatment based on that diagnosis, they first must be vigilant and open to the possibility of allergy being present. This level of clinical suspicion is critical among physicians and other health care personnel and should be reinforced and encouraged.

In order to better appreciate the range of allergic diseases, an understanding of the basic and clinical science involved in these illnesses is important. An appreciation for and working knowledge of these areas is vital for the clinician in clinically assessing the patient, reaching an appropriate diagnosis, and formulating and carrying out an effective treatment plan.

Basic Immunology

The primary function of the immune system is to guard against invasion of the host organism by foreign substances. It is composed of a number of interrelated elements, including cells and soluble mediators, which work as an integrated unit in defending the body from injury. These factors utilize a variety of mechanisms to regulate immune function and to protect against: (1) invasion from external pathogens such as viruses, bacteria, and parasites, and (2) malignant transformation of cells. The immune system has evolved over many thousands of years and is highly efficient and effective in the human species.

The immune system is adaptive yet specific. It is able to respond to a wide variety of environmental challenges, and to do so in a way that is specifically directed toward the type and magnitude of the assault. It is programmed by exposure to foreign invaders, and has memory for those specific invaders that allows it to respond with robustness and immediacy to additional challenges.

The term “immune” is derived from the Latin word immunitas that refers to the specific exemption that was granted to Roman senators in their state duties. This concept is carried forward into today’s legal system, where witnesses can be given immunity from prosecution for cooperating with a criminal investigation. In health and disease, the immune system is designed to provide this same exemption or protection through preventing or limiting the effects of the disease on the organism. The immune system has a number of properties, which are detailed in Box 1.1.