CHAPTER 1 ENDOCRINOLOGY AND THE ENDOCRINE PATIENT

CHAPTER 1 ENDOCRINOLOGY AND THE ENDOCRINE PATIENT
Principles and Practice of Endocrinology and Metabolism

CHAPTER 1 ENDOCRINOLOGY AND THE ENDOCRINE PATIENT

KENNETH L. BECKER, ERIC S. NYLÉN, AND RICHARD H. SNIDER, J R.

Definitions
Role of the Endocrine System
Hormones
 
Chemical Classification
 
Sources, Controls, and Functions
 
Transport
 
 
Types of Secretory Transport
 
 
Overlap of Exocrine and Endocrine Types of Secretion
Tyranny of Hormone Terminology
Endocrine System Interaction with all Body Systems
Genetics and Endocrinology
Normal and Abnormal Expression or Modulation of the Hormonal Message and its Metabolic Effect
The Endocrine Patient
 
Frequency of Endocrine Disorders
 
Cost of Endocrine Disorders
 
Factors that Influence Test Results
 
 
Reliability of the Laboratory Determination
 
 
Determination of Abnormal Test Results
 
Risks of Endocrine Testing
 
Cost and Practicability of Endocrine Testing
Conclusion
Chapter References

DEFINITIONS
Endocrinology is the study of communication and control within a living organism by means of chemical messengers that are synthesized in whole or in part by that organism.
Metabolism, which is an integral part of the science of endocrinology, is the study of the biochemical control mechanisms that occur within living organisms. The term includes such diverse activities as gene expression; biosynthetic pathways and their enzymatic catalysis; the modification, transformation, and degradation of biologic substances; the biochemical mediation of the actions and interactions of such substances; and the means for obtaining, storing, and mobilizing energy.
The chemical messengers of endocrinology are the hormones, endogenous informational molecules that are involved in both intracellular and extracellular communication.
ROLE OF THE ENDOCRINE SYSTEM
The mammalian organism, including the human, is multicellular and highly specialized with regard to sustaining life and reproductive processes. Reproduction requires gametogenesis, fertilization, and implantation. Subsequently, the new intrauterine conception must undergo cell proliferation, organogenesis, and differentiation into a male or female. After parturition, the newborn must grow and mature sexually, so that the cycle may be repeated. To a considerable extent, the endocrine system influences or controls all of these processes. Hormones participate in all physiologic functions, such as muscular activity, respiration, digestion, hematopoiesis, sense organ function, thought, mood, and behavior. The overall purpose of the coordinating, regulating, integrating, stimulating, suppressing, and modulating effects of the many components of the endocrine system is homeostasis. The maintenance of a healthy optimal internal milieu in the presence of a continuously changing and sometimes threatening external environment is termed allostasis.
HORMONES
CHEMICAL CLASSIFICATION
Most hormones can be classified into one of several chemical categories: amino-acid derivatives (e.g., tryptophan ® serotonin and melatonin; tyrosine ® dopamine, norepinephrine, epinephrine, triiodothyronine, and thyroxine; L-glutamic acid ® g-aminobutyric acid; histidine ® histamine), peptides or polypeptides (e.g., thyrotropin-releasing hormone, insulin, growth hormone, nerve growth factor), steroids (e.g., progesterone, androgens, estrogens, corticosteroids, vitamin D and its metabolites), and fatty acid derivatives (e.g., prostaglandins, leukotrienes, thromboxanes).
SOURCES, CONTROLS, AND FUNCTIONS
Previously hormones were thought to be synthesized and secreted predominantly by anatomically discrete and circumscribed glandular structures, called ductless glands (e.g., pituitary, thyroid, adrenals, gonads). However, many microscopic organoid-like groups of cells and innumerable other cells of the body contain and secrete hormones (see Chap. 175).
The classic “glands” of endocrinology have lost their exclusivity, and although they are important on physiologic and pathologic levels, the widespread secretion of hormones throughout the body by “nonglandular” tissues is of equal importance. Most hormones are known to have multiple sources. Moreover, the physiologic stimuli that release these hormones are often found to differ according to their locale. The response to a secreted hormone is not stereotyped but varies according to the nature and location of the target cells or tissues.
TRANSPORT
TYPES OF SECRETORY TRANSPORT
Hormones have various means of reaching target cells. In the early decades of the development of the field of endocrinology, hormones were conceived to be substances that traveled to distal sites through the blood. This is accomplished by release into the extracellular spaces and subsequent entrance into blood vessels by way of capillary fenestrations. The most appropriate term for such blood-bone communication is hemocrine (Fig. 1-1).

FIGURE 1-1. Different types of hormonal communication detailed in the chapter. The darkened areas on the cell membrane represent receptors. (H, hormone.) See text for explanations.

Several alternative means of hormonal communication exist, however. Paracrine communication involves the extrusion of hormonal contents into the surrounding interstitial spaces; the hormone then interacts with receptors on nearby cells (see Fig. 1-1 and Chap. 4 and Chap. 175).1 Direct paracrine transfer of cytoplasmic messenger molecules into adjacent cells may occur through specialized gap junctions (i.e., intercrine secretion).2 Unlike hemocrine secretion, in which the hormonal secretion is diluted within the circulatory system, paracrine secretion delivers a very high concentration of hormone to its target site. Juxtacrine communication occurs when the messenger molecule does not traverse a fluid phase to reach another cell, but, instead, remains associated with the plasma membrane of the signaling cell while acting directly on an immediately adjacent receptor cell (e.g., intercellular signaling that is adhesion dependent and occurs between endothelial cells and leukocytes and transforming growth factor-a in human endometrium).3,4
Hormones may be secreted and subsequently interact with the same cell that released the substance; this process is autocrine secretion (see Fig. 1-1).5 The secreted hormone stimulates, suppresses, or otherwise modulates the activity of the secreting cell. Autocrine secretion is a form of self-regulation of a cell by its own product.
When peptide hormones or other neurotransmitters or neuromodulators are produced by neurons, the term neurocrine secretion is used (see Fig. 1-1).6 This specialized form of paracrine release may be synaptic (i.e., the messenger traverses a structured synaptic space) or nonsynaptic (i.e., the messenger is carried to its local or distal site of action by way of the extracellular fluid or the blood). Nonsynaptic neurocrine secretion has also been called neurosecretion. An example of neurosecretion is the release of vasopressin and oxytocin into the circulatory system by nervous tissue of the pituitary (see Chap. 25).
Several peptides and amines are secreted into the luminal aspect of the gut (e.g., gastrin, somatostatin, luteinizing hormone– releasing hormone, calcitonin, secretin, vasoactive intestinal peptide, serotonin, substance P).7 This process may be called solinocrine secretion (see Fig. 1-1), from the Greek word for a hollow tube. Solinocrine secretion also occurs into the bronchi, the urogenital tract, and other ductal structures.8
Commonly, the same hormone can be transported by more than one of these means.9
Extracellular transportation may not always be necessary for hormones to exert their effects. For example, some known hormonal secretions that are transported by one or more of these mechanisms are also found in extremely low concentrations within the cytoplasm of many cells. In such circumstances, these hormones do not appear to be localized to identifiable secretion granules and probably act primarily within the cell. This phenomenon may be called intracrine secretion. As shown in Figure 1-1, the process comprising uptake of a hormone precursor H1 and intracellular conversion into H2 (e.g., estrogens) or H3 (e.g., androgens) and subsequent binding and nuclear action is also a form of intracrine communication.
OVERLAP OF EXOCRINE AND ENDOCRINE TYPES OF SECRETION
Classically, an exocrine gland is a specialized structure that secretes its products at an external or internal surface (e.g., sweat glands, sebaceous glands, salivary glands, oxyntic or gastric glands, pancreatic exocrine glandular system, prostate gland). An exocrine gland may be unicellular (e.g., mucous or goblet cells of the epithelium of mucous membranes) or multicellular (e.g., salivary glands). Many multicellular exocrine glands possess a structured histologic organization that is suited to the production and delivery of secretions that are produced in relatively large quantities. A specialized excretory duct or system of ducts usually constitutes an intrinsic part of the gland. Some exocrine glandular cells secrete their substances by means of destruction of the cells themselves (i.e., holocrine secretion); an example is the sebaceous glands. Other exocrine glandular cells secrete their substances by way of the loss of a portion of the apical cytoplasm along with the material being secreted (i.e., apocrine secretion); an example is the apocrine sweat glands. Alternatively, in many forms of exocrine secretion, the secretory cells release their products through the cell membrane, and the cell remains intact (i.e., merocrine secretion); an example is the salivary glands. The constituents of some exocrine glands, particularly those opening on the external surface of the body, sometimes function as pheromones, which are chemical substances that act on other members of the species.10
Many exocrine glands contain cells of the diffuse neuroendocrine system (see Chap. 175) and neurons; both cell types secrete peptide hormones. Peptide hormones, steroids, and prostaglandins are found in all exocrine secretions (e.g., sweat, saliva, milk, bile, seminal fluid; see Chap. 106).11,12,13 and 14 Although they usually are not directly produced in such glands, thyroid and steroid hormones are found in exocrine secretions as well.15,16,17 and 18
The preferred approach is to view the term “exocrine” as a histologic-anatomic entity and not as a term that is meant to be antithetical to or to contrast with the term “endocrine.” Endocrinologists are concerned clinically and experimentally with all means of hormonal communication. The word “endocrine” is best used in a global sense, indicating any and all means of communication by messenger molecules.
TYRANNY OF HORMONE TERMINOLOGY
Hormones usually are named at the time of their discovery. Sometimes, the names are based on the locations where they were first found or on their presumed effects. However, with time, other locations and other effects are discovered, and these new locations or effects often are more physiologically relevant than the initial findings. Hormonal names are often overly restrictive, confusing, or misleading.
In many instances, such hormonal names have become inappropriate. For example, atrial natriuretic hormone is present in the brain, hypothalamus, pituitary, autonomic ganglia, and lungs as well as atrium, and it has effects other than natriuresis (see Chap. 178). Gastrin-releasing peptide is found in semen, far from the site of gastrin release. Somatostatin, which was found in the hypothalamus and named for its inhibitory effect on growth hormone, occurs in many other locations and has multiple other functions (see Chap. 169). Calcitonin, which initially was thought to play an important role in regulating serum calcium and was named accordingly, appears to exert many other effects, and its influence on serum calcium may be quite minor (see Chap. 53). Growth hormone–releasing hormone and arginine vasopressin are found in the testis, where effects on growth hormone release or on the renal tubular reabsorption of water are most unlikely. Vasoactive intestinal peptide is found in multiple tissues other than the intestines (see Chap. 182). Insulin, named for the pancreatic islets, is found in the brain and elsewhere.19 Prostaglandins have effects that are far more widespread than those exerted in the secretions of the prostate, from which their name derives (see Chap. 172).
The endocrine lexicon also contains substances called hormones that are not hormones. In the human, melanocyte-stimulating hormone (MSH) is not a functional hormone, but it comprises amino-acid sequences within the proopiomelanocortin (POMC) molecule: a-MSH within the adrenocorticotropic hormone (ACTH) moiety, b-MSH within d-lipotropin, and d-MSH within the N-terminal fragment of POMC (see Chap. 14).
Numerous peptide hormones exist that, because of their effects on DNA synthesis, cell growth, and cell proliferation, have been called growth factors and cytokines (see Chap. 173 and Chap. 174). These substances, which act locally and at a distance, often do not have the sharply delineated target cell selectivity that was attributed to them when they first were discovered. Their terminology also is confusing and often misleading.
Aside from occasional readjustments of hormonal nomenclature, no facile solution appears to exist to the quandary of terminology, other than an awareness of the pitfalls into which the terms may lead us.
ENDOCRINE SYSTEM INTERACTION WITH ALL BODY SYSTEMS
Although speaking in terms of the cardiovascular, respiratory, gastrointestinal, and nervous systems is convenient, the endocrine system anatomically and functionally overlaps with all body systems (see Part X). Extensive overlap is found between the endocrine system and the nervous system (see Chap. 175 and Chap. 176). Hormonal peptides are synthesized in the cell bodies of neurons, are transported along axons to nerve terminals, and are released at the nerve endings. Within these neurons, they coexist with classic neurotransmitters and often are coreleased with them. These substances play a role in neuromodulation or neurosecretion by means of the extracellular fluid. The nerves in which peptide hormones appear to play a role in the transmission of information are called peptidergic nerves.20 It is the ample similarity of ultrastructure, histochemistry, and hormonal contents of nerve cells and of many peptide-secreting endocrine cells that has led to the concept of the diffuse neuroendocrine system.
GENETICS AND ENDOCRINOLOGY
The rapid application of new discoveries and new techniques in genetics has revolutionized medicine, including the field of endocrinology. DNA probes have been targeted to selected genes, and the chromosomal locations of genes related to many hormones and their receptors have been determined. A complete map of the human genome is gradually emerging.21 This approach has led to new knowledge about hormone biosynthesis and has provided important information concerning species differences and evolution. The elucidation of the chromosomal loci for genes controlling the biosynthesis of hormone receptors should provide insights into the physiologic effects of hormones. Clinically, these techniques have potential significance as a diagnostic aid in evaluating afflicted patients, a means of identifying asymptomatic heterozygotes, and a method for identification of unborn individuals at risk (i.e., prenatal diagnosis; see Chap. 240). Delineation of processes of genetic expression is revealing the mechanisms of hormonal disease (e.g., obesity22) and also may lead to gene therapy for some forms of endocrine illness or humoral-mediated conditions.23
NORMAL AND ABNORMAL EXPRESSION OR MODULATION OF THE HORMONAL MESSAGE AND ITS METABOLIC EFFECT
A sophisticated and faultless machinery is required for appropriate hormonal expression. The hormonal messenger is subject to modifications that may occur anywhere from its initial synthesis to its final arrival at its target site. Subsequently, the expression of the message at this site (i.e., its action) may also be modified (see Chap. 4). The modulations or alterations of the hormonal message or its final action may be physiologic or pathologic. Table 1-1 summarizes some of the normal and abnormal modulations of a hormonal message and its subsequent metabolic effects.

TABLE 1-1. Modulation of the Hormone Message and Its Subsequent Physiologic or Pathologic Metabolic Effects

On a physiologic level, the first steps in the genetic ordering of hormonal synthesis, the subsequent posttranslational processing of the hormone, the postsecretory extracellular transport, the receptor mediation of the hormone and subsequent transduction, and the inactivation and clearance of the hormone all contribute to expressing, diversifying, focalizing, and specifying the hormonal message and its ultimate action. On a pathologic level, all of these steps are subject to malfunction, causing disease. Our increased knowledge of endocrine systems has forced us to rethink many traditional concepts. To dispel some common misconceptions, listing several “nots” of endocrinology may be worthwhile (Table 1-2).

TABLE 1-2. Several “Nots” of Modern Endocrinology

THE ENDOCRINE PATIENT
FREQUENCY OF ENDOCRINE DISORDERS
In a survey of the subspecialty problems seen by endocrinologists, the six most common, in order of frequency, were found to be diabetes mellitus, thyrotoxicosis, hypothyroidism, nontoxic nodular goiter, diseases of the pituitary gland, and diseases of the adrenal gland. Some conditions seen by endocrinologists are infrequent or rare (e.g., congenital adrenal hyperplasia, pseudohypoparathyroidism), whereas others are relatively common (e.g., Graves disease, Hashimoto thyroiditis), and some are among the most prevalent diseases in general practice (e.g., diabetes mellitus, obesity, hyperlipoproteinemia, osteoporosis, Paget disease). The third most common medical problem encountered by general practitioners is diabetes mellitus, and the tenth most frequent problem is obesity.66
Of the total deaths in the United States (i.e., both sexes, all races, and all ages combined), diabetes mellitus is the seventh most common cause. The most common cause of death (heart disease) and the third most common (cerebrovascular accidents) are greatly influenced by metabolic conditions such as diabetes mellitus and hyperlipemia.67
COST OF ENDOCRINE DISORDERS
The frequency and morbidity of endocrine diseases such as osteoporosis, obesity, hypothyroidism, and hyperthyroidism, and the grave consequences of other endocrine disorders such as Cushing syndrome and Addison disease demonstrate that the expense to society is considerable. In the case of diabetes, the health care expenditure is staggering. Approximately 10.3 million people have diabetes in the U.S., and an estimated 5.4 million have undiagnosed diabetes. Direct medical expenses attributed to diabetes total $44.1 billion. The total annual medical expenses of people with diabetes average $10,071 per capita, as compared to $2,669 for persons without diabetes.68 Interestingly, these expenses may be less if the appropriate specialties are involved in the care.69
FACTORS THAT INFLUENCE TEST RESULTS
In clinical medicine, hormonal concentrations usually are ascertained from two of the most easily obtained sources: blood and urine. The diagnosis of an endocrinopathy often depends on the demonstration of increased or decreased levels of these blood or urine constituents. However, several factors must be kept in mind when interpreting a result that appears to be abnormal. These may include age, gender, time of day, exercise, posture, emotional state, hepatic and renal status, presence of other illness, and concomitant drug therapy (see Chap. 237 and Chap. 239).
RELIABILITY OF THE LABORATORY DETERMINATION
The practice of clinical endocrinology far from a large medical center was previously hindered by the difficulty in obtaining blood and urine tests essential for appropriate diagnosis and follow-up care. However, accurate and rapid analyses now are provided by commercial laboratories. Nevertheless, wherever performed, some tests are unreliable because of methodologic difficulties. Other tests may be difficult to interpret because of a particular susceptibility to alteration by physiologic or pharmacologic factors (e.g., plasma catecholamines; see Chap. 86). Although many tests are sensitive and specific, they all have innate interassay and intraassay variations that may be particularly misleading when a given value is close to the clinical “medical decision point” (see Chap. 237). Some laboratory differences are due to hormone heterogeneity (e.g., growth hormone has several isoforms, which bind differently to growth hormone–binding proteins).70
DETERMINATION OF ABNORMAL TEST RESULTS
Not uncommonly, the intellectual or commercial enthusiasm engendered by a new diagnostic procedure of presumed importance is found to be unjustified, because the “test” was based on an invalid premise, because too few of ill patients were studied, because normative data to establish reference values were insufficient, or because subsequent studies were not confirmatory (see Chap. 237 and Chap. 241).
The increased sophistication of medical testing has made the physician and the patient aware of the presence of “abnormalities” that may be harmless: physiologic deviations from that which is most common, or pathologic entities that commonly remain asymptomatic. Such findings may cause considerable worry, lead to the expense and risk of further diagnostic procedures, and even cause needless therapeutic intervention.
Some “abnormalities” are the result of methods of imaging. For example, sonography of the thyroid may demonstrate the presence of small nodules within the thyroid gland of a person without any palpable abnormality of that region of the gland; most such microlesions are benign or behave as if they were.
Another “abnormality” revealed by imaging is the occasional heterogeneous appearance of a normal pituitary gland on a computed tomography (CT) examination. Intermingled CT-lucent and CT-dense areas are seen on the scan, and such nonhomogeneous areas may be confused with a microadenoma.71,72 The increasing use of magnetic resonance imaging (MRI) of the brain may reveal a bona fide asymptomatic microadenoma of the pituitary gland, but extensive endocrine workup often reveals many such lesions to be nonfunctional. They occur in as much as 10% of the normal population.73
Rathke cleft cysts of the anterior sella turcica or the anterior suprasellar cistern often are seen by MRI.74 Although an occasional patient may have a large and symptomatic lesion,75 most of these lesions are small and asymptomatic. During MRI or CT examination of the brain, the examiner often incidentally encounters a “primary empty sella,” an extension of the subarachnoid space into the sella turcica with a resultant flattening of the pituitary gland in a patient without any pituitary lesion or any prior surgery of that region (see Chap. 11). Although some of these patients may be symptomatic, most have no associated symptoms or hormonal deficit. Another, albeit rare, lesion of the pituitary region seen on MRI is a sellar spine. This asymptomatic anatomic variant is an osseous spine arising in the midline from the dorsum sella that protrudes into the pituitary fossa; it may be an ossified remnant of the cephalic tip of the notochord.76
MRI or CT scanning of the abdomen may reveal the presence of harmless morphologic variations of the adrenal gland (i.e., incidentalomas) that sometimes leads to unnecessary surgery.77 (See Chap. 84.)
RISKS OF ENDOCRINE TESTING
Endocrine testing is not always benign. Many procedures can cause mild to marked side effects.78,79,80 and 81 Other diagnostic maneuvers, particularly angiography, may result in severe illness.82 The expected benefit of any procedure that is contemplated for a patient clearly should be greater than the risk.
COST AND PRACTICABILITY OF ENDOCRINE TESTING
In addition to being aware of the many factors that influence hormonal values, the limitations of laboratory determinations, and the potential risks of some of these procedures, the endocrinologist must be aware of their expense, particularly because medical costs have increased at an annual rate that is almost twice the rate of overall inflation during the last several years.
A hypertensive patient with hypokalemia who is taking neither diuretics nor laxatives should undergo studies of the renin-angiotensin-aldosterone system, and appropriate pharmacologic or dietary manipulations of sodium balance should be instituted (see Chap. 90). But what should be done with the hypertensive patient who is normokalemic? Occasionally, such a person may have an aldosteronoma.83 Should such normokalemic patients be studied? Similarly, should the approximately 25 million hypertensive patients in the United States undergo urinary collections for determinations of catecholamine metabolites to find the rare patient with pheochromocytoma? In the context of the individual physician-patient relationship, the answers to such questions may not be difficult, but they become more controversial when placed within the framework of fiscal guidelines.
CONCLUSION
The complexity of the endocrine system presents a profound intellectual challenge. The macrosystem of endocrine glands secretes its hormones under the influence of other gland-based releasing factors or neural influences or both. The very act of secretion alters subsequent secretion by means of feedback controls (see Chap. 5). Superimposed on this already complex arrangement, the microsystem of dispersed, somewhat independent, but overlapping units throughout the body, as well as the continuous modulation of the receptors for the secreted hormones, allow general or focal actions that are coordinated with other body functions, tempered to the occasion, and appropriate to the needs of the individual. That such a complex system may go awry and that a dysfunction may have a considerable impact on the patient is not surprising.
Because endocrinology and metabolism are broad subjects that incorporate much, if not all, of normal body functions and disease states, they defy easy categorization. However, these enormous complexities, rather than deterring the clinician, researcher, or student, should provide a stimulus to probe deeper into areas difficult to understand and should hasten the eventual application of new developments to patient care.
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1.2 The history and development of public health in developed countries(cont’3)

Another feature of postwar public health concern was the shift from individual hygiene back to the environment (Hays 1987; Gottlieb 1993). To many, these heart diseases and cancers, along with other diseases and pathological conditions that seemed even more serious—for example, other forms of cancer, birth defects, lowered sperm counts—had broader structural causes and could be prevented only by comprehensive changes in the physical and social environment (Epstein 1979). Thus part of the liberal resistance to public health imposition was the argument that a focus on disciplining lifestyles came at the cost of attention to grander and more serious political issues (Tesh 1987; Turshen 1987).
While this new environmentalism had links with the nineteenth-century view of public health as environmental improvement, there were greater differences. The fear of insidious invisible radiation or the toxic chemicals that might lurk in numerous consumer products reflects the terror of germs or invisible odourless miasmas which germs replaced; however, the blame was quite differently directed. The new problems of environmental public health were those in which individuals were victimized by corporate oligopolies and by the governments they influence. While Chadwick and his associates had warned of vested interests, such as those that perpetuated slum housing, nineteenth-century environmental health problems had a communal character that was missing from the twentieth. Everyone in a nineteenth-century town produced excrement, smoke, ash, and rubbish; the great problem was to find within the community the will and means to act collectively (Wohl 1977; Kearns 1988). Few in a twentieth-century community produced radiation or toxic chemical waste, and the reasons why nothing was done about these seemed all too clear. Public health had failed in its police function; an institution that had evolved to stop the selling of spoiled food by the individual grocer or restauranteur could not cope with the conglomerate that sold goods whose harmful effects were less obvious and slower to appear but which might be much more widely distributed.
The result was an increasingly adversarial relationship between the people and the public health institutions that were supposedly safeguarding their health. To the degree that governments were seen as colluding with the proliferation of these dangerous materials, institutions of public health, as departments of government, were implicated too (Brown and Mikkelsen 1990, Edelstein 1988; Steneck 1984). Even the establishment of new departments of environmental protection, though it might be a means to apply new kinds of expertise to problems of environmental health, did not fundamentally alter the climate of distrust. Public health again became a matter for grassroots political agitation with the emergence of neopopulist Green parties, whose platforms gave prominent attention to health as part of environmental good, and who put their marginality to established governments at the centre of their appeal to the electorate.
Such a focus on bad environmental policy even informed the response to AIDS and to other new infectious diseases, like Ebola fever, that appeared in the 1980s and 1990s. While it became clear that these diseases could be largely controlled through the traditional means of changes in personal behaviour and isolation or restriction of the activities of victims, these recognitions were not fully reassuring. They did little to deflect demand for a vaccine, or the investment of hope in curative medicine. They too could be seen as environmental diseases, caused by environmental changes that had allowed animal viruses to acquire secondary human hosts for whom they were highly virulent. Chief amongst these changes was the unwise exploitation of tropical forests by an international oligopoly that put profit ahead of prudence (Garrett 1995).
Even those diseases most closely linked to lifestyle choice could be attributed to the broader social environment. People smoked, drank, used drugs, ate too much or vastly too little, practised unsafe sex, spent hours immobilized before televisions absorbing images of violence, hit their spouses and children, or shot their coworkers or themselves because they could no longer cope. To expect disciplined personal behaviour from alienated people living in a stressful world was unrealistic, and the institutions of public health should recognize this. But the critics were ambivalent as to what such an analysis implied. For some, the obvious response was to remake a society whose support structures were more consistent with the health behaviours it wished to promote. How absurd, for example, for a state to subsidize the production of tobacco and the addiction to it of people in other nations, whilst blaming its own citizens for smoking. For others such a response sounded like an even more invidiously intrusive state, bent on removing not only the means by which we satisfied unhealthful temptations, but also the temptations themselves. In this ‘critical public health’ view the lifestyle agenda was suspicious as the public health agenda of the untrustworthy state, not of its people. It was not clear that the personal benefits of delayed or denied gratification were worth it: perhaps one hould just enjoy life and rely on the miracles of modern medicine for redemption (Petersen and Lupton 1996).
This view, together with the emergence of widespread cancers and other chronic illnesses for which there was no clear preventive strategy, including the debilitating conditions of ageing, raised the question of why supportive and curative medical care did not form a part or priority of public health. It also raised the question of how far reaching the health obligations of the liberal state were to its citizens. This issue had vexed public health practitioners throughout the liberal era, though it had often been suppressed because it was seen as too politically volatile. In socialist or social democratic politics, or where the legacy of medical police remained strong (even when adopted, as in Sweden, by a democratic polity), there was often no clear boundary between public health and the public medical care most people demanded and received (Porter 1999). But elsewhere the recognition that public health was bound up in the larger issue of human welfare, which in turn included the rest of medical care, was problematic. Many of the newly prominent diseases were not infectious; they could be experienced privately without disturbing community or state, hence the reactive and police rationales for public health did not apply. But they did disrupt the fulfilment of human potential, and could justly take their place amongst the demands citizens could make of their governments.
In France, Germany, and Russia public health services had emerged from, and had remained closely linked to, medical services for the poor (Labisch 1992; Ramsey 1994; Solomon 1994). In mid-nineteenth century England, Edwin Chadwick, notwithstanding his own post as chief administrator of relief to the poor and the existence of a comprehensive national network of poor law medical officers, had deliberately severed public health (which he equated with sanitary engineering and saw as exclusively preventive) from the second-rate medical care that was offered to the poor, more on grounds of humanity than expectations of effectiveness. (It was hoped that they would thereby willingly pay for something better.) Chadwick’s English successors, while moderating the focus on sanitary engineering, retained a distinction between public health medicine and social welfare, which seemed to them only marginally medical and to have more to do with the moral chastisement of the feckless or the warehousing of the incompetent or neglected (Hamlin 1998). In Ireland, by contrast, an integrated system of public health, welfare, and medical care did emerge during the late nineteenth century, but more by accident than design (Cassell 1997). At the end of the nineteenth century, the Fabian socialists presented British parliament with a clear choice. The Fabians (mainly Beatrice Webb) proposed a much expanded scheme of prevention, though one which made even greater demands on personal and social behaviour as the price the citizen must pay for greater guarantees from the state. The liberals, whose view prevailed, would not discipline personal hygiene, but offered instead an insurance plan to pay for the medical care needed by stricken working men (Fox 1986; Eyler 1997). It was a policy acceptable to the rank and file of the medical profession and that retained and reinforced the split between public health and medicine.
Subsequent efforts to expand state responsibility for health into matters of care and cure have generally worked when medical professions have seen them as advantageous, yet the relationship between even this expanded public medicine and the broader questions of social welfare remain problematic (Starr 1982; Fox 1986). The kinds of objections that were made to Webb’s scheme still arise: however laudable prevention as a goal, ironically, as we have seen with the concerns about lifestyles and the environment, the strategies and priorities of the preventive public health of the last two centuries have not always been those most desired by the masses of people. To many, it has seemed that if the state was going to discipline behaviour for its own purposes, those who suffered that imposition deserved compensation for their trouble when things still went wrong. Such logic was clearest in compensating veterans of wars. It underwrote the postwar establishment of Britain’s National Health Service, which would provide ‘health for heroes’ and sustains the Veterans Administration medical system in the United States. Thus what some have complained of as an unrealistic demand for risk-free living, in which people demand a political right to complete freedom of action without accepting responsibility for the consequences (as if one could somehow live free of one’s biological self), may be better understood as a complaint about the fairness of the basic social contract of modern societies.
This problem of the relationship between the institutions of public health and the citizenry on whose behalf they claim to act is the greatest challenge currently facing public health in the developed world. That the problems that confront both public health and regular medical practice often stem from a wide range of social causes is plain. That it is so difficult to develop political will to respond to these problems is not chiefly a matter of epidemiological uncertainty. Such pathological phenomena are clearly the product of many causes on many levels and accordingly there are numerous points of access where defensible preventive measures might be taken. But almost all of them are likely to intrude on what are claimed as personal or cultural rights, and almost always attempts to act will be met with the response that it is fairer to act elsewhere. In such cases, epidemiology necessarily requires a large supplement, not from ethics so much as from a moral and political philosophy that must be acceptable to an increasingly diverse community. Without such a foundation, public health is forced to take refuge in science that is frequently challenged; but at the same time, it is not clear that the professional and educational institutions of public health, or the legal, political, and administrative structures that create and maintain it, will be able to initiate and implement a satisfactory enquiry about how these conflicting rights are to be adjudicated.
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Redlich, J. and Hirst, F. (1970). The history of local government in England, being a reissue of Book I of Local government in England, second edition, with an introduction and epilogue by Bryan Keith-Lucas. Augustus Kelley, New York.
Richards, P. (1977). The medieval leper and his northern heirs. Rowman and Littlefield, Totowa, NJ.
Richards, P. (1980). State formation and class struggle. In Capitalism, state formation, and Marxist theory (ed. P. Corrigan), pp. 49–78. Quartet, London.
Richardson, R. (1988). Death, dissection, and the destitute. Penguin, London.
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Roberton, J. (1827). Observations on the mortality and physical mangement of children. Longman, Rees, Orme, Brown, London.
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1.2 The history and development of public health in developed countries(cont’2)

Traditions of market regulation affected public health more broadly. Concern about water quality in metropolitan London, for example, reflected consumer outrage at high prices and poor quality and quantity well before there was any epidemiological evidence that such water was causing cholera. Equally, public willingness to accept that epidemiological evidence was tied to anger at paying too much for an irregular and visibly dirty water supply (Hamlin 1990). It is also likely, though difficult to show, that the ready acceptance of the new scientific forms of food inspection in the late nineteenth century reflected consumer expectations that the service was necessary and appropriate for government to undertake.
In the case of environmental nuisances too, institutions of public health took over from long-standing institutions for settling civil disputes. The term ‘nuisance’, drawn from the Anglo-French for annoyance, is peculiar to the English common law tradition, but analogous concepts operated in other cultures. ‘Nuisance’ referred to an accusation, and later to the legal determination, that actions on one person’s property or in the public domain interfered with another’s enjoyment of the rights of property, which included a right to enjoy health (Blackstone 1892; Novak 1996; Hamlin, in press). While in earlier centuries the concept had been very broad—including excessive noise, disturbances of the peace, the blocking of customary light—by the middle of the nineteenth century urban dung, human and animal, and action against nuisances acquired a basis in statute law that supplemented its status in civil law. Beginning with the first English Nuisances Removal Act of 1847, passed in expectation of the return of cholera, doctors, and later a new functionary called an inspector of nuisances (later a sanitary inspector) were charged with identifying nuisances and taking steps to have them removed (Wilson 1881; Hamlin, in press). The legislation reflects concern that a legal tradition built upon the power of property was unsuited to a situation in which most property was not occupied by its owners, and that one which depended upon an outrage to sensibility was unsuited in a situation in which peoples’ sensibilities were insufficiently attuned to the particular states of environment presumed to be associated with cholera. But while this change was an emergency response to cholera, its effects were more far reaching; in effect, it represented the investing of community standards in a permanent institution with enforcement powers, rather than leaving them to be worked out, incident-by-incident, through the common law of nuisance and tort. The inspectors of nuisances did not restrict themselves to the causes of cholera; they and their successors responded to community complaints, which sometimes were primarily aesthetic. They became the defenders of the ever rising and increasingly universal standards of middle-class life, and however far their activities might stray from any direct relation to disease control, the inspectors carried the authority of public health (Hamlin 1988, 1994; Kearns 1991). Towards the end of the nineteenth century some epidemiologists, recognizing that the tracing of cases and contacts provided a more exact means of disease control, suggested that concern with these broad measures of environmental quality was an unjustified expense that deflected the attention of public health departments from what really mattered (Casseday 1962; Rosenkrantz 1974). In some cases they were effective in severing sanitation and public works from public health, but often they found that the public, which tended to support clean streets and pleasant neighbourhoods, continued (and continues) to appeal to public health as justification for their concern. Here too, medicine, however distantly it might be linked to the environmental condition under scrutiny, gave public action a legitimacy that would otherwise have been difficult to create.
The medicalization of public police that these examples suggest was clearly underway by the middle of the eighteenth century. The concept of medical police arose first in Germany and Austria, later in Scotland, Scandinavia, Italy, and Spain; in France the rough equivalent was hygiene publique. In America and in England the term and concept never really caught on. Medicine’s rise to prominence reflected an alliance between medical practitioners who sought state patronage and the ‘enlightened despots’—rulers who, like Austria’s Joseph II, sought a science of good government that would significantly strengthen their states. Increasingly, rulers like Joseph felt obliged to test their policies against some tenets of rationality; health seemed to offer a well-defined arena of rational government, a set of means to improve the state and to measure the progress of that improvement (Rosen 1974a, b). How much the regulation of personal behaviour could improve the health of soldiers and sailors was becoming recognized; why not practice the same techniques on the rest of society? The effect of this medicalization was to move matters of police further from the realm of local social relations—for example, the determination and enforcement of community standards over cleanliness or food quality—and towards that of scientific rationality.
The classic text of eighteenth century medical police is Johann Peter Frank’s six volume System einer Vollständingen Medicinischen Polizey, or A System of Complete Medical Police, which appeared between the 1779 and 1819 (Frank 1976). Frank (1745–1821) had a distinguished career as a medical professor and a public health and hospital administrator, mainly in Vienna. He began his giant work with a discussion of reproductive health (two volumes), including suggestions for the regulation (and encouragement) of marriage, prenatal care, obstetrical matters, and infant feeding and care. He turned then to diet, personal habits, public amusements, and healthy buildings. The fourth volume covered public safety, which involved everything from accident prevention to the injuries supposedly inflicted by witches, the fifth volume dealt with safe means of interment, and the sixth with the regulation of the medical profession. In Frank’s cameralist view, anything that adversely affected health was a matter for public policy and an appropriate subject for regulation—rights, traditions, property, and freedoms, had no status if they interfered with the welfare of the population.
In its most far-reaching definitions, modern public health approaches the domain of a comprehensive police. It also recognizes that a wide range of factors are implicated in health conditions—current public health concerns include the effects of violent entertainment, the prevention of gun violence, and the conditions of the work place. But in modern liberal democracies, much of what Frank saw as the obvious business of the state is deeply problematic. For, in the nineteenth century, public health shifted radically in mission and constituency. It became less a means of maintaining the state, and more a means by which the state served its sovereign citizens with an (increasing) standard of health that they (increasingly) took as a right of citizenship.
The public health of human potential
The emergence of a public health that is not merely reactive or regulative, but that takes as its goal the reduction of rates of preventable mortality and morbidity, is a product of the eighteenth century. It is also one of the most remarkable changes of sensibility in human history. Its causes are complex but poorly understood. It clearly required the development both of knowledge of the problem and of the means to solve it. The concepts of preventable mortality and excess morbidity required being able to show that death and illness existed at much higher rates in some places than in others. Whilst there were a few attempts in seventeenth and eighteenth century Europe to determine local bills of mortality they were too few to provide a basis for comparison. In contrast, by the late nineteenth century annual mortality rates were an important focus of competition amongst English towns. The central government’s public health officials, notably John Simon, chief medical officer of the Privy Council from 1857 to 1874, badgered towns with poor showings to analyse the reasons for their excess mortality and to take appropriate action (Brand 1965; Lambert 1965; Eyler 1979; Wohl 1983). By the end of the century, and during the twentieth century, reliable morbidity statistics were available to provide a better understanding of the remediable causes of disease. The gathering and analysis of such data has become a central part of modern public health.
The mission of prevention was also tied to a very real growth in knowledge of the means of prevention. The widespread adoption of inoculation and, after 1800, of vaccination for smallpox was the first clearly effective means to intervene decisively to prevent a deadly disease. Initially through the development of the numerical method and the cultivation of pathological anatomy in the Paris hospitals in the first decades of the nineteenth century, and subsequently through bacteriological and later serological methods, infectious diseases were distinguished and their discrete causes and vectors identified (Ackerknecht 1967; Bynum 1994). Such recognition led ultimately not only to the ‘magic bullet’ thinking of vaccine development; it also underwrote campaigns to improve water quality and provide other means of sanitation, and sometimes, as with tuberculosis and typhoid, programmes to identify, monitor, and regulate carriers.
Yet these factors alone cannot account for the widespread conviction that human health could, and must be, significantly improved. They are means, not ends. Whatever the symbolic significance of effective action against smallpox in boosting confidence, vaccination successes did not imply that all infectious diseases were amenable to a similar strategy. In most cases the new medical knowledge did not precede the determination to improve the health of all but was developed in the process of achieving that goal. A great deal of success was achieved despite quite erroneous conceptions of the nature of the diseases and their causes. The great sanitary campaign against urban filth (based on a vague and flexible concept of pathogenic miasms) is the best known example.
Recognition of differential mortality was not new in the early 1800s, but it did not necessarily convey a need for action. That there was a mortality penalty associated with poverty, infancy, and urban living was clear; but some regarded the town as a necessary corrective to the overfecundity of the countryside, and characterized the poor as occupying a fixed station in life whose biological characteristics included higher mortality than the virtuous middle classes (though not necessarily than the profligate aristocracy) amongst compensating benefits (like less anxiety and a simple, healthy, diet) (Sadler 1830; Weyland 1969). And even humane and optimistic writers saw infant mortality rates of 25 per cent or more as providential (Roberton 1827). To the influential eighteenth-century Lutheran clergyman Christoph Christian Sturm, God’s providence was evident in the symmetry of the curve of mortality by age: mortality rates were high amongst the very young and very old, and low in between (Sturm 1832). This is in contrast with the modern sensibility which admits no justifiable reason (beyond, perhaps, the climatic factors that determine the range of some disease vectors) for differential mortality or morbidity.
The age of liberalism: health in the name of the people 1790 to 1880
The rise of liberalism changed all this. Whilst ‘liberalism’ covered a wide range of philosophical, political, economic, and religious ideas, at its heart were notions of individual freedom and responsibility, and usually, of equality in some form. In 1890, when John Simon, the pioneer of English state medicine, surveyed progress in public health during the past two centuries in his English Sanitary Institutions, he included a lengthy chapter on the ‘New Humanity’. In it he covered the antislavery movement, the rise of Methodism, growing concern about cruelty to criminals and animals, legislation promoting religious freedom, the replacement of patronage by principle as the motor of parliamentary democracy, the introduction of free markets, the rationalization of criminal and civil law, and efforts towards international peace. Simon saw little need to explain how this concerned public health; he was sketching a fundamental change in ‘feeling’ that underlay changes in public health policy.
Society had become readier than before to hear individual voices which told of pain or asked for redress of wrong; abler … to admit that justice does not weight her balances in relation to the ranks, or creeds, or colours, or nationalities of men.
No longer were humans so much cannon fodder; the best policies were those which maximized ‘human worth and welfare’ (Simon 1890; compare with Pettenkofer 1941; Coleman 1974; Haskell 1985).
What Simon recognized was that with the granting of equal political and economic rights and responsibilities, it had become impossible to see health status as the birthmark of class, race, or sex. Nineteenth-century French and English liberals recognized that some—particularly women, children, or the poor—still suffered ill health disproportionately owing to the workings of the labour market, but they saw such consequences as incidental, accidental, and often, as temporary; in principle all had an equal claim to whatever version of human and health rights a society was prepared to recognize. As Simon also recognized, this change in feeling was both cause and product of the widening distribution of the political power it sanctioned.
And yet liberalism was no clear and compact doctrine, and its implications for public health were, and still are, by no means clear. Few of the pioneers of liberal political theory bothered to translate human rights into terms of health. They wrote mainly with middle-class men in mind, and saw the threats to life, liberty, and property as political rather than biosocial. The expansion (or translation) of political rights into rights to health was gradual, piecemeal (it has never been the rallying cry of revolution), complicated, and even fundamentally conflictual—it was and is not always the case that the choices free individuals make will be compatible with protecting the public’s health, or even their own. Concern with public health arose accidentally, and quite differently and at different times in the developed nations. At the beginning of the twenty-first century an obligation to maintain and/or improve the health of all citizens exists only in varying degrees in the politics of developed nations.
Many early liberals found health rights hard to recognize because so much of public health had been closely associated with the medical police functions of an overbearing state. In revolutionary France the first instinct was to free the market in medical practice by abolishing medical licensing, a policy quickly recognized as disastrous for maintaining the armies of citizen-soldiers who were protecting the nation (Foucault 1975; Riley 1987; Weiner 1993; Brockliss and Jones 1997). Even after new, meritocratic and science-based medical institutions had been established, the cadre of public health researchers that it fostered—at the time the world’s leaders in public health epidemiology—found it difficult to conceive how their findings of the preventable causes of disease could be translated into proposals for preventive legislation. Poverty, and to some degree working and living conditions, were dictated by the market; government mandates would induce dependence or simply shift the problem elsewhere. Thus France was the scientific leader in public health for the first half of the nineteenth century without finding a viable political formula for translating that knowledge into prevention (Coleman 1982; LaBerge 1992).
In early nineteenth-century Britain the ideas of T.R. Malthus led a broad range of learned public opinion, liberal and conservative, to similar conclusions. Disease was amongst the natural checks that kept population within the margins of survival. Successful prevention of disease would be temporary only; it would postpone an inevitable equilibration of the food–population balance that would occur through some other form of human catastrophe (Dean 1991; Hamlin 1998). Malthusian sentiment blocked attempts to establish foundling hospitals. Notwithstanding the fact that such institutions were notoriously deadly to their inmates, it was felt that their existence encouraged irresponsible procreation—faced with full economic responsibility for their actions, men (or women, depending on how one viewed the prevailing legal arrangements for child support) would stifle their urges (McClure 1981).
By 1850, in both France and England it was no longer possible to maintain what for many was a complacent and convenient faith in the welfare-maximizing actions of a completely free society. A number of factors shattered this faith. Firstly, no government ever adopted the programme of the early nineteenth-century liberals in full. In central, eastern, and southern Europe the old concerns of state security continued to govern their public health. In Sweden and later France, concern about a state weakened by depopulation fostered attention to the health and welfare of individuals. Secondly, working-class parties, while often generally sympathetic with political liberalism, saw no advantage in economic liberalism. Often they demanded adherence to the moral economy of the old order, which damped fluctuations in grain prices and backed up the working conditions that craft guilds had established. Most important is that many liberals themselves arrived at what is properly called a biosocial vision, a concept of society which recognized that it was impractical, inhumane, and injudicious to impose economic and political responsibilities on people who were biologically incapable of meeting those responsibilities: liberty had biological prerequisites.
These considerations were central to debates in France and Britain in the 1830s and 1840s. Governments in both countries were apprehensive about revolution and wary of an alienated underclass, urban and rural, of people who could not be trusted with political rights and seemed immune to the incentives of the market. Such people represented a reservoir of disease, both literal physical disease and metaphorical social disease, that could infect those clinging precariously to the lower rungs of the respectable working classes. Reformers proposed somehow to transform these dangerous classes, usually with Bibles, schools, or experimental colonies. Such was the political background against which Edwin Chadwick (1800–1884), secretary of the English bureau charged with overseeing the administration of local poor relief, developed ‘the sanitary idea’ in the late 1830s (Finer 1952; Lewis 1952; Chadwick 1965; Richards 1980; Hamlin 1998). Chadwick justified public investment in comprehensive systems of water and sewerage on the grounds that saving lives—particularly of male breadwinners—would be recompensed in lowered costs for the support of widows and orphans. But he also suggested that sanitation would remoralize the underclass, and for many supporters this was its most important feature. Politically, sanitation was a brilliant idea, since every other general reform was deeply controversial: proposals for religion and education were plagued by sectarianism; calls to improve welfare by allowing free trade in grain (leading to lower food prices) ran afoul of powerful agricultural interests; proposals for regulating working conditions were unacceptable to powerful industrial interests. Notwithstanding complaints that towns be permitted to undertake it in their own way and their own good time, sanitation achieved remarkable popularity in nineteenth-century Britain as the locus of hope not just for improved health, but in general, for a prettier, happier, and better world.
In treating insanitation as the universal cause of disease, Chadwick hoped to establish a public health that was truly liberal. He sought to deflect attention from other causes of disease, such as malnutrition and overwork, for these were areas of great potential conflict between public health and liberal policy. For many, the liberty of the free (and in the case of women unmarried) adult to bargain in the market for labour without state intervention to limit hours or kinds of work was axiomatic. And the need for food was to be the spur for work and self-improvement. Interventions by what has recently been called a ‘nanny state’ seemed to imply an obligation to the state and to affirm the desirability of dependence and subjugation. There were grounds for such concern: the relations of political status to health were fraught with ambiguity. Frank had written passionately of misery as a cause of disease amongst the serfs of Austrian Italy, but had not advocated the elimination of serfdom. Virchow argued in 1848 that liberal political rights were the answer to typhus in Silesia while in Scotland W.P. Alison argued on the contrary that too rigorous a liberal regime was the cause of poverty-induced typhus (Frank 1941; Rosen 1947; Weindling 1984; Hamlin 1998).
For about a generation, from 1850 to 1880, sanitation was unchallenged in Britain (and in much of its empire) as the keystone of improved health. Chadwick’s campaigns led to a series of legislative acts, beginning with the Public Health Act of 1848 and culminating with a comprehensive act in 1875, that established state standards for urban sanitation and a bureau of state medicine, staffed by medical officers in central and local units of government and charged with detecting, responding to, and preventing outbreaks of disease (Wohl 1983). Outside Britain, sanitation did not have the same purchase. While continental towns and states took on sanitary projects for a variety of pragmatic reasons, adopting eventually the English paradigm of a water-centred sanitary system, the sanitary idea did not dominate public health (Simson 1978; Göckenjan 1985; Goubert 1989; Labisch 1992; Münch 1993; Ramsay 1994; Hennock 2000; Melosi 2000). They concerned themselves more with establishing networks of local medical officers and with controlling the transmission of contagious diseases through the regulation of travel and prostitution. Through the 1880s, the United States remained an exceptional case, coming closest to following a policy that an individual’s health was a private matter alone. The national government maintained a system of marine hospitals along the coasts and navigable rivers, but less for controlling the spread of epidemics than for relieving ports of the burden of caring for sick seamen. In the early 1880s it established a National Board of Health to advance knowledge on public health issues of common import, but despite a superb research performance, it was scrapped within a few years on the grounds that public health was the business of the individual states (Duffy 1990). Often dominated by rural interests, many state legislatures had little enthusiasm for public health. Louisiana, which established a state board of health to combat yellow fever, was an exception (Ellis 1992). Towns and cities were more active, but often only sporadically, taking steps when faced with epidemics. States that did establish boards of health usually focused on specific problems rather than on public health generally: in Massachusetts the allotment of pure water resources was a key issue; elsewhere it was food quality, care for the insane, vital statistics, or the threat of immigrants (Rosenkrantz 1972; Shattuck 1972; Kraut 1994). In Michigan concern about kerosene quality (it was being adulterated with volatile and explosive petroleum fractions) and arsenical wallpaper dyes spurred the establishment of a state board of health in 1873 (Duffy 1990).
1880 to 1970: the golden age of public health?
By the 1880s the classic liberalism of the first half of the nineteenth century was giving way to a resurgent statism. The European nations, the United States, and later Japan competed for colonies and international influence. If the newly liberated or the newly enfranchised had some claim to a right to health, they also had a duty to the state to be healthy. In most of the industrialized nations there was renewed interest in monitoring social conditions. While the emerging techniques of empirical social research gave this inquiry the aura of quantitative precision, the surveys disclosed little that was distinctly new about the lives or health of the mysterious poor, the usual targets of public health and social reform. Much of it seemed new, however, because it now registered as problematic. For example, the enormous contribution of infant deaths to total mortality had long been clear, but only towards the end of the century did infant mortality, persistently high even in relatively well-sanitized Britain, become a problem in itself as distinct from an indicator of sanitary conditions in general. The health conditions of women too, and of workers, began to command attention in a way that they had not done previously.
While these newly recognized public health problems partly reflected the changing distribution of political power, they also reflected anxiety about the nation’s vulnerability, and even the decadence of its population. Worried about the strengths of their armies, states like Britain discovered in the 1890s that too few of those they would call up were competent to be mobilized, and they attributed the problem to a vast range of causes: poor nutrition (coupled with lack of sunlight in smoky cities), bad sanitation, bad mothering, and bad heredity (Soloway 1982; Pick 1989; Porter 1991a, 1999). Epidemics of smallpox following the Franco-Prussian War of 1870 and again in the 1890s disclosed the gaps in vaccination programmes (Baldwin 1999; Brunton, in press). The usual response was to redouble the state’s efforts to take responsibility for the immune status of its population. The persistence of syphilis registered at a new level of unacceptability (Brandt 1985; Baldwin 1999).
This led to an expanded public health, one highly successful in terms of reduced mortality and morbidity. It was undertaken jointly in the name of the state and the people, but it involved the regulation of an individual’s life—home, work, family relations, recreation, sex—that went beyond the medical police of the previous century. From a contemporary standpoint such intimate regulation of the individual by the state may seem overbearing, but, with some notable exceptions, the populations of developed countries accepted it as an appropriate and even desirable role for the state.
New diseases, or old diseases that were (or seemed) more prevalent or virulent, new institutions for the practice of public health medicine, and advances in medical and social science contributed to this new relation between states and people. During the 1860s a long-standing analogy of disease with fermentation matured into the germ theory of disease as the research of Louis Pasteur and John Tyndall made clear the dependence of fermentation on some microscopic living ferment (Pelling 1978; Worboys 2000). During the 1880s, primarily through the work of emerging German and French schools of determinative bacteriologists, it became possible to distinguish many microbe species from one another, to ascertain the presence of particular species with some degree of confidence, and therefore to link individual species with particular diseases (Bulloch 1938). Through serological tests developed in the succeeding decades, the presence of a prior infection could be determined, regardless of whether anyone had noticed symptoms. Notwithstanding the increasing recognition of the many ways microbial agents of disease were transmitted from person to person, the effect of the rise of the germ theory was to focus attention on the body that housed and reproduced the germ—for example, the well-digger working through a mild case of typhoid—even when there were alternative strategies (water filtration or, by the second decade of the twentieth century, chlorination) that protected the public reasonably well most of the time (Hamlin 1990). The general interest in the human as germ bearer and culture medium brought with it an emphasis on the labour-intensive business of case-tracing, of keeping track not only of those who showed symptoms of the disease but also those with whom they had contact (Winslow 1980; Coleman 1987). In the key diseases of typhoid fever, syphilis, and tuberculosis concern with the inspection and regulation of people was exacerbated by the recognition that not all who were infected were symptomatic. The case of ‘Typhoid Mary’ Mallon, the asymptomatic typhoid carrier who lived for 26 years as an island-bound ‘guest’ of the City of New York, is notorious, but it was also important in the working out of both legal limits and cultural sensibilities with regard to the trade-off between civil rights and public health (Leavitt 1996). Newly virulent forms of diphtheria and scarlet fever, deadly childhood diseases transmitted person to person or by common domestic media, also gave immediacy to decisive public health intervention.
Such monitoring could not have occurred without a large rank and file of local public health officers. It was during the late nineteenth century that public health was identified as a distinct division of medicine and that most of the developed countries solidified a reasonably complete network of municipal and regional public health officers: in Germany, the Kreisartz; in France, the Officier de Santé; and in Britain, the Medical Officer of Health, assisted by the sanitary inspector. Increasingly these officers worked as part of hierarchical national health establishments to which they reported local health conditions and from which they received expert guidance. While preceding generations of public doctors had often been drawn from the ranks of undercapitalized young doctors, beginning in the mid-1870s many were specially trained and certified for public health work (Novak 1973; Watkin 1984; Acheson 1991; Porter 1991b). A commitment to public health was increasingly incompatible with ordinary medical practice, not so much because of its specialized knowledge, but because it was built upon a quite different ethic. There had long been economic tension between public and private medicine in areas of practice like vaccination, in which public authorities either took over entirely or inadequately compensated private practitioners for services that had traditionally been part of the ordinary medical marketplace (White 1991; Brunton, in press). But monitoring healthy carriers and those who might be susceptible to disease introduced a new regime of medicine—one which responded to an ethic of public good, even if there were no client-defined complaint. Effectively, bacteriology, epidemiology, and associated measures of immunological status redefined disease away from patient complaint. The healthy carrier might see no need to seek medical care, but to the public health doctor that person was a social problem. On occasion private doctors were appealed to for a diagnosis (bronchitis, pneumonia) that would protect one from the health officer’s diagnosis of tuberculosis, which would bring loss of employment and social stigma (Smith 1988).
Rivaling the germ theory as the major motif of public health thinking from the 1890s to the 1930s was the application of the emerging science of heredity to the improvement of the human populations, the science and practice of eugenics (Paul 1995; Kevles 1995). Whether or not eugenic concerns were the source of the greatest anxiety about the public’s health is debatable, but they were the locus of the greatest hope for health progress, the home of a residue of utopianism that had coloured the medical police and sanitary literature. Even more than other forms of public health, eugenics exposed a class, and sometimes a racial, division that had long been a part of public health: much of public health practice was predicated on a distinction between those, usually the poor, who were seen to represent the objects of public health efforts and those, often the well to do, who authorized intervention, whether to improve the lot of the poor, to protect ‘society’, or perhaps even to block the physical or moral contagia that might infect their own class (Kraut 1994; Anderson 1995). Eugenics appealed mainly to those with wealth and power: those others who were to improve their lot rarely identified heredity as the source of their unfortunate circumstances.
Such an attitude is reflected in the most infamous application of the eugenic viewpoint, the attempt by Nazi Germany to exterminate Jews and other ‘races’ regarded as inferior and unfit not only to intermarry with so-called ‘true Aryans’, but even to survive. While historians’ views of the origins of the Holocaust differ, some of the immediate precedents for a state policy of negative eugenics

1.2 The history and development of public health in developed countries

1.2 The history and development of public health in developed countries
Oxford Textbook of Public Health

1.2
The history and development of public health in developed countries
 
Christopher Hamlin

Introduction
 
Themes and problems in the history of public health
The public health of epidemic crisis: reaction
The public health of communal life: police
The public health of human potential
 
The age of liberalism: health in the name of the people 1790 to 1880
 
1880 to 1970: the golden age of public health?
 
The return of liberalism, 1970 to the present day: lifestyle, environment, and welfare
Chapter References

Introduction
Much more than is usually realized, public health is both a central and a problematic element of the history of the developed world—here conceived as Europe and the ‘Neo Europes’, i.e. the set of nations in broad latitude bands in the northern and southern hemispheres in which European institutions and biota have been particularly successful (Crosby 1986). It could be argued that a history of these regions in the last three centuries has broadly been a history of their health. It is in health terms that our lives are most profoundly different from those of our ancestors. We live longer; fewer parents experience the death of their young children and fewer adults experience the gradual ‘consumption’ of pulmonary tuberculosis; affluence and transportation mean most of us are no longer subject to periodic famines, and much less subject to epidemics of deadly infectious diseases, though we are less confident about that than we were two decades ago. Nor are most of us wracked with chronic pain, with abcesses, or induced deformities; most of us do not see life as a continuously painful experience and death as a merciful release, a view that is found fairly commonly in books of theology from three centuries ago (Browne 1964).Our health is adversely affected by aspects of the world we have built and the ways we choose to live individually and communally. A good deal is known about how to prevent those effects even if we do not always do so. Nonetheless, an expectation of health, and a preoccupation with it, are hallmarks of modernity. The freedom of action that ideally characterizes the lives of individuals in the developed world is predicated on health; so much of the agenda of development concerns health, that this transformation in health has some claim as one of the monumental changes in human history. It might be argued that economic and political progress are subordinate to securing health—they are means; health, which surely translates into life, liberty, and the pursuit of happiness, is the end.
If health is what we are all striving for, why is public health so invisible a part of our past? Until recently historians have been unconscionably negligent in investigating its history. Few general texts give it much attention (but see McNeill 1976); vast gaps in our empirical knowledge remain, and there is little good comparative work (but see Baldwin 1999; Porter 1999). Compared with the grand dramas of history, public health can seem a marginal function of modern society, representing little diversity, and nothing controversial. After all, we provide medicine, collect and evaluate demographic data, test water, and keep cities clean in roughly similar ways, according to the conventions of science, technology, and public administration that developed mainly in the nineteenth century. This view partly reflects a distortion of the history of public health by the modern professions and institutions of public health, which have often found it prudent to reduce the significance of the fact that they are necessarily political, even if their business is politics by medical means.
Public health is treated more broadly in this chapter, by examining actions taken in the name of a public to protect or improve the health of the public in general. Even that story is complicated by ambiguities—conceptual, causal, and definitional. Questions of what ‘health’ is, of what we mean by ‘public’, and of what we understand to be the proper domain of ‘public health’ are now, and have always been, contested matters. To define public health as that part of health that is the responsibility of the state does not help us to define these terms as what constitutes the state varies in time and place. However broadly or narrowly we define ‘health’, it will probably be admitted that many things that the public does will affect the public’s health. Hence a central issue will be the enigmatic relationship between that universal goal, the health of the public, and public health—as profession, science, component of public administration, and vision (Rosen 1958; Fee 1993; Porter 1999). Within that framework there will be more diversity, contingency, complexity, and controversy in its history than is usually apparent. Ultimately, however, there can be no single historical narrative. A history of public health is necessarily part of an ongoing conversation about a systematic endeavour that is both rational and moral. Inevitably the story we tell will depend on what public health is conceived to be, yet our notions of public health will themselves be a product of the evolution of the professions and institutions we have inherited, and of the myths, memories, and sensibilities that sustain them.
Themes and problems in the history of public health
It will help at the outset to recognize several of the most troublesome issues that face any historian of public health. Amongst these are the following.
The units of public health: states and publics

1.
The public and the state. ‘State’ and ‘public’ are not always interchangeable terms. The state, concerned with population, may arrive at different health-related policies from a public sphere of groups of citizens, carrying out a rational and critical dialogue amongst equals.

2.
The diversity of states. Even when there arose widely accepted reasons of state and agendas of state responsibility, not every state was in the position to act on them. The focus of public health was quite often at the level of local states, whose responsibility and jurisdiction were often unclear or overlapping. However, the state itself became an artificial unit for addressing global problems, and those beyond the merely human.

3.
Goals of the state. While health is now thought of in terms of the biological autonomy of individuals, that has rarely, and only recently, been the goal of programmes of public health. Health has meant a good supply of labour or of soldiers, control of excess population, protection of élites, enhancement of the genetic stock of a population, or environmental stability.
The condition that is truly health

1.
The definition of health. The combating of epidemic infectious diseases has often seemed the core of public health. When we go beyond these diseases, questions arise of what level and kind of physical and mental well being the state should guarantee or require of its citizens, and of the status of health as a source of imperatives in competition with other imperatives such as the market, the environment, or individual liberty. What sort of normality will a society insist upon?

2.
The problem of causation of disease. In a broad sense, diseases have many causes—personal, social, cultural, political, and economic, as well as biological. Amongst the multiple antecedents that converge in the production of epidemic or endemic disease, there are numerous opportunities to intervene. Notions of rights that must be respected, or of political or technical practicality, narrow that list. Discussion of cause has often included notions of responsibility or preventability—of where in a social system there is flexibility, of who or what must change to prevent disease.

3.
Equality and rights—race, class, gender. The idea of ‘health for all’ disguises the fact that the interests of the public have not always been the interests of all of its members. Public health actions have often reflected, and sometimes exacerbated, a view of the world in which some groups were seen primarily as a threat to others. Often views of the standards of health that were matters of state differed for different groups: key divisions were by sex, by age (infants, working adults, and the aged all had a different status), by wealth, and by race, religion, or historical heritage (indigenous people had a different status from colonial rulers). Whether the public’s response to disease was to advise, aid, or condemn, or to imprison, banish, or kill, reflected the allocation of rights and the distribution of power more than the status of the biological threat.
The health that is truly public

1.
Health and public health. Most modern states have in principle distinguished aspects of health that are the business of the public from those that are for the individual to pursue in the medical marketplace, although the borders have been drawn in many different ways.

2.
Medical and non-medical public health. Whilst public health has evolved into a subdivision of medicine with minimal and subordinate inclusion of the ancillary disciplines of engineering and the social sciences, the fact that health has been improved by many non-medical factors—economic prosperity, town planning, architecture, religious and humanitarian charity, the power of organized labour, and even broader political changes resulting in the greater availability of political or economic rights—suggests that any comprehensive account of improved health must include non-medical factors.

3.
Health as authority. Given the amorphous nature of the concept of health and its status as the supreme good of human existence, it has been attractive as an imperative for political action. If other ‘reasons of state’ carry more immediacy, public health has better claim to the moral high ground because it is seen to be universal and apolitical, exactly the qualities that make it attractive to act politically in the name of health.
These questions are too many to address individually in this chapter, but they inform what follows. The history of public health in the developed world can be conceived in terms of three relatively distinct missions: public health as reaction to epidemics, as a form of police, and as a means of betterment. Public health was first reactive. Faced with the threat of an epidemic, European states closed borders and ports, instituted fumigation, shut down piggeries, and isolated victims. The second is public health as police. It is probably the case that wherever humans live in communities customs arise for the regulation of behaviour and the maintenance of the communal environment. Gradually much of the enforcement of these community standards became medical. The control of food adulteration or prostitution, of the indigent and the transient, or concern over dung or smoke overlapped with the control of epidemics, but went well beyond it, and occurred in normal as well as in epidemic times. Last to arise was public health as a proactive political vision for the improvement of the health of all. Even into the nineteenth century the view was widespread that remarkably high urban or infant death rates were inevitable. A proactive public health involved a determination that normal conditions of health, if they could be improved, were not acceptable conditions of health. That this sensibility changed was due partly to technical achievements, such as smallpox inoculation and later vaccination, and to better demographic information, due also to a more optimistic view of the possibility of human progress. Such visions sustained the building of comprehensive urban water and sewerage systems before there was wide acceptance that these needed to be universal features of cities; such visions have periodically led public health to venture beyond recognizably medical bounds, to recognize, for example, nuclear warfare or gun violence as public health problems.
The public health of epidemic crisis: reaction
Regardless of their virulence and pervasiveness, epidemic (and even more so, endemic diseases) do not necessarily warrant comment or action—they may simply be acknowledged as part of life. For a public to decide to fight an epidemic it must believe it can do something to mitigate it. A belief in the possibility of effective action is a prerequisite for public health; one of the most intriguing problems in its history is the emergence of that belief. It does not coincide with the replacement of supernatural by natural explanations of disease causation. ‘Will-of-God’ explanations of disease have sometimes incited public action, but on other occasions implied abject resignation. Similarly, naturalistic explanations, attributing epidemics to a mysterious element in the atmosphere or, as in the case of classical conceptions of smallpox, to a normal process of fermentation in the growing body, have on some occasions been taken as proof that we can do nothing beyond giving supportive care and on other occasions sanctioned preventive public action. In each case assessments of technical and political practicality are mixed with assessments of propriety—is taking such action part of our cultural destiny?
These issues are already evident in the first European account of a widely fatal epidemic, the unidentified plague that struck Athens in 430 BC. Athenians both recognized contagion and acknowledged a duty to aid the afflicted, Thucydides informs us, but these recognitions did not translate into expectations of prevention, mitigation, or escape (Thucydides 1950; Longrigg 1992). Few fled; on the contrary, the epidemic was exacerbated by an influx from the countryside. While it was appreciated that those who survived the disease were unlikely to take it again, and some hoped it would bring permanent immunity from all afflictions, the main response was to accept one’s fate. The disease was attributed to seasons, as well as to gods, and said to have been prophesied. Such resignation would be central in the moral philosophies of the Roman world, Stoicism and Epicureanism, both of which taught one to accept what was fated or necessary (Veyne 1987). Later writers in the Christian world attributed the failure of Islam to take active steps against plague to such an outlook. While classical Islamic doctors developed a science of hygiene to a remarkable degree, it did not follow that one should apply that knowledge in an epidemic: if plague came that was Allah’s will. To fight it would be futile and impious; one’s duty was to trust (Dols 1977; Conrad 1992).
In contrast, the response to epidemic disease in the medieval Christian Latin countries was activist. One could prevent disease from taking hold in a community, or extinguish it if it did, or at least avoid it personally. This activism had many targets, reflective of the syncretism of medieval Latin culture. In the Old and New Testaments alone, disease had a multiplicity of conflicting significations. It represented the dispensation of God to an individual, perhaps as punishment or a test. To act against disease by intervening to help others stricken by a dangerous epidemic was an act of devotion. If one died in such a situation that was a sign of grace; if one did not die, and helped to save others, that was equally a sign of grace. The laws of hygiene in the Pentateuch permitted a naturalistic interpretation of disease. Unclean acts or other transgressions, like failing to isolate lepers from society, generated the retribution of disease, perhaps through God’s appointed secondary or natural causes. Disease might even be naturally communicative; in such a case, communal decisions to maintain the levitical laws were means not only of acting against potential epidemics but of maintaining the police of the community and perhaps of augmenting its welfare (Douglass 1966; Winslow 1980; Amundsen and Ferngren 1986; Dorff 1986). Such views would become widespread amongst nineteenth-century sanitarians.
The two diseases that did spur medieval Europeans to comment and react were leprosy and the plague. Whilst it is difficult to assess how much leprosy there was in medieval Europe, the common view is that there was a vast over-reaction, in terms of both investment in institutions to house victims of the disease—there were said to be several thousand leprosaria—and of detecting and isolating cases to prevent transmission of the disease. In keeping with the prominence of leprosy in the Bible, the professionals who diagnosed it were churchmen, not medical men. The diagnosis was a loose one; it might be based on skin blemishes alone. Often it involved an accusation. It led to the expulsion of the victim from ecclesiastical and civil society, symbolized in a ceremony resembling a funeral. Subsequently, no one was to touch or come near the leper or to touch what the leper touched. The theory of contagion provided the rationale for such action, but Skisnes has argued that the clinical characteristics of the disease itself—for example, its slow development, the visible disfigurement it produced—triggered such a reaction (Skisnes 1973; Brody 1974; Richards 1977; Carmichael 1997). Even if leprosy precautions did embody empirical knowledge of contagion, it, like most other diseases, belonged to the sphere of providence. While leprosy was sometimes seen as a punishment of sin, it might also reflect grace: God’s singling out of an individual to bear a particular burden of suffering.
The prototypical institutional responses to epidemic disease, however, were those that arose in response to plague. The first wave of plague, the Black Death, spread across Europe from 1347 to 1351, and thereafter the disease returned to most areas about once every two decades for the next three centuries. This was a catastrophic disease, with case-fatality rates ranging from 30 to nearly 100 per cent depending on the strain of plague, the means of transmission, and the immunological state of the population. Plague and accompanying diseases reduced the European population by roughly a third in the fourteenth century and were responsible for only a very slow population growth during the following two centuries. As with leprosy, the aetiology of plague and the associated means of prevention and mitigation of the disease were conceived in terms of divine will and natural process, though even more clearly than with leprosy the distinction is misleading: Nature, whether in the courses of the stars, in meteorological phenomena, or in the process of contagion, was God’s instrument (Nohl 1926; Ziegler 1969).
It is clear that in many communities the coming of plague was unacceptable. It could not be reconciled with the usual course of events, but indicated some fundamental violation of the cosmos, of an order which included human society. Boccaccio, whose Decameron is a document of the Black Death, testifies to one form of activism—a discarding of social convention and religious duty, a devil-may-care indulgence in the present founded in the recognition that life was short and the future uncertain. Those who could often fled plague-ridden places. Others, taking the view that the plague reflected God’s just anger with hopelessly corrupt civil and ecclesiastical authority, saw a clear need to take charge of matters temporal and spiritual, to cleanse themselves, the state, and the church. Righteousness would end the plague. Thus the plague precipitated a social crisis, as would epidemics of other diseases in subsequent centuries. Beyond the massive disruption caused by high mortality and morbidity and an interruption of commerce and industry, the loss of faith in the conventions and institutions of society was a critical blow. Why respect property or family or communal obligations, pay taxes, invest money, or tolerate rivals and others? Latent tensions within society had an excuse to become active.
When people acted precipitately and independently, civil and ecclesiastical institutions were threatened, and it is in their responses that we clearly see the emergence of public health as a form of public authority. For a state, to act in a crisis was to keep the state going; one maintained authority by acting authoritatively. If some state actions were rational in terms of naturalistic aspects of theories of the plague, the viability of civic authority itself was probably more crucial than any lives they might save.
All these issues are evident in the manifold responses to plague from the mid-fourteenth to the early eighteenth century. Particularly in Germany, the response to the Black Death was to challenge civil and ecclesiastical authority. In 1349, lay flagellant groups paraded from town to town, giving public penitential performances to end the plague. While they were usually well received, and while their practices were not unorthodox, they did draw attention to what the Church had failed to do, and Pope Clement VI condemned the movement. But the state response to such actions was not uniform, for medieval and early states were not monoliths, but fragile alliances of multiple levels and kinds of authority, existing in continual tension with one another. In Basel, the majority Christian population blamed the plague on Jews—either it came by direct divine action because Jews had been allowed to live in the town, or through a natural agent with which the Jews had presumably poisoned the town’s water. The town’s Jews were rounded up, sequestered on an island, and burned. Here it was a local state, the town council, that took the action. Its credibility was at stake; it needed to be seen to act boldly to secure an end to the epidemic; its action built on pre-existing antisemitism. But to the central state, the Holy Roman Empire, such actions against one group of its subjects verged on anarchy. Emperor Charles IV condemned the persecution and asserted on the basis of medical and religious authority that the Jews were not responsible for the plague (Ziegler 1969).
In contrast, the approaches to plague prevention and control developed in the next two centuries in the Italian city states were humane, focused mainly on naturalistic intervention, and probably relatively successful. Plague control measures emerged out of a tradition of close municipal management, and in a cosmopolitan intellectual environment. Italy, after all, was the main European centre for receiving Galenic and Islamic medical knowledge. Included were concepts of hygiene, disease causation, and the purifying of enclosed spaces. The preventive measures taken in Italian city states were eclectic. They included the development of the 40-day hold on ships or other traffic coming from potentially infected places (the quarantine), the isolation of victims (and families of victims), and numerous means of purifying the air and/or destroying contamination: bonfires, burning sulphur, burning clothes and bedding, washing surfaces with lime or vinegar, killing or removing urban animals. Such actions were predicated on an understanding that the disease moved from place to place through some medium or media, possibly involving, though probably not limited to, person-to-person contact. But while the eclecticism of this response is certainly indicative of uncertainty about how plague spread, the actions do show a responsive civil authority (Cipolla 1979, 1992). Indeed, in some ways plague prevention initiatives were themselves a means of state growth. Plague control required officials to oversee quarantine or isolation procedures. It required a staff to disinfect, and a structure to gather information on health conditions in remote ends of the state. An embassy, which in the high Middle Ages signified an official visit by one state to another, became in the Italian city states the permanent presence of one state in the territory of another. Its initial purpose was to monitor the public health in the host country and to send word home if plague broke out (Cipolla 1981; Slack 1985).
The patterns and practices of the plague form the core of the catalogue of public responses to later epidemics of other diseases—flight, the exacerbation of social tensions leading to scapegoating, a heightening of religious seriousness (often combined with a collapse of normal customs and obligations), and a mix of pragmatic efforts to disinfect people, places, goods, or the environment, and to isolate victims or potentially contagious strangers (Briggs 1961). The particular mix of these actions reflected the current state of debate between proponents of atmospheric theories, including miasmatic theories, which located the origins of the epidemic in some unusual state of air, and of contagionist theories, which emphasized various forms of interpersonal transmission, and presumed that epidemics could spread only as far as infected humans (or human products) carried them (Ackerknecht 1948).
Thus, in the nineteenth century the series of cholera pandemics which arrived in Europe in the early 1830s brought forth accusations by the poor that the rich were poisoning them (particularly the doctors who wanted their bodies for teaching and research), and by the rich that the poor wantonly persisted in living in disease-nurturing squalor. It also engendered calls for public fasts, pure living, and declamations against sinful society, and a variety of attempts to disinfect, quarantine, and isolate (Briggs 1961; Rosenberg 1962; McGrew 1965; Durey 1979; Delaporte 1986; Richardson 1988; Evans 1990; Snowden 1995). In nineteenth-century America, the response to yellow fever and malaria was regular flight and the abandonment of cities during the summer by those who could afford to do so (Ellis 1992; Humphreys 1992). The summer home, in cooler, cleaner, and higher ground, became a mark of upper-middle-class life.
Significant new elements of that pattern entered in connection with efforts to control epidemics of three other diseases: venereal diseases, particularly syphilis, smallpox, and a mix of diseases including typhus, typhoid, and relapsing fever that was known as continued fever.
Whether syphilis came to Europe from America or Africa, or had been present in Europe in milder form (perhaps labelled as leprosy), is a question that has been much debated. What is clear is that a virulent epidemic known often as the French disease or pox began to spread quickly in the last years of the fifteenth century, and can be traced to the intercourse between Italian prostitutes and French and Spanish soldiers during the siege of Naples in 1494. The connection of the disease with sex was made quickly, partly because of the initial symptoms on the external genitalia—the more expressive German term lustseuche had been adopted by 1510. As had not been the case with plague or leprosy, syphilis represented a serious epidemic disease that constituted a state problem, particularly because it affected military strength, but which was not susceptible to large-scale public action. It was further complicated by having variable symptoms and effects, having a long course during parts of which it was not clearly manifest, and varying in contagiousness and virulence. If syphilis was to be controlled, states must prevail on individuals to avoid behaviours that spread the disease. One might expect that the moral opprobrium that went with contracting a disease that was usually acquired through illicit sexual contact to have had some role in discouraging such practices, but it did not. For an adventurous young man, a case of pox was a cost of doing business, even a badge of achievement. The disease was deemed curable, chiefly through mercurial treatments. While there are suggestions that by the eighteenth century syphilis had become something to hide (though not necessarily for moral reasons), such was not the case during the sixteenth century, when the disease was spreading rapidly (Arrizabalaga 1993; Arrizabalaga et al. 1997).
State attention shifted from cure to prevention only in the eighteenth century, partly because syphilis was becoming more clearly distinguished from other venereal conditions and as the varied phenomena of tertiary syphilis were becoming more evident. While the European states varied significantly in the priority they put on syphilis as a public problem, their approaches did not vary greatly: the disease was to be controlled by regulating prostitutes, who were regarded as the reservoir that maintained the contagion. Such approaches may well have had a significant effect in controlling the disease, but they exposed tensions between state and individual rights that have since become common in public health. Such conflicts developed first in the United Kingdom following the first Contagious Diseases Act of 1862, even though its programme against venereal disease was much smaller than that of France, where prostitution regulation was a central feature of public hygiene. The British Act allowed the police in designated garrison towns to arrest and inspect women presumed to be prostitutes and to confine infected women in hospital. It led to a sustained campaign for repeal that was ultimately successful in 1885. The repealers represented a broad coalition. Some objected that the legislation was morally indefensible because it acquiesced in the immoral industry of prostitution, others that it singled out women as responsible for a problem that was as much the responsibility of the men who used the services of prostitutes, while still others objected that the practice of arresting women was arbitrary (except with respect to class) and stigmatized working-class women who were not prostitutes (Walkowitz 1980; McHugh 1982).
The problem that the British parliament faced stemmed from liberal principles of human rights. Ironically, the Contagious Diseases Acts had been touted as respecting rights—the rights of men: the state would inspect women because male soldiers and sailors would not put up with genital inspection. Nor should they be expected to in a state in which the male franchise was broadening and the public was becoming increasingly uneasy with declarations that part of its population existed as cannon fodder. But recognizing the rights of men simply made it all the more clear that they were not accorded to women.
The issues that arose in combating venereal diseases arose in a more general way with regard to smallpox. While the ninth-century doctor Al-Razi had viewed smallpox as a normal childhood condition, a particularly dangerous part of growing up, it had become more virulent in fifteenth and sixteenth century Europe (Clendening 1942). By the eighteenth century it was accounting for 10 to 15 per cent of deaths. It was then widely recognized as a contagious disease of childhood, one sufficiently deadly that many parents exposed young children to it if it were present. Sooner or later one would be exposed—the older child who died from it was a time investment lost; the younger one who survived was subsequently immune. Accordingly, the practice arose in many parts of the world to induce smallpox. Whilst folk therapeutics owed nothing to medical statistics, it was recognized that some means of inducing the disease made it significantly less virulent. Mortality rates of 25 per cent or more might drop to a few per cent. Notwithstanding assertions that such practice defied providence, and its inherently counterintuitive character, such logic and experience had much to do with the relatively rapid acceptance of inoculation after 1721, when it was introduced into Western Europe by Lady Mary Wortley Montagu, a particularly ell-connected aristocrat, who had observed the process in Turkey. It was taken up first in the British Isles; its subsequent spread elsewhere depended on the patronage of royalty and nobility, on increases in the safety of the procedure, especially when carried out by the most highly skilled practitioners, and the acquiescence of at least a segment of the medical profession (Miller 1957; Razell 1977; Hopkins 1983).
In 1798 the English practitioner Edward Jenner made immunization significantly safer by introducing the practice of vaccination with cowpox. Increasingly, smallpox prevention, which had hitherto been a personal matter, became a state concern. Presumably, the institutions that orchestrated quarantines could also ensure universal vaccination. But here too there was ambiguity: in whose interests were vaccination programmes to be undertaken? England began offering free vaccination in 1840, made it compulsory in 1853, and instituted fines for non-compliance in 1873. The initial assumption that all would take advantage of this free medical service proved unfounded; as the authorities sought to give the vaccination laws more teeth, they encountered growing opposition and decreasing rates of compliance. In 1898 antivaccinationists achieved permission for conscientious objectors to forego having their children vaccinated. The opposition was able to show that the dangerous procedure was not carried out everywhere with sufficient skill or care; and a real decline in smallpox meant decreasing risk to the unvaccinated. But mandatory vaccination also exposed underlying tension between the state and the public: in an atmosphere of distrust of the state, the more insistent the state became, the more convinced became the public that the state’s actions were not in its interests (Porter and Porter 1988; Baldwin 1999; Brunton, in press).
It is important to emphasize that for most of the history of the West, efforts to combat epidemic disease had not reflected any sense of obligation to the health of individuals. At stake was the military, commercial, and cultural welfare of the state; the welfare of individual subjects (a better term than ‘citizens’ for much of the period) was incidental. While states devoted substantial resources to enforcing quarantines and other health regulations (and absorbed considerable costs in lost commerce), it would be misleading to think of them acting in some quasi-contractual way as agents of groups of individuals who had recognized that public actions were necessary to secure their own health. Whilst many places had town or parish doctors, and while there was often an expectation that the state take steps to protect the welfare of its subjects (such as making food affordable in times of dearth), early modern political theorists recognized no obligation of the state to protect the health of individuals. What was at risk in an epidemic was the state itself: the collection of taxes, the maintenance of defence, the continuance of commerce, and even the orderly transfer of property at a time of high mortality.
Perhaps nowhere was the tension between individual and state so great as in the combating of what was called continued fever. Typhus, typhoid, relapsing fever, and yellow fever were amongst the several epidemic diseases that appeared or became increasingly prominent in the aftermath of the Black Death. This ‘continued fever’ was endemic as well as epidemic, and amidst vast disagreement about classification and cause, there was general agreement about its frequent association with social catastrophe and squalor

1.1 Current scope and concerns in public health (cont’2)

Public health strategies
Surveillance and monitoring
The backbone of public health strategy is the development, implementation, and maintenance of an accurate reliable health information or surveillance system. Donald A. Henderson, who led the successful campaign to eliminate smallpox, has said that ‘surveillance serves as the brain and nervous system for programmes to prevent and control disease.’ The elimination of smallpox from the world would not have been possible without effective surveillance. Surveillance can be used to establish the extent and distribution of a disease and the prevalence of risk factors or behaviours for disease in the population, to monitor the trends of disease or health factors in the community, to establish appropriate programme priorities and allocate resources, and to evaluate the impact of intervention strategies.
Surveillance systems can include information on the occurrence of infectious and chronic diseases, environmental information (including occupational exposures), behavioural characteristics of the population, and availability of medical facilities. It has become increasingly apparent that many infectious and chronic diseases and risk factors for them are determined by human behaviour. Thus, to implement effective intervention strategies it is necessary to know the behavioural characteristics of the population, including their sexual behaviour, and whether it is changing over time. To be most useful, information must be collected on a regular basis and reported rapidly while action in response to the information is still likely to be effective, particularly for infectious diseases and hazardous environmental/occupational exposures. Tardy information about disease outbreaks or sudden environmental exposures such as radiation hazards, for example, precludes the early implementation of effective intervention procedures when they are most likely to be effective. Surveillance systems are expensive to implement and maintain so it is important that they be evaluated periodically to assure that they remain cost-effective and are providing the information which is essential for the resolution of contemporary problems.
The most extensive experience in surveillance work has concerned the communicable diseases. There are fewer mechanisms for reporting chronic diseases, other than mortality. Currently, surveillance for environmental hazards and occupational exposures is even less satisfactory than surveillance for either infectious or chronic diseases. Most urban areas in developed countries have systems for monitoring quality of air and quality of water for human consumption, although provisions for monitoring new contaminants, such as cadmium and magnesium, have been inadequate. Considerable attention also needs to be directed to surveillance of recreational waters, toxic dump sites, and radiation sources. In addition, workers continue to be exposed to unsafe working conditions, particularly in small industries which are more difficult to monitor and regulate. Until permanent information systems which provide reliable, accurate, and rapid reporting of all principal factors affecting community health can be implemented, effective programmes cannot be fully realized. Implementation of effective surveillance is particularly difficult in developing countries that have limited resources or fewer health professionals with the necessary expertise. Yet, it is developing countries that have the greatest need for information on the prevalence of disease and risk factors for disease.
Intervention
Effective intervention forms the heart of public health efforts to protect communities from health hazards. These efforts include reducing the number of individuals vulnerable to infectious and chronic diseases, treating people early in the course of disease, modifying the environment, and promoting healthy behaviour of both communities and individuals.
Technological advances play a key role in developing effective intervention programmes, but often implementation of these programmes depends on the use of innovative epidemiological strategies, behavioural modification of individual lifestyles, and changing the political will of the community. For example, a satisfactory vaccine for smallpox existed for centuries before eradication was made possible by changing from an untargeted mass vaccination approach to an active surveillance and containment strategy supported by adequate resources. Legislation to control tobacco use by increasing the tax (and therefore the price) of tobacco products, restricting advertising for them and the places they can be used, denying access to youngsters, and requiring warning labels can change the whole social milieu regarding tobacco use and thus reduce it substantially, as has happened in California. Likewise, reduction of air pollution has been achieved by legislation requiring necessary corrective action after inspection of vehicles for pollutant levels and curtailing industrial pollution of the atmosphere.
Epidemiological research has identified many risk factors for cardiovascular disease, but implementation of intervention strategies to reduce these risk factors depends on convincing people to alter their basic habits such as diet and exercise. Methods for prevention of most sexually transmitted diseases, including AIDS, are well known, and treatment of many of them has been available for decades. Nonetheless, efforts to reduce the incidence of these diseases have been largely unsuccessful because of the difficulty of modifying this most intimate aspect of lifestyle. The source of many of the pollutants affecting the major cities of both the developed and the developing world are known, but techniques to reduce these pollutants involve major expenses by both the public and industry, and often cause inconvenience for the public.
Intervention through legislation typically invokes strong resistance, but that resistance can be overcome as has been demonstrated with the reduction of water and air pollution in Los Angeles through legislation that regulates industrial wastes and vehicle emissions. Changing the public’s concept of what is socially acceptable can result in change, as has been demonstrated by the current attitude towards smoking in the United States and the current attitude towards vehicles that obviously pollute the environment in many cities of the developed world.
In summary, successful public health intervention is the result of technical advances coupled with the use of innovative epidemiological strategies, education of the public about the need for intervention, implementation of effective behavioural modification techniques, and induction of the political will.
Evaluation
An essential component of public health strategies is evaluation. The effectiveness of surveillance and intervention programmes changes over time due to changes in the incidence of disease, the development of new health hazards, and the development of new technologies for measurement and control. Thus, evaluation should be an ongoing, integral part of all public health surveillance and intervention programmes. For many years vaccination of all people in the United States against smallpox persisted even though the risk of an adverse outcome was greater from the vaccine than the risk of acquiring smallpox. Ultimately, the worldwide eradication of smallpox eliminated the need for vaccination against that disease. Since any immunization is associated with some adverse reactions, continued use must provide more benefit than risk. Because this ratio changes in relation to many factors, the relationship must continually be re-evaluated.
The effectiveness of different strategies of community intervention for promotion of healthy lifestyles can also be evaluated. Numerous studies have demonstrated, for example, that providing information about health hazards is seldom sufficient to motivate people to change their lifestyle.
Evaluation of environmental intervention has progressed less rapidly, partly because of the need for appropriate technology to identify and measure levels of pollutants in air, water, land, and the workplace, and partly because of the difficulty in identifying disease outcomes that may take years of chronic exposure. There is a need for earlier markers of disease processes resulting from exposure to pollutants which would permit faster evaluation. The cost of implementing environmental controls means that the public will be unlikely to pay for controls that have not been evaluated and demonstrated to result in improvement in health.
In summary, surveillance, intervention, and evaluation are the backbone of public health strategies to prevent disease, eliminate health hazards, and promote health in the community.
Organization of public health
Government structure
Organization of health services, both public and private, is largely conditioned by the cultural, political, and organizational patterns of the countries in which they are located. Thus in the United Kingdom and many European countries a national health service covers preventive, community, and clinical health services. Conversely, in the United States the tendency has been towards state and local governmental autonomy in environmental and health education services and medical care for the indigent population. Clinical services have been left principally in the private sector with federal governmental payments only for limited segments of the population.
United States
The United States constitution provides for the states to relinquish only those governmental powers that are essential to maintain the union. Accordingly, state and local governments historically have taken the main responsibility for public health, with most programmes being conducted at the local level under state regulation and only broad directions and incentives provided by the federal government. Thus the local jurisdictions (the county, city, or township), through authority delegated from the states, typically have undertaken communicable disease surveillance and control, maternal and child health services, environmental surveillance and control, and other traditional public health activities.
The role of the federal government in public health has evolved for the most part on a piecemeal basis. Usually it has assumed responsibility for meeting those needs not otherwise met by private, local, or state agencies. Generally, these initiatives have been categorical in nature, directed primarily at specific disease problems, such as cancer, or towards segments of the population, such as the poor. Exceptions to this approach have been the creation of the National Institutes of Health, the major research funding source in the United States, certain regulatory agencies such as the Environmental Protection Agency and the Food and Drug Administration, and the agencies and programmes stemming from the 1935 Social Security Act, the basic social security legislation for the nation.
Healthy People 2000, the National Promotion and Disease Prevention Objectives (US DHHS 1991), and other United States government documents do not have the force of legislation but serve as important guidelines and encouragement for local health agencies. The role of the federal government thus remains largely to suggest and encourage actions (sometimes with specific subsidies) that are either implemented (or ignored) at the local level.
Europe
In the European nations the philosophy of central control of public health has predominated, perhaps because of their smaller size and more homogeneous populations. The majority of the European nations have a national health scheme that is administered federally. Thus, to a larger degree than in the United States, public health activities are implemented centrally through an organized system.
The presence of a national health scheme, however, has not guaranteed more effective public health programming. Often the agencies within these federal governments do not command the respect and resources accorded the clinical components and therefore are not as effective as they could be. Also, many European countries lack schools of public health or their equivalents to prepare professionals for public health careers. Nonetheless, equity in access to medical care has generally been greater in the European systems than in the United States.
Whatever the government structure for public health, the need for good management is increasingly recognized. The responsibility for handling budgets that are often substantial, complex organizations involving many different categories of people, and maintaining effective relationships with a wide array of health agencies as well as other bodies, requires great managerial skill. The inadequate preparation in management skills of many health professionals who have previously occupied public health administrative posts has induced some governing authorities to call upon ‘managers’ rather than public health experts for the key positions in public health. This is increasingly true in the United States. Too often, public health administration has been reduced to budget control or complying with already adopted laws and regulations. As a result, little attention is given to analysing health problems or devising innovative solutions. The ideal is to combine the talent for leadership in public health with managerial skill.
Developing countries
In the developing countries the organization of public health is determined to a greater extent by economic and developmental considerations. Governments in developing countries tend to provide health services, although not at the level of sophistication available in the developed countries. In most of the developing countries responsibility for public health is usually assumed by the federal government through its Ministry of Health. Typically, a network of public health centres is established at the provincial and local levels, for example, the establishment of a network of anti-epidemic stations in China which are under the broad direction of the federal government. Often these provincial and local centres provide not only the usual public health services, but also provide care at local and provincial hospitals. The poorest of the developing countries also depend to a great extent upon support from non-governmental organizations and international agencies such as the WHO. These organizations do not always share the same vision of public health as the individual countries. Furthermore, they tend to provide assistance for specific diseases or subpopulations which often distort the priorities for health efforts. Health must compete with other governmental priorities for limited resources and often comes out second best. Because of the pressing need to address disease problems, particularly infectious disease problems, and the economic constraints under which they must operate, very few developing countries have developed plans for safeguarding the environment and assuring that it is healthy. Finally, there is often a shortage of health professionals trained in modern public health to design and implement effective public health programmes.
In summary, the organization of public health in various countries appears to be largely determined at every level—local, state, and national—by economic, cultural, and historical factors resulting in a wide array of often complex organizational arrangements.
Non-governmental public health agencies
Voluntary health agencies have flourished in the United States and to a somewhat lesser extent in Europe. They tend to be organized around specific entities: for example, the American Cancer Society, the American Heart Association, and the American Lung Association. Their success has encouraged the development of many more such groups, devoted to practically all the major diseases and several lesser ones.
Typically organized at the national level in the United States, with state divisions and local chapters, these voluntary health agencies bring together health professionals who are leaders in their particular fields and interested members of the public. They involve millions of people in fund raising for, and operation of, disease control activities. In this way they have contributed much to the level of enlightenment and activity concerning health, particularly in the United States. Their programmes usually include support of health research, professional education, public education, and demonstration services devoted to their own particular disease category.
These voluntary health agencies have become a considerable force in public health. They are able to operate with fewer constraints than governmental departments in the developed nations and thus have often broken new ground in the field. The American Heart Association and the American Cancer Society, for example, have been particularly active in bringing the concepts of risk factors and healthy lifestyles before the American public.
In the developing nations non-governmental organizations have played an even more important role in promoting health. Often governments in developing countries are constrained from specific activities by political and economic limitations. Non-governmental agencies, because they are not subject to these constraints, often play a key role in disease intervention and promotion of health. In the poorest countries, however, the health ministries must sometimes subjugate their health priorities to those of the non-governmental organizations because the latter have the funds and the freedom to implement activities that the governments cannot. In extreme cases the different non-governmental organizations may have conflicting health agendas making the setting of priorities by local public health professionals very difficult. Internationally, the increasing importance of non-governmental organizations in assisting the poorest countries to attack their major health problems is reflected in the number of non-governmental organizations recognized and affiliated with the WHO.
Another force in developing public health policy has been private foundations such as the Robert Wood Johnson Foundation, the Pew Memorial Fund, the Kellogg Foundation, the Rockefeller Foundation, and, most recently, the Gates Foundation and the California Wellness Foundation. These foundations support studies and trials of various approaches to health care, medical education, and public health. Thus they often point the way towards new ventures in public health. The Rockefeller Foundation, for example, has fostered an international network of doctors in clinical epidemiology by sponsoring selected training programmes in medical schools in developing countries. This has had a major impact both in promoting epidemiology and in increasing its profile within medical schools in the participating countries. By supporting programmes and studies with particular social and medical implications, these foundations will probably continue to play an important role in influencing public health policy.
Summary
The scope of public health in the last part of the twentieth century has expanded greatly (Fielding 1999). Not only have the number of recognized health hazards to the public increased, the strategies available to solve them have grown commensurately. Public health has borrowed and adapted knowledge from the physiological, biological, medical, physical, behavioural, and mathematical sciences, and has been quick to recognize the potential of new fields such as the computer sciences for improving, safeguarding, maintaining, and promoting the health of the community.
As the major communicable diseases have been brought under control through public health measures, more effort has been directed at chronic disease control, mental health, assuring a safe environment, reduction of accidents, violence, and homicide, and promotion of healthy lifestyles in developed countries. Although developing countries must continue to address persisting infectious diseases, they increasingly suffer from the ills of developed countries, particularly degradation of the environment. The biological sciences remain an important underpinning element of public health, but the contributions of the physical, mathematical, and behavioural sciences are increasingly recognized. As in the past, improvements in the health of the public in the future will be achieved by inducing public awareness and concern, which results in behaviour change, and the introduction and passage of effective legislation and regulations that are implemented by professionals committed to the principles of public health.
The previous effectiveness of such efforts, and the realization of the cost-effectiveness of preventive strategies for promoting and maintaining health, have brought renewed attention to public health and have set the stage for a new public health revolution.
Chapter References
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Breslow, L. (1999) From disease prevention to health promotion. Journal of the American Medical Association, 281, 1030–3.
Breslow, L. and Breslow, N. (1993). Health practices and disability: some evidence from Alameda County. Preventive Medicine, 22, 86–95.
Detels, R., Tashkin, D.P., Sayre, J.W., et al. (1991). The UCLA Population Studies of Chronic Obstructive Respiratory Disease (CORD): X. A cohort study of changes in respiratory function associated with chronic exposure to SOx, NOx, and hydrocarbons. American Journal of Public Health, 81, 350–9.
Fauci, A.S. (1996). AIDS in 1996; much accomplished, much to do. Journal of the American Medical Association, 276, 155–6.
Fielding, J.E. (1989). Frequency of health risk assessment activities at US work-sites. American Journal of Preventive Medicine, 5, 73–81.
Fielding, J.E. (1999) Public health in the twentieth century; advance and challenges. Annual Review of Public Health, 20, xiii–xxx.
Graunt, J. (1662). National and political observations mentioned in a following index, and made upon the bills of mortality. Printed by Thomas Roycroft for John Martin, James Allestry, and Thomas Dicas, London. Reprinted (1939), Johns Hopkins Press, Baltimore, MD.
Green, L.W. and Kreueter, M.W. (1998). Health promotion planning: an education and environmental approach, (3rd edn). Mayfield Publishing, Mountain View, CA.
Institute of Medicine (1999). Leading health indicators for healthy people 2010, Second Interim Report. Committee on Leading Health Indicators for Healthy People 2010, Division of Health Promotion and Disease Prevention, Institute of Medicine. National Academy Press, Washington, DC.
Kuczmarski, R.J., Flegal, K.M., Campbell, S.M., and Johnson, C.L. (1994). Increasing prevalence of overweight amongst United States adults: the National Health and Nutrition Examination Surveys, 1960 to 1991. Journal of the American Medical Association, 272, 205–11.
Last, J.M. (ed.) (1995). A dictionary of epidemiology, (4th edn). Oxford University Press.
McGinnis, J.M. and Foege, W.H. (1993). Actual causes of death in the United States. Journal of the American Medical Association, 270, 2207–12.
Manley, M., Epps, R.P., Husten, C., Glynn, T., and Stropland, D. (1991). Clinical intervention in tobacco control. Journal of the American Medical Association, 286, 3172–84.
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NIAID (National Institute of Allergy and Infectious Diseases) Division of AIDS (2000). Vaccine concepts/designs. Website: http://www.niaid.nih.gov/aids/vaccine/concepts.htm
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Part 1 – GENETICS and OCULAR EMBRYOLOGY

Part 1 – GENETICS and OCULAR EMBRYOLOGY

Janey L. Wiggs

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Chapter 1 – Fundamentals of Human Genetics

JANEY L. WIGGS

DNA AND THE CENTRAL DOGMA OF HUMAN GENETICS
The regulation of cellular growth and function in all human tissue is dependent on the activities of specific protein molecules. In turn, protein activity is dependent on the expression of the genes that contain the correct DNA sequence for protein synthesis. The DNA molecule is a double-stranded helix. Each strand is composed of a sequence of four nucleotide bases—adenine (A), guanine (G), cytosine (C), and thymine (T)—joined to a sugar and a phosphate. The order of the bases in the DNA sequence forms the genetic code that directs the expression of genes. The double-stranded helix is formed as a result of hydrogen bonding between the nucleotide bases of opposite strands.[1] The bonding is specific, such that A always pairs with T, and G always pairs with C. The specificity of the hydrogen bonding is the molecular basis of the accurate copying of the DNA sequence that is required during the processes of DNA replication (necessary for cell division) and transcription of DNA into RNA (necessary for gene expression and protein synthesis; Fig. 1-1 ).[2] [3]
Gene expression begins with the recognition of a particular DNA sequence, called the promoter sequence, as a start site for RNA synthesis by the enzyme RNA polymerase. The RNA polymerase “reads” the DNA sequence and assembles a strand of RNA that is complementary to the DNA sequence. RNA is a single-stranded nucleic acid composed of the same nucleotide bases as DNA, except that uracil takes the place of thymine. Human genes (and genes found in other eukaryotic organisms) contain DNA sequences that are not translated into polypeptides and proteins. These sequences are called intervening sequences or introns. Introns do not have a specific function, and although they are transcribed into RNA by RNA polymerase, they are spliced out of the initial RNA product (termed heteronuclear RNA, or hnRNA) to form the completed messenger RNA (mRNA). The mRNA is the template for protein synthesis. Proteins consist of one or more polypeptide chains, which are sequences of specific amino acids. The sequence of bases in the mRNA directs the order of amino acids that make up the polypeptide chain. Individual amino acids are encoded by units of three mRNA bases, termed codons. Transfer RNA (tRNA) molecules bind specific amino acids and recognize the corresponding three-base codon in the mRNA. Cellular organelles called ribosomes bind the mRNA in such a configuration that the RNA sequence is accessible to tRNA molecules and the amino acids are aligned to form the polypeptide. The polypeptide chain may be processed by a number of other chemical reactions to form the mature protein ( Fig. 1-2 ).[4]
Human DNA is packaged as chromosomes located in the nuclei of cells. Chromosomes are composed of individual strands of DNA wound about proteins called histones. The complex winding and coiling process culminates in the formation of a chromosome. The entire collection of human chromosomes, called the human genome, includes 22 paired autosomes and two sex chromosomes. Women have two copies of the X chromosome, and men have one X and one Y chromosome ( Fig. 1-3 ).[5] [6]

Figure 1-1 Structure of the DNA double helix. The sugar-phosphate backbone and nitrogenous bases of each individual strand are arranged as shown. The two strands of DNA pair by hydrogen bonding between the appropriate bases to form the double-helical structure. Separation of individual strands of the DNA molecule allows DNA replication, catalyzed by DNA polymerase. As the new complementary strands of DNA are synthesized, hydrogen bonds are formed between the appropriate nitrogenous bases.
Mitosis and Meiosis
In order for cells to divide, the entire DNA sequence must be copied so that each daughter cell can receive a complete complement of DNA. The growth phase of the cell cycle terminates with the separation of the two sister chromatids of each chromosome, and the cell divides during mitosis. Prior to cell division, the complete DNA sequence, which comprises the entire human genome, is copied by the enzyme DNA polymerase in a process called DNA replication. DNA polymerase is an enzyme capable of the synthesis of new strands of DNA according to the exact sequence of the original DNA. Once the DNA is copied, the old and new copies of the chromosomes pair, and the cell divides such that one copy of each chromosome pair belongs to each cell ( Fig. 1-4 ). Mitotic cell division produces a daughter cell that is an exact replica of the dividing cell.

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Figure 1-2 The central dogma of molecular genetics. Transcription of DNA into RNA occurs in the nucleus of the cell, catalyzed by the enzyme RNA polymerase. Mature mRNA is transported to the cytoplasm, where translation of the code produces amino acids linked to form a polypeptide chain, and ultimately a mature protein is produced.
Meiotic cell division is a special type of cell division that results in a reduction of the genetic material in the daughter cells, which become the reproductive cells—eggs (women) and sperm (men). Meiosis begins with DNA replication, followed by a pairing of the maternal and paternal chromosomes (homologous pairing) and an exchange of genetic material between chromosomes by recombination ( Fig. 1-5 ). The homologous chromosome pairs line up on the microtubule spindle and divide such that the maternal and paternal copies of the doubled chromosomes are distributed to separate daughter cells. A second cell division occurs, and the doubled chromosomes divide, which results in daughter cells that have half the genetic material of somatic (tissue) cells.
BASIC MENDELIAN PRINCIPLES
Two important rules central to human genetics emerged from the work of Gregor Mendel, a nineteenth-century Austrian monk.[7] The first is the principle of segregation, which states that genes exist in pairs and that only one member of each pair is transmitted to the offspring of a mating couple. The principle of segregation describes the behavior of chromosomes in meiosis. Mendel’s second rule is the law of independent assortment, which states that genes at different loci are transmitted independently. This work also demonstrated the concepts of dominant and recessive traits. Mendel found that certain traits were dominant and could mask the presence of a recessive gene.
A practical example of Mendel’s two laws is seen in the inheritance of human eye and hair color. Blue eyes and blond hair are recessive traits, while brown eyes and hair are dominant traits. This means that for an individual to have blond hair and blue eyes, he or she must have two genes for blond hair and two genes for blue eyes (one from the mother and one from the father). An individual with brown eyes and brown hair may have two genes for brown eye color and two genes for brown hair color; however, because the brown genes are dominant, brown eyes may occur when an individual has one gene for brown eye color and one gene for blue eye color. A homozygous individual has two of the same genes (i.e., two blue eye-color genes or two brown eye-color

Figure 1-3 The packaging of DNA into chromosomes. Strands of DNA are wound tightly around proteins called histones. The DNA-histone complex becomes further coiled to form a nucleosome, which in turn coils to form a solenoid. Solenoids then form complexes with additional proteins to become the chromatin that ultimately forms the chromosome.
genes), whereas a heterozygous individual has two different genes (i.e., one blue eye-color gene and one brown eye-color gene).
Mendel’s rules on segregation and independent assortment are evident when the possible matings and offspring of individuals with blond or brown hair and blue or brown eye color are observed ( Fig. 1-6 ). If two blond-haired, blue-eyed individuals mate, all their offspring will have blond hair and blue eyes, because these individuals must be homozygous, and the only genes available to the offspring are those for blue eyes and blond hair. If a blond-haired, blue-eyed individual mates with a brown-haired, brown-eyed individual who is homozygous for brown hair genes and brown eye genes, all the offspring from this mating will have brown hair and brown eyes because the brown genes are dominant. However, all these offspring will be heterozygous for genes at these loci, because they must have inherited recessive blue eye and blond hair genes.
The law of independent assortment becomes evident when the offspring of two individuals who are heterozygous for eye and hair color are examined. Among the offspring of this mating, 25% will have blue eyes, and 75% will have brown eyes (50% will be heterozygous

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Figure 1-4 The mitotic cell cycle. During mitosis, the DNA of a diploid cell is replicated, which results in the formation of a tetraploid cell that divides to form two identical diploid daughter cells.
for eye color, and 25% will be homozygous for brown eye color). Similarly, 25% of the offspring will have blond hair, and 75% will have brown hair (again, 50% will be heterozygous for hair color, and 25% will be homozygous for brown hair color). However, the 25% of offspring with blue eyes will not necessarily have blond hair. Some offspring will have blond hair and blue eyes, and some offspring will have brown hair and blue eyes. This is because the eye color and hair color genes are located at distinct loci that segregate independently of each other. Independent segregation, or assortment, occurs because maternal and paternal chromosomes segregate randomly into gametes during meiosis, and because of the random recombination that occurs between homologous chromosomes when they pair during meiosis.
At the same time that Mendel observed that most traits segregate independently, according to the law of independent assortment, he unexpectedly found that some traits frequently segregate together. The physical arrangement of genes in a linear array along a chromosome is the explanation for this surprising observation. On average, a recombination event occurs once or twice between two paired homologous chromosomes during meiosis

Figure 1-5 The meiotic cell cycle. During meiosis, the DNA of a diploid cell is replicated, which results in the formation of a tetraploid cell that divides twice to form four haploid cells (gametes). As a consequence of the crossing over and recombination events that occur during the pairing of homologous chromosomes prior to the first division, the four haploid cells may contain different segments of the original parental chromosomes. For brevity, prophase II and telophase II are not shown.
( Fig. 1-7 ). Most observable traits, by chance, are located far away from one another on a chromosome, such that recombination is likely to occur between them, or they are located on entirely different chromosomes. If two traits are on separate chromosomes, or a recombination event is likely to occur between them on the same chromosome, the resultant gamete formed during meiosis has a 50% chance of inheriting different alleles from each loci, and the two traits respect the law of independent assortment. If, however, the loci for these two traits are close together on a chromosome, with the result that a recombination event occurs between them only rarely, the alleles at each loci are passed to descendant gametes “in phase.” This means that the particular alleles present at each loci in the offspring reflect the orientation in the parent, and the traits appear to be “linked.” For example, in Mendel’s study of pea plants, curly leaves were always found with pink flowers, even though the genes for curly leaves and pink flowers are located at distinct loci. These traits are linked, because the curly-leaf gene and the pink-flower gene are located close to each other on a chromosome, and a recombination event only rarely occurs between them.

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Figure 1-6 Independent assortment of mendelian traits. Shown are the results of a mating between a blond-haired, blue-eyed father and a blond-haired, blue-eyed mother; a mating between a blond-haired, blue-eyed father and a brown-haired, brown-eyed mother; and a mating between a couple heterozygous for blond and brown hair and for blue and brown eyes.
Recombination and linkage are the fundamental concepts behind genetic linkage analysis.[8] The search for a gene responsible for a phenotypic trait (or disease) depends on the ability to observe linkage between the trait and mapped genetic markers. The identification of a marker that segregates with the trait (i.e., is linked genetically to the trait) defines the location of the gene for that trait, because the lack of recombination between the marker and the trait means that the gene responsible for the trait is located physically near the linked marker. The chromosomal locations of genetic markers are readily available to the public as a result of the successful efforts of the nationally funded Human Genome Project.[9] Once an approximate location of a gene responsible for a trait has been determined, analysis of rare recombination events between markers in the region and that trait can help further define the precise physical location of the gene on the chromosome. In this way, “positional cloning” of genes may be accomplished.[9] [10]
MUTATIONS
Mutations are changes in the gene DNA sequence that result in a biologically significant change in the function of the encoded

Figure 1-7 Genetic recombination by crossing over. Two copies of a chromosome are copied by DNA replication. During meiosis, pairing of homologous chromosomes occurs, which enables a crossover between chromosomes to take place. During cell division, the recombined chromosomes separate into individual daughter cells.

Figure 1-8 Expanded trinucleotide repeat and anticipation in myotonic dystrophy. Results of a study to determine the size of the trinucleotide repeat in three individuals affected by myotonic dystrophy.[12] The results from a normal individual are shown at the far left. The size of the repeat element increases with the severity of the disease in the affected individuals.
protein. If a particular gene is mutated, the protein product might not be made, or it might be produced but work poorly. In some cases, mutations create proteins that have an adverse effect on the cell (dominant negative effect). Point mutations (the substitution of a single base pair) are the most common mutations encountered in human genetics. Missense mutations are point mutations that cause a change in the amino acid sequence of the polypeptide chain. The severity of the missense mutation is dependent on the chemical properties of the switched amino acids and on the importance of a particular amino acid in the function of the mature protein. Point mutations also may decrease the level of polypeptide production because they interrupt the promoter sequence, splice site sequences, or create a premature stop codon.
Gene expression can be affected by the insertion or deletion of large blocks of DNA sequence. These types of mutations are less common than point mutations but may result in a more severe change in the activity of the protein product. A specific category of insertion mutations is the expansion of trinucleotide repeats found in patients affected by certain neurodegenerative disorders. An interesting clinical phenomenon, “anticipation,” was understood on a molecular level with the discovery of trinucleotide repeats as the cause of myotonic dystrophy.[11] [12] Frequently, offspring with myotonic dystrophy were affected more severely and at an earlier age than their affected parents and grandparents. Examination of the disease-causing trinucleotide

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Figure 1-9 Reciprocal translocation between two chromosomes. The Philadelphia chromosome (responsible for chronic myelogenous leukemia) is shown as an example of a reciprocal chromosomal translocation that results in an abnormal gene product responsible for a clinical disorder. In this case, an exchange occurs between the long arm of chromosome 9 and the long arm of chromosome 22.
repeat in affected pedigrees demonstrated that the severity of the disease correlated with the number of repeats found in the myotonic dystrophy gene in affected individuals. This phenomenon has been observed in a number of other diseases, including Huntington’s disease ( Fig. 1-8 ).
Chromosomal rearrangements may result in breaks in specific genes that cause an interruption in the DNA sequence.[13] Usually, the break in DNA sequence results in a truncated, unstable, dysfunctional protein product; occasionally, the broken gene fuses with another gene to cause a “fusion polypeptide product,” which may have a novel activity in the cell. Often such a novel activity results in an abnormality in the function of the cell. An example of such a fusion protein is the product of the chromosome 9;22 translocation that is associated with many cases of leukemia ( Fig. 1-9 ).[14]
DNA-BASED DIAGNOSIS
The use of molecular tools to demonstrate causative DNA mutations and identify individuals at risk for an inherited condition is called DNA-based diagnosis. [15] The goal of genetic diagnosis is early recognition of a disease so that intervention can be undertaken to prevent or reverse the disease process.[16] This was one of the goals of the Human Genome Project.[17] Two general approaches have been used to detect mutations in genes. The indirect approach uses genetic linkage analysis,[18] and the direct approach identifies specific changes in DNA sequence.
Linkage analysis can be used to diagnose any genetically mapped disorder. Segregation of genetic markers known to be linked to a gene responsible for a condition is used to determine whether an individual has inherited a chromosome that carries the abnormal gene. This method does not require physical isolation and sequencing of the gene. Linkage analysis is useful when large genes with many possible mutations are responsible for a disease ( Fig. 1-10 ). Several important disadvantages of this approach must be recognized. First, analysis of DNA from multiple family members is required to identify the markers that segregate with the abnormal chromosome in each affected pedigree. Second, not all genetic markers provide useful information for this analysis. Some individuals may not be “informative” at a particular marker, and a definitive demonstration of the abnormal chromosome may not be possible. Third, recombination may occur between the genetic markers used for testing and the disease-causing mutation. Although the markers selected for the analysis are physically close to the disease gene, a rare recombination event may occur and result in a misdiagnosis because

Figure 1-10 DNA diagnosis using genetic linkage analysis. This pedigree shows a mother and two daughters affected by a condition inherited as an autosomal dominant trait. Analysis carried out using a marker closely linked to the disease gene shows that allele 1 segregates with the condition. The daughter in the third generation has inherited this allele from her affected mother, which suggests that she has also inherited the disease gene and is therefore at risk for development of the condition.
of an apparent separation between the genetic markers that define the normal and abnormal chromosomes.
Direct mutation analysis uses a variety of techniques based on the DNA sequence of a gene to identify the specific base-pair change that is responsible for the disease. Because this method does not rely on the segregation of genetic markers to identify the abnormal chromosome, multiple family members are not usually required. Also, potential errors caused by rare recombination events between the markers and the disease gene do not occur with this method, but there are several drawbacks to direct mutation analysis. The gene responsible for the disease must first be isolated and sequenced. Some genes are very large (e.g., the gene for retinoblastoma spans more than 200,000 kilobases of DNA sequence) and are difficult and time-consuming to sequence. Multiple mutations and novel mutations present in a single gene may require complete sequencing of the DNA for each diagnostic test.
In some disorders, the majority of stricken individuals are affected by the same mutation. For example, 70% of individuals affected by cystic fibrosis have the delta 508 mutation.[19] For disorders of this type, a simple screening test based on the particular mutation may be developed. This technique involves the synthesis of an oligonucleotide probe that hybridizes only to the mutated sequence. Such a probe, called an allele-specific oligonucleotide, is very useful when the DNA sequence that causes the genetic disease is known and the number of disease-causing mutations is limited ( Fig. 1-11 ). Those patients whose DNA hybridizes with the normal sequence do not have the mutation, and those patients whose DNA hybridizes with the mutant sequence do have the mutation.
GENETIC COUNSELING
Genetic counseling has become an important part of any clinical medicine practice. In 1975, the American Society of Human Genetics adopted the following descriptive definition of genetic counseling[20] :
Genetic counseling is a communication process which deals with the human problems associated with the occurrence or risk of occurrence of a genetic disorder in a family. This process involves an attempt by one or more appropriately trained persons to help the individual or family to: (1) comprehend the medical facts including the diagnosis, probable course of the disorder, and the available management, (2) appreciate the way heredity contributes to the disorder and the risk of recurrence in specified relatives, (3) understand the alternatives for dealing with the

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Figure 1-11 DNA diagnosis using an allele-specific oligonucleotide. Oligonucleotides specific for mutations are synthesized, as well as oligonucleotides that correspond to the normal sequence. DNA purified from individuals to be tested is placed on a small “dot” on a piece of filter paper and allowed to hybridize (base pair) with the specific oligonucleotides. Individuals A and B are normal, as their DNA hybridizes with the normal sequence only and not with the mutant sequence. Individual C’s DNA hybridizes with both the normal and the mutant sequences; hence, this individual has one normal gene and one mutant gene. Individual C is a carrier of the disease if it is a recessive condition or is affected by the disease if it is a dominant condition.
risk of recurrence, (4) choose a course of action which seems to them appropriate in their view of their risk, their family goals, and their ethical and religious standards and act in accordance with that decision, and (5) to make the best possible adjustment to the disorder in an affected family member and/or to the risk of recurrence of that disorder.
An accurate diagnosis is the first step in productive genetic counseling.[21] The patient-physician discussion of the natural history of the disease and of its prognosis and management is entirely dependent on the correct identification of the disorder that affects the patient. Risk assessment for other family members and options for prenatal diagnosis also depend on an accurate diagnosis. In some cases, appropriate genetic testing may help establish the diagnosis.
A complete family history of the incidence of the disorder is necessary to determine the pattern of inheritance of the condition. The mode of inheritance (i.e., autosomal dominant, autosomal recessive, X-linked, or maternal) must be known to calculate the recurrence risk to additional family members, and it helps confirm the original diagnosis ( Fig. 1-12 ). A family history is recorded most easily as a pedigree using universally recognized nomenclature ( Fig. 1-13 ). For the record of family information, the gender and birth date of each individual and his or her relationship to other family members are indicated using the standard pedigree symbols. It is also helpful to record the age of onset of the disorder in question (as accurately as this can be determined). The pedigree diagram must include as many family members as possible. Miscarriages, stillbirths, and consanguineous parents are indicated.
Occasionally, a patient may appear to be affected by a condition that is known to be inherited, but the patient is unable to provide a family history of the disease. Several important explanations for a negative family history must be considered before the conclusion is made that the patient does not have a heritable condition. First, the patient may not be aware that other family members are affected by the disease. Individuals frequently are reluctant to share information about medical problems, even with close family members. Second, many disorders exhibit variable expressivity or reduced penetrance, which means that other family members may carry a defective gene that is not expressed or results in only a mild form of the disease that is not readily observed. Third, false paternity may produce an individual affected by a disease that is not found in anyone else belonging to the acknowledged pedigree. Genetic testing can easily determine the paternity (and maternity) of any individual if blood samples are obtained from relevant family members. Fourth, a new mutation may arise that affects an individual and may be passed to offspring, even though existing family members show no evidence of the disease.
Once the diagnosis and family history of the disorder are established, risk prediction in other family members (existing and unborn) may be calculated. The chance that an individual known to be affected by an autosomal dominant disorder will transmit the disease to his or her offspring is 50%. This figure may be modified, depending on the penetrance of the condition. For example, retinoblastoma is inherited as an autosomal dominant trait, and 50% of the children of an affected parent should be affected. However, usually only 40–45% of the children at risk are affected, because the penetrance of the retinoblastoma trait is only 80–90%, which means that 5–10% of children who have inherited an abnormal copy of the retinoblastoma gene do not develop ocular tumors.
An individual affected by an autosomal recessive trait will have unaffected children unless he or she partners with another individual affected by the disease or with an individual who is a carrier of the disease. Two individuals affected by an autosomal recessive disease produce only affected offspring. (There are some rare exceptions to this rule. If the disease is the result of mutations in two different genes, it is possible for two individuals affected by an autosomal recessive trait to produce normal children. Also, in rare cases, different mutations in the same gene may compensate for each other, and the resultant offspring will be normal.) If an individual affected by an autosomal recessive disease partners with a heterozygous carrier of a gene defect responsible for that disorder, the chance of producing an affected child is 50%. Among the offspring of an individual affected by an autosomal recessive disease, 50% will be carriers of the disorder. If one of these offspring partners with another carrier of the disease, the chance of producing an affected child is 25%.
X-linked disorders are always passed from a female carrier who has inherited a copy of an abnormal gene on the X chromosome received from either her mother (who was a carrier) or her father (who was affected by the disease). Man-to-man transmission is not seen in diseases caused by defects in genes located on the X chromosome. Among sons born to female carriers of X-linked disorders, 50% are affected by the disease, and 50% of daughters born to female carriers of X-linked disorders are carriers of the disease. All the daughters of men affected by X-linked disorders are carriers of the disease.
Mitochondrial disorders are inherited by sons and daughters from the mother. The frequency of affected offspring and the severity of the disease in affected offspring depend on the number of abnormal mitochondria present in the egg that gives rise to the affected child. Diseased and normal mitochondria are distributed randomly in all cells of the body, including the female gametes. As a result, not all the eggs present in a woman affected by a mitochondrial disorder have the same number of affected mitochondria (heteroplasmy). Men affected by mitochondrial disorders only rarely have affected children, because very few mitochondria in the developing embryo are derived from the sperm used to fertilize the egg.[22]
With careful diagnosis and family history assessment, even sporadic cases of heritable disorders are identifiable. In such cases, an estimate of recurrence risk can be calculated using the available pedigree and clinical information and the statistical principle called Bayes’ theorem. These individuals should be referred to clinical genetics services, such as those commonly found in hospital settings ( Box 1-1 ).

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Figure 1-12 Patterns of inheritance. For pedigrees with an autosomal dominant trait, panel 1 shows inheritance that originates from a previous generation, panel 2 shows segregation that originates in the second generation of this pedigree, and panel 3 shows an apparent “sporadic” case, which is actually a new mutation that arises in the most recent generation. This mutation has a 50% chance of being passed to offspring of the affected individual. For pedigrees with an autosomal recessive trait, panel 1 shows an isolated affected individual in the most recent generation (whose parents are obligatory carriers of the mutant gene responsible for the condition), panel 2 shows a pair of affected siblings whose father is also affected (for the siblings to be affected, the mother must be an obligate carrier of the mutant gene), and panel 3 shows an isolated affected individual in the most recent generation who is a product of a consanguineous marriage between two obligate carriers of the mutant gene. For pedigrees with an X-chromosomal trait, panel 1 shows an isolated affected individual whose disease is caused by a new mutation in the gene responsible for this condition, panel 2 shows an isolated individual who inherited a mutant copy of the gene from the mother (who is an obligate carrier), and panel 3 shows segregation of an X-linked trait through a multigeneration pedigree (50% of the male offspring are affected, and their mothers are obligate carriers of the disease). For pedigrees with a mitochondrial trait, the panel shows a large, multigeneration pedigree—men and women are affected, but only women have affected offspring.
GENE THERAPY
Mutations in the DNA sequence of a particular gene can result in a protein product that is not produced, works poorly, or has adopted a novel function that is detrimental to the cell. Gene therapy involves the delivery of a normal gene to the tissue that contains the flawed gene.[23] Theoretically, a normal copy of the gene can physically take the place of the flawed gene and restore the gene function of the cell. In practice, however, actually replacing the flawed gene with a normal gene is a difficult task.[24] Currently, the aim of gene therapy is to add a useful gene to the cell or tissue that suffers the consequences of the flawed gene. In some cases, the new gene may code for an entirely different protein whose function compensates for the protein encoded by the flawed gene. Useful genes may be delivered to specific tissues that require treatment using modified viruses as vectors.[25] Normally, certain types of viruses invade a host cell, are incorporated into

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Figure 1-13 Basic pedigree notation. Typical symbols used in pedigree construction are defined.

Types of Clinical Genetics Services and Programs
CENTER-BASED GENETICS CLINIC
OUTREACH CLINICS
INPATIENT CONSULTATIONS
SPECIALTY CLINICS
• metabolic clinic
• spina bifida clinic
• hemophilia clinic
• craniofacial clinic
• other single-disorder clinics (e.g., neurofibromatosis 1 clinic)
PRENATAL DIAGNOSIS PROGRAM: PERINATAL GENETICS
• amniocentesis/chorionic villus sampling clinics
• ultrasound program
• maternal serum a-fetoprotein program
GENETIC SCREENING
• newborn screening program/follow-up clinic
• other population-screening programs (e.g., for Tay–Sachs disease)
EDUCATION/TRAINING
• health-care professional
• general public
• school system
• teratology information services

the host genome, and express the viral genes required for replication of the virus. The mature virus eventually takes over the cell, with the result that the cell dies and releases new, infectious viral products that can infect adjacent cells. A general approach to gene therapy is to use an altered (recombinant) virus to carry the gene of interest to the desired tissue. Using genetic engineering techniques, the viral DNA is modified so that the viral genes required for virus proliferation are removed and the therapeutic gene is put in their place. Such a virus may invade the diseased tissue, become incorporated into the host DNA, and express the desired gene. Because the modified virus does not have the viral genes required for viral replication, the virus cannot proliferate, and the host cell does not die ( Fig. 1-14 ). A successful example of this approach has recently been demonstrated by the restoration of vision in a canine model of Leber congenital amaurosis using a recombinant adeno-associated virus carrying the normal gene (RPE65).[26]

Figure 1-14 Gene therapy using a retrovirus vector. A therapeutic gene is engineered genetically into the retrovirus DNA and replaces most of the viral DNA sequences. The “recombinant virus” that carries the therapeutic gene is allowed to replicate in a special “packaging cell,” which also contains normal virus that carries the genes required for viral replication. The replicated recombinant virus is allowed to infect the human diseased tissue, or “target cell.” The recombinant virus may invade the diseased tissue but cannot replicate or destroy the cell. The recombinant virus inserts copies of the normal therapeutic gene into the host genome and produces the normal protein product.
Diseases caused by mutations that create a gene product destructive to the cell need to be treated using a different approach. In these cases, genes or oligonucleotides that may inactivate the mutated gene are introduced into the cell. This is called “antisense therapy,” and it is proving to be a useful approach for diseases caused by the “gain of function mutations.” A number of different viral vectors likely to be useful for gene therapy are currently under investigation. In addition, evaluation of nonviral mechanisms for the introduction of therapeutic genes into diseased tissue is ongoing.
In general, most of the current approaches to gene therapy are aimed at repairing the somatic cells of the particular tissue affected by the disease gene.[27] Gene delivery may be tailored to the somatic cells affected by the disorder. Gene therapy of ocular disorders benefits from the accessibility of the eye, the ability to visualize the diseased tissue, and the large number of specific

11
gene defects known to be responsible for many inherited eye disorders.[28]
Specific treatment of the diseased cells does not affect the other cells of the body, which include the germline cells. Because the germline cells continue to carry flawed copies of the gene, the disease may still be passed to offspring of the affected patient. Gene therapy targeted to germline cells as well as the diseased somatic cells results in successful treatment of the disease in the affected individual and prevents transfer of the disease to any offspring.

REFERENCES

1. Watson JD, Crick FHC. Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid. Nature. 1953;171:737–8.

2. Clayton DA. Structure, replication, and transcription of DNA. In: Leder P, Clayton DA, Rubenstein E, eds. Introduction in molecular medicine. New York: Scientific American; 1994.

3. Kelman Z, O’Donnel M. DNA replication: enzymology and mechanisms. Curr Opin Genet Dev. 1994;4:185–95.

4. Murray A, Hunt T. The cell cycle: an introduction. Oxford: Oxford University Press; 1994.

5. Bentley DR, Dunham I. Mapping human chromosomes. Curr Opin Genet Dev. 1995;5:328–34.

6. Gardiner K. Human genome organization. Curr Opin Genet Dev. 1995;5:315–22.

7. McKusick VA. Mendelian inheritance in man: catalogs of autosomal dominant, autosomal recessive, and X-linked phenotypes, ed 11. Baltimore: Johns Hopkins University Press; 1994.

8. McKusick VA. Medical genetics: a 40-year perspective on the evolution of a medical specialty from a basic science. JAMA. 1993;270:2351–6.

9. International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 2001;409:860–921.

10. Collins FS. Positional cloning moves from perditional to traditional. Nat Genet. 1995;9:347–50.

11. Harper PS, Harley WG, Reardon W, Shaw DJ. Anticipation in myotonic dystrophy: new light on an old problem. Am J Hum Genet. 1992;51:10–6.

12. Warren ST. The expanding world of trinucleotide repeats. Science. 1996;271: 1374–5.

13. Shaikh TH, Kurahashi H, Emanuel BS. Evolutionarily conserved low copy repeats (LCRs) in 22q11 mediate deletions, duplications, translocations, and genomic instability: an update and literature review. Genet Med. 2001;3:6-13.

14. Rabbitts TH. Chromosomal translocations in human cancer. Nature. 1994;372: 143–9.

15. Korf B. Molecular diagnosis. N Engl J Med. 1995;332:1218–20.

16. Caskey CT. Presymptomatic diagnosis: a first step toward genetic health care. Science. 1993;262:48–9.

17. Collins FS, Patrinos A, Jordan E, et al. New goals of the US Human Genome Project: 1998–2003. Science. 1998;282:682–9.

18. Ott J. Analysis of human genetic linkage, ed 2. Baltimore: Johns Hopkins University Press; 1991.

19. Bobadilla JL, Macek M Jr, Fine JP, Farrell PM. Cystic fibrosis: a worldwide analysis of CFTR mutations—correlation with incidence data and application to screening. Hum Mutat. 2002;19:575–606.

20. National Academy of Sciences. Genetic screening: programs, principles and research. Washington, DC: National Academy of Sciences; 1975.

21. Harper PS. Practical genetic counseling, ed 4. Oxford: Butterworth Heinemann; 1993.

22. Wallace DC. Mitochondrial DNA sequence variation in human evolution and disease. Proc Natl Acad Sci U S A. 1994;91:8739–46.

23. Friedmann T, Roblin R. Gene therapy for human genetic disease. Science. 1972; 175:949–55.

24. Wolff JA, Malone RW, Williams P, et al. Direct gene transfer into mouse muscle in vivo. Science. 1990;247:1465–8.

25. Lee RJ, Huang L. Lipidic vector systems for gene transfer. Crit Rev Ther Drug Carrier Syst. 1997;14:173–206.

26. Acland GM, Aguirre GD, Ray J, et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet. 2001;28:92–5.

27. Brenner MK. Human somatic gene therapy: progress and problems. J Intern Med. 1995;237:229–39.

28. Bennett J, Maguire AM. Gene therapy for ocular disease. Mol Ther. 2000;1:501–5.

 

1.1 Current scope and concerns in public health (cont’)

Biostatistics
Biostatistics is the science used to quantify relationships observed in public health and medicine. Through the correct application of biostatistical techniques, public health professionals can test and quantify the magnitude of the relationship of a factor or factors to the health of the community.
Advances in epidemiological methodology have been accompanied by rapid progress in biostatistics, particularly the development of computer technology. Through its application, biostatisticians have developed multivariate techniques to sort out the independent relationship of multiple factors to disease occurrence while simultaneously observing the relationship of these variables to each other. Sophisticated techniques for the analysis of events in relation to time are enhancing the value of the cohort study design. Because the computer can process massive amounts of information rapidly, it has been possible to develop and test mathematical models that describe hypothetical relationships and disease outcomes based on a variety of assumptions. The degree to which the actual occurrence of disease matches the model confirms or refutes these relationships. These models can be used to predict the future course of disease both in the individual and in the community. Both are useful for public health administrators responsible for allocation of scarce resources.
These new statistical techniques have been used to determine the strength of a relationship between a suspected risk factor and disease occurrence or causation, and to determine the efficacy of preventive strategies such as vaccines and health education, the level of efficacy of drugs through clinical trials, and the future course of epidemics. Through further development of biostatistical strategies and innovative computer methodology, the potential of statistics to contribute to public health will be even greater.
Biological and physical sciences
The laboratory sciences have long played an essential role in public health. Many of the new advances leading to the control of infectious diseases depend upon microbiology to provide new techniques to identify and isolate disease agents, to describe relevant variations within a group of agents (e.g. polio types 1, 2, and 3), to describe host variations in susceptibility to disease, and to identify markers of prior infection or exposure. The rapid expansion of vaccines to prevent viral diseases reflects new procedures for isolating viruses using cell cultivation techniques that were developed in the late 1930s. These cell culture techniques facilitated the manufacture of live vaccines using attenuated viruses, that is, viruses that have lost their virulence characteristics for humans but not their capacity for stimulating immunity. Recently, microbiologists have fragmented disease agents into specific components and selected those that are responsible for the protective immune response. Vaccines are now also being developed that utilize genetic recombination and synthetic peptide chains (NIAID 2000). It is likely that within the next few years vaccines based on DNA will become a reality. New techniques have been developed for identifying levels of viral DNA and RNA in cells and serum. These techniques can be used to provide new insights into the early stages in the infective process, to identify chronic diseases that have a viral aetiology, and to guide therapy.
Startling as these recent developments in microbiology and immunology have been, equally important contributions to public health continue to come from the laboratory sciences of chemistry, biochemistry, and engineering. These disciplines provide information about the levels of pollutants in the air, water, and soil which is used by epidemiologists to determine their health effects. The studies of the chemical interactions of primary pollutants in the atmosphere led to the discovery that the products of these interactions, such as photochemical oxidants, can cause permanent compromise of lung function. Physical scientists continue to develop monitors that can measure specific pollutant exposures even at the personal level. Knowledge of chemical interactions has also led to the development of catalytic converters which have played a major role in reducing pollutant levels due to vehicle exhaust emissions in urban areas. Further advances in the physical sciences can be expected to provide a more healthful environment in the future.
Advances in the laboratory sciences can be rapidly translated into new techniques for identifying infection and disease, as well as environmental and occupational hazards. For the epidemiologist they provide tools to identify and measure disease agents and knowledge which leads to the development of testable hypotheses. Thus, these new advances often lead to new techniques and strategies for intervention and control of threats to the public health.
Behavioural and social sciences
In addition to their influence on choice of exercise, levels of personal hygiene, eating patterns, and alcohol consumption in disease occurrence, behavioural factors also determine the response to illness, particularly to subtle manifestations of disease. Thus, they significantly affect the ability of the individual to live in a healthy way and to respond to disease. The role of the behavioural and social sciences (including psychology, sociology, and anthropology) in public health is therefore increasing as the nature of disease problems is changing. Experience with HIV/AIDS as well as cardiovascular disease and cancer over the past few years dramatically illustrates the need for changing types of behaviour that promote disease occurrence (Fauci 1996; Mann and Tarantoloa 1996).
Behavioural science techniques have proved valuable in understanding important influences on health. Social science, particularly its relationship to statistics in developing survey methodology and its increasing application to smaller population groups, for example, has greatly enhanced our capacity to discriminate the possible connections of behaviour and ecological factors to disease and thus to discern trends that are highly important to public health. Psychological investigations of people’s knowledge and attitudes yield insight into the habitual and lifestyle practices that are related to health and often suggest ways of promoting health. Sociological investigation of group processes that determine a community’s norms and values, and adherence to them, likewise leads to an understanding of how people behave and how they can be influenced to follow a healthy lifestyle. Anthropology elucidates the cultural traditions that affect what people do in everyday life and suggests approaches to health promotion specific to various cultural groups.
Within the field of public health, health education draws upon these disciplines to develop effective techniques for cultivating health-promoting behaviour (Green and Kreueter 1998). As emphasized above, the social milieu largely determines the choices that people make. Economic and other social conditions of life profoundly impact what people do about health-related actions. Lifestyle does not consist of behaviour elements selected by individuals in a void but depends upon their life circumstances. Hence public health must be concerned with the social conditions in which people live and direct substantial effort towards their improvement on behalf of health. The social sciences provide knowledge that guides analytic effort, in that regard, as well as for organizing and managing appropriate interventions; and they therefore contribute to formulating and implementing policy for public health.
Demography, vital statistics, and health information
Demography delineates the nature of populations, focusing on trends such as growth in their various segments, i.e. the excess of births over deaths, and immigration over emigration. Public health statistics are concerned with information about the health of populations. Both fields are devoted to satisfying social concerns about people. Mutual interest in factors such as those determining fertility illustrates the continuing interrelationships of public health and demography.
John Graunt is commonly considered the father of vital statistics because of his early studies of the Bills of Mortality in London and a parish town in Hampshire. He collected and examined the birth and death records maintained by parish clerks from 1603 to 1662 (Graunt 1662). From that work he drew important inferences about the population and its health. He analysed mortality, including infant mortality, seasonal variation of deaths, and longevity, as well as fertility and the excess of male births. His studies laid the groundwork for what has become vital statistics, which now include:

(1)
births and the rates of their occurrence in various segments of the population;
(2)
fertility, i.e. the ratio of births to women aged 15 to 49 years;
(3)
mortality, including deaths amongst infants and in subsequent ages, as well as trends, specific causes, and determinants of deaths;
(4)
migration patterns.

Information about health may be obtained through aggregated data from vital statistics, surveys, disease reporting, and disease registries as well as demographic statistics. Computer technology facilitates analysis of such data in relation to the characteristics of people affected. In addition, information from other sources can be linked to the occurrence of health events, thus providing additional information about factors in these events.
Data concerning non-lethal diseases are more difficult to obtain than the birth and death information that must be recorded by law. In the United States, the Centers for Disease Control and Prevention publishes a Morbidity and Mortality Weekly Report, which contains information on certain diseases, obtained through reporting from local health departments. Hospital discharge abstracts and summaries provide further information. Special surveys for specific diseases or factors affecting health may be carried out, in addition to ongoing national health surveys administered to a probability sample of the population. Cancer registries in several countries provide information about changing trends in cancer occurrence, mortality, treatment effectiveness, and duration of survival. Comparable data registries are also being developed for diabetes, coronary heart disease, congenital malformations, and other chronic diseases.
Programmatic scope of public health
Goal setting
Success in achieving the WHO’s objective of eradicating smallpox throughout the world and, more recently, its initiative to eradicate poliomyelitis by 2005 (which has already been accomplished in the western hemisphere), have inspired other efforts to set and popularize explicit goals in public health (WHO 2000). For example, in 1980 the United States Department of Health and Human Services established specific objectives for 1990 in various health domains and a data collection and publication process to track progress in meeting the objectives (US DHHS 1980). It also delineated the measures necessary to reach those objectives. Based on experience with that venture, the agency set new goals in priority areas for the year 2000 (US DHHS 1991). For some specific objectives the trends have been on track, but for others, such as obesity, the trend was in the wrong direction. New goals for health priorities are now being formulated for the year 2010 (Table 6) (Institute of Medicine 1999).

Table 6 Core list of candidate leading health indicators for Healthy People 2010

Prevention of disease and promotion of health
The ultimate goal of public health has always been and remains the prevention of disease and the promotion of health in communities. Attention to quality of life is also growing, and represents a more positive goal than the traditional target of disease control in the health field (Breslow 1999). Although great strides have been made towards that goal, many conditions still cause considerable unnecessary deterioration in the quality of life as well as in disability and premature death. Furthermore, many people in both the developed and the developing world have not yet benefited from the public health achievements of the twentieth century. A major goal of public health in the developed countries in the future, therefore, will remain the prevention of diseases such as cancer, heart disease, trauma, and AIDS, which are currently responsible for most premature mortality and diminished quality of life. Achieving that goal requires assurance that public health advances reach those groups of people still suffering heavily from morbidity and mortality that can be avoided using current knowledge and technology. These include the poor and those not yet adequately integrated into the mainstream of society. In developing countries, reduction of infectious diseases and malnutrition often still must take priority, but increasingly, reduction of chronic diseases, accidents and trauma, and environmental threats to health are becoming goals there as well.
Prevention can be achieved through:

(1)
emphasizing preventive aspects of medical care, such as immunizations and screening for selected conditions;
(2)
health education and behavioural modification, including social influences on these aspects of health;
(3)
control of the environment for health;
(4)
cultivating political will for public health initiatives.

Medical care
Beginning with Bismarck, the Western nations have generally provided medical care of varying kinds and degree as a social benefit to industrialized workers. In most countries care has also been extended to others, particularly to families of workers, the elderly, and the poor. The British National Health Service, for example, covers the whole population. Conversely, the United States relies mainly on private arrangements for employed people, and large-scale governmental assistance for health-care services goes only to the elderly and the poor, while one-sixth of the population has no coverage.
Medical care can be examined from several perspectives: medical and economic, for example, as well as from the standpoint of public health. The medical profession, reflecting both the centuries-old tradition of healing, as well as recent advances in medical science, looks upon medical care as the principal means to relieve suffering and restore health in individuals. Economists view medical care in terms of its cost and therefore are concerned about the increasingly large expenditures for it. Public health considers medical care to be one means of protecting and improving the health of people, but also is vigilant about its cost and financing, especially in so far as that constitutes a barrier to health care for some groups. Public health’s focus on medical care emphasizes its potential for enhancing a community’s health, with its cost a consideration in the same sense that environmental protection raises financial issues. Public health usually does not assume responsibility for the actual delivery of health care to the individual, but is concerned with the quality, access, and equity of the care that is provided.
Provision of medical services is usually determined in a specific country by cultural and traditional patterns, although these medical service patterns are constantly evolving. Thus, in the United Kingdom the individual general practitioner with a panel of patients comprises the predominant care module, with referral to the hospital consultant as necessary. However, a current trend is for general practitioners to work within group practice prepayment plans; for example, in the United States the former lifelong doctor–patient relationship is often replaced by health centres or clinics where the patient may be seen by a primary care doctor, by some specialists, such as paediatricians, general internists, or obstetricians, who see patients only during certain limited periods of their lives, and, to a growing extent, by free-standing emergency medical services. The number and type of various medical service arrangements and payment methods are rapidly expanding in the United States.
Public health relies upon doctors primarily to achieve preventive medical care. Thus, public health agencies have organized immunization activities and often maternal and child health services both through existing sources of medical care, and, where necessary, through direct provision of these services. In recent decades these efforts have contributed to spectacular achievements in control of communicable disease, for example the eradication of smallpox and the extensive control of poliomyelitis.
Curative services, however, generally receive funding priority over preventive services on the grounds of urgency. Most doctors and medical care agencies adhere to what may be termed the complaint–response system of medicine; patients are encouraged to recognize and bring their health complaints to the doctor, whose response is to diagnose and treat any illness that may be present. Prevention, if advocated at all, is usually a minor consideration.
A new system of medical care that gives priority to promoting health and preventing disease has been slowly emerging. The health of individuals is monitored through periodic appraisal geared to age and other factors that determine both current and future prospects of health. Thus, infant care concentrates on growth, appearance of defects, immunization status, and any necessary corrective action to assure the healthiest possible development. When a person has reached 50 years of age, the focus shifts to blood pressure, weight-to-height ratio, blood sugar, blood cholesterol, cancer detection, cigarette and alcohol consumption, and other physical and behavioural characteristics. Many industrial leaders in the United States have started to provide health risk assessment and health counselling services for their employees. Arrangement for these services at or in connection with work is one of the fastest growing aspects of medical care in the United States (Fielding 1989).
While medical care services have absorbed a rapidly increasing proportion of total expenditures for all goods and services in some developed nations, the developing world has not had the resources to commit to such an effort. Vast numbers of people can thus receive only the most elementary medical services, if any. Furthermore, as medical education advances in the developing nations, a substantial number of doctors seek training in the high-tech training centres around the world. Those returning to their native countries then try to introduce the procedures they have learned, but these are pertinent and available mainly to the élite in their societies. That circumstance aggravates the tendency to spend the money largely on curative services rather than on the huge backlog of needed preventive services in the developing world. Use of community health workers, i.e. people recruited from the communities themselves and trained to promote health, as developed in several countries, may help to alleviate the problem.
In addition to the relative emphasis that should, worldwide, be accorded preventive vis-à-vis curative efforts, several other issues currently affect the public health approach to medical care. Previously many procedures and drugs have come into widespread use without sufficient consideration of their effectiveness. Initiatives are now underway, for example, by the Medical Research Council and the Departments of Health and Social Security in the United Kingdom, and the Congressional Office of Technology Assessment in the United States, to establish better systems for evaluating the effectiveness of medical technologies, including drug regimens, as well as to shorten the interval between the development of a drug and its licensing.
These initiatives reflect concern about the rapidly rising cost of medical care in the Western nations and about features with questionable, or even negative, relevance to health. Another rising issue is the efficiency of medical service, that is, how the best possible quality of medical care be provided within a given amount of resources. New facilities for ‘ambulatory surgery’, for example, make it possible to carry out many procedures without the extra expense entailed in admission to a hospital. Organizing medical personnel into groups, as well as providing incentives to personnel, offer possibilities for increasing the productivity of medical services. However, another cost-related issue is the extent to which medical resources should be used for highly expensive procedures and devices, such as heart replacement, that benefit only a few people at great expense. Recently, managed care organizations, which are private for-profit organizations, have become popular as a cost-effective strategy for providing care. Managed care organizations emphasize primary care, but the primary care doctor and a review board in them also act as the gatekeeper for seeing specialists and reducing costs. This latter role has raised questions about the quality of care delivered by managed care organizations which may limit referrals to specialists deemed necessary by primary care doctors as well as their patients.
Limited resources, together with the application of expanding technology for dubious gains, are forcing consideration of the ethical as well as the health and economic consequences of medical care. Resistance is growing to the technological prolongation of life when the quality of life has deteriorated beyond the point where it is worth saving. The state of Oregon, in the United States, has even introduced the concept of limiting funding for very expensive procedures to patients who fit certain criteria deemed to make the procedure cost-effective.
The principal aims of public health in the immediate future must be to find an appropriate balance between the provision of (a) sophisticated, technology-dependent health care at an affordable cost; (b) curative, complaint-driven medicine; and (c) preventive/health promotion services. The ideal balance will be partly determined by the resources that the country can devote to medical care. In developing countries greater emphasis should be placed on cost-effective preventive/health-promotion services than on expensive curative complaint-driven care.
Influencing behaviour
As noted above, the circumstances of life and the way people live largely determine their health. Thus a prime responsibility for public health is to develop effective strategies to promote healthful conditions and lifestyles. One approach is to assure that local, national, and even international milieux favour healthful behaviour, as in the various national and WHO campaigns against cigarette smoking and the worldwide struggle to promote breast feeding of infants. Such activities, however, often result in confrontation with powerful entrenched economic interests. Tactics in the struggle to turn public policies explicitly towards the side of health, therefore, must be high on the public health agenda.
Another approach is the so-called medical model: that is, using the doctor–patient relationship, or analogues of it, through a one-to-one or sometimes a small-group effort in a health-oriented environment to guide individuals towards healthful behaviour. It offers promise particularly when people have, or can be induced to have, concern about particular health problems such as cancer or heart disease, and then are willing to undertake the indicated habit changes. Doctors often have been reluctant to devote the effort needed, partly because of their discouragement with the results. Positive change, however, can be achieved with adequate protocols (Manley et al. 1991).
A third approach is to use the community intervention model for promoting more healthful behaviour. Particularly in developing countries people tend to consider themselves primarily as a member of a family and a community. Changing established community norms can, therefore, often influence people to adopt healthier behaviours. Community intervention can be initiated by identifying the leaders or trend setters in a community and enlisting their assistance in influencing the members of their community.

1.1 Current scope and concerns in public health

1.1 Current scope and concerns in public health
Oxford Textbook of Public Health

1.1
Current scope and concerns in public health
 
Roger Detels and Lester Breslow

Introduction
Health problems
 
Communicable disease
 
Non-communicable disease
 
Trauma
 
Mental disorders
Determinants of health
 
Nutrition
 
Environmental and occupational hazards
 
Growing recognition of lifestyle
 
Population
 
Income
Scientific approaches
 
Epidemiological strategies
 
Biostatistics
 
Biological and physical sciences
 
Behavioural and social sciences
 
Demography, vital statistics, and health information
Programmatic scope of public health
 
Goal setting
 
Prevention of disease and promotion of health
Medical care
Influencing behaviour
Environmental control
Public health strategies
 
Surveillance and monitoring
 
Intervention
 
Evaluation
Organization of public health
 
Government structure
 
Non-governmental public health agencies
Summary
Chapter References

Introduction
Public health is the process of mobilizing and engaging local, state, national, and international resources to assure the conditions in which people can be healthy. In the nineteenth and early twentieth centuries health problems reflected primarily faecal contamination of water supplies and the widespread undernutrition, crowding, and exhaustion associated with early industrialization. These conditions resulted in a high prevalence of tuberculosis, enteric infections, infant mortality, and acute respiratory diseases. In response, communities, provinces, and nations developed successful ways of dealing with these important problems through public action to promote health. From the outset, public health embraced both social action and scientific knowledge. This partnership meant linking the antipoverty (reform) movement with the findings from epidemiological and bacteriological investigations, for example, to combat such diseases as tuberculosis and typhoid fever.
Now, at the beginning of the twenty-first century, these problems persist in many parts of the world, but another set of health problems, including new infectious diseases and major non-communicable diseases, confront the United Kingdom, Japan, the United States, and other highly industrialized nations, and they have also emerged as important problems in many of the developing countries. These non-communicable diseases stem from an overly rich diet, cigarette use, excessive alcohol consumption, too little physical activity, and other conditions that typify the way many people now live. In developing countries communicable diseases are still a major cause of death. Increasing numbers of people in these countries, however, are now encountering relative affluence for the first time and thus are beginning to suffer the same health consequences as people in developed countries. This chapter broadly presents the current scope and concerns of public health as well as issues that confront public health organizations in both industrialized and developing societies. Subsequent chapters will present specific topics in greater detail.
The first part of this chapter outlines the major health problems facing the world today, including infectious diseases, chronic diseases, trauma, and mental health. Determinants of health, such as nutritional problems, environmental hazards, and disorders resulting from lifestyle choices are discussed in the second part. The third part presents the scientific strategies that public health uses to cope with the problems, including strategies basic to public health, such as epidemiology, and those that are borrowed and modified from other disciplines, including the social, biological, and physical sciences. The four major public health strategies for influencing health—preventing disease and promoting health, improving medical care, promoting health-enhancing behaviour, and controlling the environment—are outlined in the fourth part. The fifth section presents the techniques for applying these scientific approaches to public health problems, and the final section discusses the interaction of the various governmental and voluntary actions aimed at improving the health of communities.
Public health is only one of the major influences on a community’s health. The basic economic and social conditions of existence directly impact people’s level and mode of living and thus constitute the foundation of health. These conditions limit and, to a considerable extent, determine the resources that can be devoted specifically to health promotion and disease intervention. Prevailing economic and social conditions also affect health in ways beyond the level of living and the concomitant ability of people to obtain the necessities of healthy life. Strong economic forces expressed in agriculture, manufacturing, commerce, and politics, for example, may sway people to use tobacco and thus injure their health.
The magnitude and success of public health efforts will vary both in time and place in different areas of the world. Nevertheless, the principles of public health remain the same. The actions that should be taken are determined by the nature and magnitude of the problems affecting the health of the community. What can be done will be determined by scientific knowledge and the resources available. What is done will be determined by the social and political situation existing at the particular time and place.
Health problems
Health problems vary considerably in the different parts of the world. Although communicable diseases once dominated the scene, the non-communicable diseases in recent years account for six out of seven deaths in the developed world and about half of all deaths in the developing world (Table 1).

Table 1 Distribution of deaths by broad cause group and region, 1990

Communicable disease
Infectious diseases account for 25 per cent of deaths worldwide (Fig. 1). Forty-eight per cent of deaths among people 0 to 44 years of age occur from an infectious disease (Fig. 2). Even in the developed countries of the world infectious diseases are the third most common cause of death. Sixty-three per cent of deaths in children worldwide are due to infectious diseases (Fig. 3). Clearly, infectious diseases remain a major public health challenge in the modern world.

Fig. 1 Leading causes of death. (Source: WHO 1999.)

Fig. 2 Main causes of death among people 0 to 44 years of age. (Source: WHO 1999.)

Fig. 3 Main causes of death amongst children. (Source: WHO 1999.)

In the past decade the leading infectious diseases worldwide in terms of both death and disability have been acute respiratory infections, AIDS, diarrhoeal diseases, tuberculosis, malaria, and measles (Fig. 4). These diseases can be treated effectively and can be largely prevented through relatively simple means. In fact, all have been substantially reduced in some parts of the world.

Fig. 4 Leading infectious killers. (Source: WHO 1999.)

Factors which contribute to the persistence of infectious diseases include poverty and social inequalities, illiteracy, the low status of women, inadequate nutrition, poor sanitation, inadequate housing, rapid urbanization, failure to implement known preventive strategies, changing lifestyles which promote greater social and sexual mixing, limited access to health care, and inadequate surveillance systems.
The major infectious disease problems in developed countries (and increasingly in developing countries) are related to changing lifestyles, better survival of immunologically compromised individuals, and overuse/misuse of antimicrobial agents. Increased acceptance of multiple sexual partners and use of recreational drugs in both developed and developing countries have led to the current epidemic of sexually transmitted infections, including HIV/AIDS which have been exacerbated by the emergence of resistant strains of gonorrhoea and syphilis. People who have had their bone marrow or other organs replaced, or who are on chronic steroid treatment, are more susceptible to infectious disease agents.
Unstable political conditions in countries such as Rwanda and the former Yugoslavia have created increased numbers of refugees amongst whom infectious diseases spread rapidly. Another group of migrant people especially vulnerable to disease results from emphasis on manufacturing as a means for developing countries to increase income. The development of factories leads to increasing urbanization and migration of the rural poor to the industrial centres in search of jobs. The new migrants often must live in poor housing resulting in crowding and poor sanitation. Furthermore, many of the temporary migrants to urban areas leave their families in the villages, but engage the services of commercial sex workers and, thus, become at risk for sexually transmitted infections and HIV/AIDS.
Poverty remains one of the most important cofactors for infectious diseases in both developed and developing countries. Crowding, poor nutrition, limited access to health care, uncontrolled reproduction, and low educational levels, which are common amongst the poor, cause increased exposure and susceptibility to infectious disease agents and increased likelihood of death from them. Poor children are less likely to be immunized, to attend well-baby clinics, and to be introduced to medical attention early in the course of illness when intervention is most likely to be effective.
The advances that we have seen in the past decades have been due largely to the provision of safe drinking water, better handling of sewage, development and effective use of vaccines, improved personal hygiene, health education, and improved nutrition. Nonetheless, all of these simple strategies to reduce and prevent infectious diseases have not yet reached many people of the world, especially the rural poor and the urban slum dwellers.
Control of existing or known infectious diseases, however, is inadequate to ensure the health of the public. New diseases are continually emerging. The most dramatic recent example was the discovery of AIDS in 1980 and the recognition 3 years later that it was due to an infectious agent. AIDS is now the second leading cause of death from infectious diseases worldwide and the third leading infectious cause of disability-adjusted life years. Other agents that have emerged in the last two decades include hantavirus and nipah virus. New variants of an existing agent causing human disease include the H5N1 influenza strain that erupted in Hong Kong in 1998 and required the slaughter of millions of poultry. The discovery of a new variant of bovine spongiform encephalitis in cattle in the United Kingdom required the slaughter of thousands of cows and caused the implementation of trade restrictions and political tensions between the United Kingdom and its trading partners. A variant of emerging diseases is the development of drug-resistant variants of common agents such as gonorrhoea and tuberculosis induced by overuse and misuse of antimicrobials. Because of rapidly increasing world travel, control of infectious diseases, including emerging diseases, is going to require multisectorial international co-operation. New technologies are being developed to recognize new agents. An example is the National Molecular Subtyping Network for Foodborne Disease Surveillance (PulseNet), which is a molecular subtyping network in the United States. These types of efforts will need to be implemented internationally as well.
While public health advances have resulted in dramatic reductions in the incidence of infectious diseases in most countries, for example the elimination of poliomyelitis from North and South America, public health professionals need to be continually alert to the emergence of new agents, new manifestations of previously known agents, and the presence of groups in the population that are particularly susceptible to disease through poverty or other factors. The control of infectious diseases in the future will require the continued use of often difficult but proven public health strategies including improvement in living conditions, more effective health education messages to induce behaviour changes, the continued development of new technologies for identification and control of infectious agents, the development of new drugs for treatment and prevention, and improved access to the means, such as condoms, to prevent transmission of infectious agents.
Dr Gro Harlem Brundtland, the Director-General of the World Health Organization (WHO), has said recently that ‘Illness and death from infectious diseases can be, in most cases, avoided at an affordable cost’ (WHO 1999). As in all of public health, what is needed is the commitment of the public to that goal and a willingness to commit the necessary resources.
Non-communicable disease
Beginning in the nineteenth and continuing throughout the twentieth century, industrialization and commercialization have vastly changed the way people live and, correspondingly, the nature of their health problems. This change becomes apparent in examining the leading causes of death in the United States in 1900, 1950, 1990, and 1997 (Table 2). Coronary heart disease, the major epidemic of the twentieth century in the heavily industrialized nations, reached a peak around 1960, and declined rapidly thereafter; and cancer mortality has been falling in the United States since 1990. Still, these two conditions remain the leading causes of death in most of the developed nations. Moreover, in the developing countries where infectious diseases have predominated, coronary heart disease and other chronic diseases are now coming to the fore (Table 3).

Table 2 Leading causes of death in the United States (1900, 1950, 1990, 1997)

Table 3 Proportions of mortality, selected causes, in high income, and low and middle income nations of the world, estimates for 1998

Moving beyond mortality and its trends, another system of evaluating the impact of disease and other factors affecting survival has recently been introduced: years of potential life lost. This term usually indicates the total number of years of life lost before a certain age due to various causes of death (Table 4). Thus, causes of death that tend to occur in early life (such as injuries) are weighted more heavily than those that occur later in life. Furthermore, years of potential life lost is also dependent on the age distribution of the population; populations with higher proportions of young people have a greater years of potential life lost than populations with smaller proportions of young people, even if the age-specific rates by cause of death are the same for the two populations. Nonetheless, this is a useful measure for decision makers to estimate the public health impact of the various causes of death in order to plan prevention strategies.

Table 4 Potential years of life lost before age 75 for selected causes of mortality in the United States (1980 and 1997)

The years of potential life lost measure, however, tends to obscure the fact that since 1950 the increase in life expectancy in the industrialized world beyond 65 years has accounted for a much greater proportion of the expanded longevity than during the first half of this century; in recent decades because of reductions in non-communicable disease mortality which tends to occur in the later years of life, it has accounted for almost half of the increase throughout life compared with one-tenth earlier (Table 5). The main element extending the average duration of life in the developing nations continues to be reduction in the fatal diseases of infancy and early years of life, but mortality during the later years of life is becoming a more important factor.

Table 5 Life expectancy at birth and at 65 years of age in the United States (1900, 1950, 1997)

The major interest in preventing and controlling non-communicable disease is not just extending the duration of life; maintaining the quality of that lengthened life is increasingly important. The fact that non-communicable disease and its associated disability tends to increase with age has led many to express concern that longer lives will bring more such disease and greater medical costs.
In the later years of life diseases also tend to be multiple and complicated, and hence long term; emphasis on the consequent disability is growing. Therefore, a tendency is developing to measure disability-free life expectancy (Robine et al. 1992). For example, in Canada the difference in life expectancy between the poorest and the richest men is 6 years, but the difference in disability-free life expectancy is 14 years. Another measure of disease burden in a population is the disability-adjusted life year which combines a measure of premature mortality with a measure of life impairment due to disability (WHO 1996).
Trauma
Injuries constitute the cause of one-tenth of all deaths worldwide—11 per cent in the developing world and 8 per cent in the developed (WHO 1996). Unintentional injuries are a leading cause of years of potential life lost in the United States where they account for 15 per cent of years of potential life lost (US DHHS 1998). Sixty per cent of years of life lost due to unintentional injuries are caused by motor vehicle traffic accidents. The Carter Center estimated in 1985 that motor-vehicle-related deaths and injury could be reduced by 75 per cent, and injuries due to accidents occurring at home could be reduced by 50 per cent, by applying a broad-based mixed strategy for prevention (Smith 1985). As of 1996, however, motor-vehicle-related deaths had been reduced by only about 10 per cent.
Suicide and homicide also account for a substantial amount of years of potential life lost (Table 4). The rates of suicide and homicide, however, are not evenly distributed within a population, tending to occur more amongst young males and at different rates in the various racial groups (US DHHS 1998). In the United States, suicide amongst white males, for example, is responsible for 1.4 times as many years of potential life lost as amongst African-American males. Suicide is a major cause of premature death in most developed countries, especially in northern Europe and Scandinavia. Unfortunately, the causes for suicide are not well understood and satisfactory predictors of who will commit suicide have not been developed, making the development of preventive strategies particularly difficult. Often suicides amongst young people tend to occur in clusters.
Although declining, homicide remains a major public health problem in the United States where it is currently the leading cause of death amongst young African-American males aged 15 to 24 years; in 1996 it was nine times more common amongst them than amongst white males in that age group (US DHHS 1998).
As advances in public health over the last decades have caused declines in many major diseases, injuries have become a major public health problem that must be resolved; they are particularly important because they often affect the young disproportionately. The public health agenda for the twenty-first century must therefore address more intensively than before the issue of premature mortality due to trauma. Improvements in roads, seat belt laws, and improved car design have reduced injuries and death due to motor vehicle traffic accidents, and improvements in such everyday items as design of ladders have reduced accidents in the home. Better planning may not prevent disasters but it has, and can still further, reduce the damage from them. Forums for resolution of international differences and long-standing ethnic hatreds are gaining prominence but armed conflict over such matters has continued throughout the twentieth century, resulting in huge mortality tolls and other health tragedies.
More vigorous applications of intervention strategies should further reduce deaths and injuries from all types of trauma, but the nature of many factors causing death and injury from many types of trauma are still unknown. Further success in reducing injuries will therefore require multidisciplinary research to find the causes of these various types of injury. Such research should identify strategies that can be used for effective intervention programmes.
Mental disorders
The concept of mental disorders has been expanding to include not only psychoses, neuroses, and mental retardation, but also alcoholism, dependency disorders, child abuse, and learning disabilities. Progress in understanding these disorders, especially the biological basis for many of them and what can be done about them, is accelerating. The discovery of syphilis as the cause of general paresis, and nutritional deficiency as the cause of pellagra, were early notable achievements. One can add the more recent identification of a specific genetic abnormality (trisomy 21) and lead intoxication as key factors in mental retardation, and the inappropriate use of drugs, especially in older people, as the cause of a vast amount of mental disorder. Also, pharmacotherapy in recent years has been proving remarkably effective in the treatment of increasingly recognized depression, thus relieving a tremendous burden from the lives of many people.
Despite considerable progress in elucidating the aetiology and therapy of mental disorders, however, the public health response has not kept pace with the huge problem they represent. The lag in implementing what can be done about mental disorders seems partly to reflect the lingering hostile attitude towards ‘strange’ people. Rather than simply placing them in custodial institutions and thereby excluding them from society, a more enlightened approach has developed in recent decades with more effective prevention and therapy. For example, treatment of syphilis prevents general paresis, Down’s syndrome may be avoided through acting on amniocentesis results; and appropriate use of pharmaceuticals will minimize many cases of psychoses, particularly depression, which accounts for about one-sixth of the years lived with disability worldwide (WHO 1996).
The problem of mental disease is not diminishing. Increased longevity amongst people with congenital forms of mental retardation means more life years with that disorder, and lengthened life amongst older people is enlarging the problem of dementia, including Alzheimer’s disease and arteriosclerosis of the brain.
Significant developments in the past few decades towards prevention and treatment of mental disorders include the following:

(1)
increased numbers of mental health professionals and the increased range of services that they can provide;
(2)
understanding that personal and community support systems can help individuals with mental health problems;
(3)
awareness that early intervention may avoid chronicity;
(4)
advances made in understanding the biological mechanisms of mental disorders;
(5)
development of drugs for effective treatment of depression, one of the most common mental disorders.

The means to provide the mentally ill with the rights taken for granted by the vast majority of people in industrialized nations are now becoming available. Assuring these rights to those suffering from mental illness must become part of the public health agenda together with efforts to assure widespread application of the growing means of dealing with the problem.
Determinants of health
Nutrition
Diet has been scientifically and extensively linked to disease. The relationship between high-fat diets and coronary heart disease, and between undernutrition and infectious diseases, has been well established. Thus, the health of a community depends both on the adequate availability of safe food and the intelligent consumption of it.
Seventy-five years ago the major nutritional problems throughout the world were lack of adequate, safe, and affordable supplies of food, inadequate understanding of dietary needs, and widespread ignorance concerning the relationship of nutrition to health and disease. Most people, even in the developed countries, were not aware of the need for a balanced diet including components from several major food groups. Essential foods were often not available because of poverty, transportation, and distribution problems. For example, fresh fruits and other major sources of vitamin C were often unobtainable in northern climates for many months of the year. Finally, providing safe foods—uncontaminated by parasites, bacteria, and viruses—was difficult in the absence of refrigeration and pest control.
The high prevalence of infective and parasitic disease conditions led to undernutrition and, in turn, made individuals more susceptible to infectious disease agents because of their compromised nutritional status. For example, individuals with Ascaris infection could be undernourished in the face of what appeared to be an adequate diet, making them more susceptible to infection by other disease agents.
Most of the nutritional problems of 75 years ago have now been resolved in the developed nations through improved technology and education about nutrition. However, these problems persist in most developing countries and even amongst some groups of people in developed countries; for example, the poor and new migrants from developing countries who often lack both the fundamental knowledge of nutrition and the resources to purchase healthful food.
The major nutritional problem in developed countries now appears to be excessive consumption of fats, especially saturated and ‘trans’ fatty acids, refined carbohydrates, and salt, and inadequate consumption of fibre and cereals. This situation promotes diseases such as coronary heart disease, diabetes, hypertension, and dental caries. The United States National Health and Nutrition Survey documented a startling increase in obesity amongst American adults aged 20 to 70 years during the 1980s (Kuczmarski et al. 1994). The prevalence jumped from about 25 per cent, already high, during 1960 to 1980, to 33 per cent in 1990. The prevalence is even higher amongst the elderly and some other segments of the population and carries profound non-communicable disease and medical cost implications. Nutritional problems, moreover, are not confined to the developed countries; developing countries in transition also suffer from problems of overnutrition in the wealthier segments of their populations. Thus, developing countries suffer a double burden due to both overnutrition and undernutrition.
Another problem in developed countries is food faddists who advocate unhealthy diets especially to those wishing to lose weight. These diets lead to nutritional imbalances that can cause severe disease. Also, modern agricultural practices may not always lead to safer food. For example, the practice of adding hormones and antibiotics to animal feed may induce disease, including more rapid development of organisms resistant to current antibiotics. More research needs to be done to assure that modern technology to increase productivity does not lead to problems in consumers.
Appropriate nutrition can be assured through monitoring of populations using questionnaires, anthropometric measurements such as ponderal index, skinfold thickness, and height/weight indices; through education about the need for a properly balanced diet, particularly amongst expectant mothers, parents of small children, and amongst the elderly in whom nutritional problems are more likely to occur; and assurance of adequate, affordable food supplies. Finally, there are opportunities for intervention through nutritional fortification of common foods, such as the addition of vitamin D to milk and vitamins to bread. Adequate nutrition, however, requires sufficient income to buy healthy foods and, thus, alleviation of extreme poverty is essential for improved nutrition.
Environmental and occupational hazards
In the early part of the twentieth century public health professionals were concerned with ensuring the provision of biologically safe water and food to the public, and the safe removal of sewage and rubbish. The hazards of exposure to such substances as asbestos, lead, and radiation were unrecognized.
Systems are now in place in most developed countries to ensure biologically safe water and foods, and the proper removal of sewage and waste. However, the outbreak in 1993 of Cryptosporidium in the water supply in Milwaukee, Wisconsin, demonstrates the need for continued vigilance. Despite having the means to control pollution, many cities in the developed world and most of those in the developing world still suffer from levels of air pollution which are harmful, especially to children (Detels et al. 1991). Many lakes remain unfit for swimming and recreational use, and even the oceans adjacent to most major urban areas are still unsafe not only due to biological contamination, but also to chemical contamination. Even ground water in rural agricultural areas may be contaminated by concentrations of pesticides.
The environmental problems of importance in developed countries are now due largely to the explosion of technology over the last several decades. The production of chemicals in the United States has increased over 200-fold since 1940. This has been accompanied by a tremendous increase in the number of chemicals to which the public is exposed. As developing countries develop industries they too become polluted by chemicals.
An example of the impact of these chemicals is the global warming due to the depletion of the ozone layer caused by the use of hydrofluorocarbons as aerosol propellants. Warming of only a few degrees will result in creating more ecosystems which are hospitable for deadly diseases such as malaria and dengue. (WHO 1999)
The impact of these chemicals is reviewed in Chapter 8.5.
The issue of environmental equity has been raised both within countries and between developing and developed countries. The poor, particularly minorities, are more likely to live in areas that are exposed to high levels of pollutants in the air, water, and soil (Rios et al. 1993). In their effort to produce cheaper goods for sale to wealthy nations developing countries have largely ignored the impact that rapid industrialization has had on their environments. Industrial areas in developing countries are now amongst the most polluted areas of the planet. Ironically, the cost of rescuing the environment will probably far exceed the cost that would have been incurred had environmental safeguards been incorporated during the process of industrialization.
Workers are subject to especially high concentrations of pollutants in the workplace. Unfortunately, health effects from pollutants may occur years after exposure and are therefore difficult to document. These health effects may be the result of cumulative burdens of chemicals in tissues or the disposition of chemicals in parts of the body that are not readily available for evaluation (e.g. the brain). A major threat to workers arises from exposure to substances not yet identified as hazardous and the reluctance of workers to wear cumbersome protective devices (Chapter 7.4). More research is needed to identify the potential health effects of acute and chronic exposure to a wide range of substances in the general environment, the food chain, and the workplace.
Safeguarding the health of the public requires regulation of pollutants. The establishment of acceptable levels of pollutants is complicated by two factors. The first is the difficulty of establishing dose–response relationships, particularly for effects with a long incubation period. The second is the economic burden that often results from regulatory actions. Whereas intervention in infectious diseases has met with enthusiastic support from the public, control of toxic substances in the environment has been supported by the public only recently. Inadequate understanding of the relationship between chemical pollutants and resultant disease, and the expense related to surveillance, regulation, and control of toxic substances has deterred action. Because stringent controls may increase costs, and even unemployment, regulation often rests more with the courts and legal procedures than on scientific expertise and judgement.
Resolution of important issues confronting society may themselves introduce health hazards. For example, the need to develop more energy efficient housing has increased the levels of pollutants such as radon and formaldehyde in homes, which, in turn, increases the potential for the occurrence of related diseases. In addition, certain personal habits may promote the action of specific toxic substances. For example, the likelihood of developing lung cancer from exposure to asbestos is increased about sevenfold in smokers, and is also increased in the non-smoker exposed to passive smoke.
Protecting the health of the public against environmental and occupational hazards in the future will depend on the following:

(1)
continued research into the acute and long-term health effects of thousands of substances being released into the environment;
(2)
surveillance of the occurrence of these hazards in the environment including the workplace;
(3)
development and implementation of techniques for eliminating, reducing, or neutralizing these hazards;
(4)
convincing the public of the need for implementing the necessary safeguards;
(5)
laws to mandate the implementation of measures for controlling hazardous exposures.

Since such efforts will sometimes be both expensive and unpopular, careful consideration should be given to seeking to implement only those regulations that will have a high probability of yielding a positive recognizable effect on the health of the community.
Growing recognition of lifestyle
Although environmental measures and medical care have prevented much disease and improved health in recent decades, it is becoming increasingly apparent that individuals themselves play a substantial role in determining their own health. They do so through decisions about their diet, use of tobacco and alcohol, and other aspects of living. These decisions are largely influenced by the milieu in which people live. Spectacular achievements in microbiology and other biomedical sciences have evoked widespread and deserved admiration; unfortunately, these achievements have tended to obscure the important influence of lifestyle on health. The circumstances of life and how people respond to these circumstances are still the major determinants of health.
Evidence indicating that disability can be mitigated, rather than being an inevitable consequences of an ageing population, comes from studies in Alameda County, California (Breslow and Breslow 1993). The same health-related practices that predict longevity (not smoking, moderate or no alcohol, sleeping 7 to 8 h per day, exercising at least moderately, maintaining a moderate weight, eating breakfast and other regular meals) also predict freedom from disability and to the same extent (Fig. 5). Thus it appears that social conditions and ways of living influence disability as well as mortality patterns. The disabilities that now affect older people may subside in future generations along with mortality rates as social conditions and ways of living change.

Fig. 5 Mortality, disability, and health practices amongst adult residents in Alameda County, California, 1965 to 1983. (Source: Breslow and Breslow 1993.)

In urban slums of developed countries as well as in developing countries, far too many people still live in extremely restricted circumstances that limit their scope of life. Most people in industrialized societies, however, have access to possibilities of consumption that, especially if followed to certain extremes, can generate serious health problems. The choices that people make when exposed to cigarettes, excessive amounts of alcohol and calories, reduced physical demand, and similar situations, exert a profound influence on whether they will suffer and die prematurely from lung cancer, coronary heart disease, diabetes, cirrhosis, chronic lung disease, trauma, or other current major causes of illness and death. Cigarette smoking alone is considered responsible for more than 400 000 (about one-fifth of all) deaths annually in the United States (McGinnis and Foege 1993). Obesity is another common and increasing factor (Kuczmarski et al. 1994).
Such health-related habits do not develop in a vacuum. The extent to which a person acquires them depends on circumstances such as the advertising and price of alcohol as well as cigarettes. Hence, social policy on these matters becomes an important public health issue. In this connection public health practitioners assure their credibility by advocating only those changes in lifestyle that are supported by scientifically sound studies.
A second aspect of lifestyle significantly associated with health embraces people’s relationships to their social support systems. Considerable evidence links health to marital status, degree of closeness to friends and relatives, and social group involvement. Such social connections are highly associated with mortality and this association is largely independent of physical health status, health practices, use of health services, socioeconomic status, age, sex, and race (Berkman and Syme 1979).
Population
Success in public health initiatives, particularly in controlling infectious diseases, has reduced death rates worldwide with a resultant increase in longevity, yielding significant population growth. In developed countries the decline in mortality took place gradually with a commensurate decline in birth rates as survival of infants increased. In developing countries the drop in mortality has occurred over a shorter time period and without a commensurate drop in birth rates. This has resulted in rapidly expanding populations, often in those countries where food and other vital resources are most limited. India, for example, has tripled its population since independence in 1947 and is expected to become the most populous country in the world within the first few years of this millennium. Overpopulation is a major cause of poverty and disease and is considered by many to be the most pressing public health problem.
Currently the less developed countries are expanding their populations four times as rapidly as the developed countries. These countries also have a much higher proportion of younger people, which means that the higher birth rates are likely to continue for at least the next several decades. However, the recent epidemic of AIDS, which affects primarily adults of child-bearing age, may have some impact in areas of high endemicity, such as southern and central Africa, where as much as 20 to 30 per cent of women of child-bearing age may be infected.
It is clear that unless efforts to control population growth are successful, the population of the earth will outstrip its ability to sustain itself despite the rapid advances in the agricultural sciences. Therefore, a major public health effort must be directed at controlling population growth. These efforts must include: the continued development and implementation of more effective and safe contraceptive methods, education efforts, both in the need for contraceptives and in their correct use, and the political commitment of the public and political leaders. The 1994 World Congress on Population brought together scientists and political and religious leaders to propose mutually agreeable policies for control of population growth (United Nations International Conference on Population and Development 1994). The goal is achievable as has been demonstrated by China with the development and enforcement of the one-child policy.
Conversely, in the more developed countries where population growth has declined to replacement levels or less, the proportion of elderly people has increased as the proportion of those in the productive years has decreased, introducing new problems. In the United States, for example, the social security system was designed on the assumption that the younger, and mostly working, population would be large enough relative to those over 65 years of age to provide support for the latter. This assumption may not hold in the future and is the subject of vigorous debate by the United States Congress and the President. Such shifts in age distribution in both developed and developing countries must be anticipated and their potential adverse effects recognized and prevented.
Income
The poor, in both developing and developed countries, are more prone to disease because their low income causes them to have poor nutrition and to be chronically exposed to unsanitary conditions. Furthermore, their low income limits their access to health care resulting in chronic disability from treatable diseases and conditions. In addition, the poor also often lack access to education and are more likely to be illiterate. Thus, it is difficult to reach them with health messages. Moreover, the poorly educated lack the social power to improve health conditions and access to health care.
Scientific approaches
Effective public health actions are based on scientifically derived information about factors influencing health and disease. The basic sciences of public health are epidemiology and biostatistics, but their effective use depends in turn on the knowledge and strategies derived from the biological, physical, social, and demographic sciences, including vital statistics.
Epidemiological strategies
Epidemiology is the core science of public health and preventive medicine. It is the scientific method used to describe the distribution, dynamics, and determinants of disease and health in human populations. Although there are many definitions, the Greek root of the word epidemiology delineates well the scope of the discipline: ‘The study of that which is upon the people.’ John Last in A Dictionary of Epidemiology (1995) has defined epidemiology as ‘the study of the distribution and determinants of health related states or events in specified populations and the application of this study to the control of health problems’ (Last 1995). The epidemiologist seeks to identify those characteristics of people, the agents of disease, and the environment which determine the occurrence of disease and health. In order to accomplish that objective, the epidemiologist describes:

(1)
disease occurrence (time characteristics);
(2)
the population affected (person characteristics);
(3)
the nature of the environment in which the disease is occurring (place characteristics), which contribute to knowledge about the natural history of the disease and ways to control it. For example, epidemiologists have observed that coronary heart disease occurs to a greater extent amongst middle-aged and older men who overeat, have high blood pressure, smoke cigarettes, do little exercise, have a family history of heart disease, and live in a developed country.

The science of epidemiology has many applications in public health as well as in medicine. These include:

(1)
establishing the natural history of a disease in a population, for example, the impact of potent antiretroviral therapy on delaying the onset of AIDS and death amongst people infected with HIV;
(2)
describing the natural history of infection and disease in the individual, for example the acute, asymptomatic, symptomatic, and clinical disease stages of HIV/AIDS;
(3)
describing the clinical picture of disease, for example, who gets the disease, who dies from the disease, what is the outcome of the disease or infection, and what are the most effective treatments;
(4)
identifying the risk factors for disease, for example the relationship of specific environmental conditions such as air pollution on the risk of developing respiratory conditions;
(5)
identifying precursors of disease, for example the relationship of high blood pressure to stroke, cardiovascular disease, and kidney disease;
(6)
identifying the major public health problems in a community, for example surveillance for the prevalence of specific diseases that are treatable or represent a threat to the health of the community;
(7)
evaluating the effectiveness of intervention programmes, for example the impact of condom promotion on prevalence of HIV and sexually transmitted infections in a community or nation;
(8)
investigating an outbreak of unknown aetiology, for example the cause of an epidemic of wasting disease in northern Luzon, Philippines.

For studying these matters, epidemiologists must have good information on the occurrence of disease, on the relevant characteristics of the population, and of the environment in which the disease is occurring. The need for this information has stimulated the development of health information systems for co-ordinating existing sources of data and guiding the development of essential new sources of information relevant to the health of the community.
Epidemiologists depend to a considerable extent upon comparing disease frequencies in different populations. Numbers of deaths are often the most readily available statistics for comparison. To make these comparisons it is necessary to estimate rates of disease occurrence or deaths due to specific causes. Information about populations is usually obtained from periodic censuses, or sometimes by a survey of a probability sample of the population. Rates that depend on census data are likely to be increasingly inaccurate with the number of years which have elapsed since the census data were collected. In addition, detailed information on populations derived from a periodic census is often not available for a year or more following the actual collection of the data. Information on population characteristics may be obtained at more frequent intervals by examining an appropriately selected probability sample of a population. This information can be particularly useful at times distant from the date of collection of census data.
The potential of epidemiology for documenting disease occurrence and developing and testing hypotheses has expanded rapidly over the last several decades. This advance is a result not only of the rapid development of computer technology but also because of the entry into the field of individuals whose major discipline is epidemiology. Although non-medical doctors, especially in the United Kingdom, made several significant contributions to epidemiological methodology (e.g. the great biostatistician, Bradford Hill) prior to the last decade, the majority of epidemiologists in the United States and United Kingdom were medical doctors who took an additional year or more of training in epidemiology to supplement their biomedical training. Now it is recognized that both medical and non-medical doctor epidemiologists are essential to the field: medical doctors for their clinical/biological expertise, and non-medical doctors because they are more likely to have expertise in methodological and statistical strategies.
Over the last several decades there has been a rapid increase in the number of techniques that distinguish factors that are truly related to disease from those factors that are related only indirectly to disease and, thus, may confound a true causal association. Greenland and Rothman discuss strategies to overcome these methodological problems in Chapter 6.10 and Chapter 6.11. Pearce and others have recently suggested that the concern for good methodology, however, has blurred the primary purpose of epidemiology to study the major public health diseases and issues in populations as opposed to individuals (Pearce 1996). The capacity of the epidemiologist for ascertaining the distribution, dynamics, and determinants of disease depends upon the availability of several other scientific disciplines. Laboratory procedures derived from chemistry, biochemistry, microbiology, and immunology, for example, can be used for obtaining information about the environment, the agents of diseases, and the changes that occur in humans. Conversely, epidemiology looks to statistics for mathematical methodologies that describe the strength of correlations amongst the multiple factors that may promote the occurrence of disease, and to the social sciences for techniques for obtaining accurate information from respondents as well as for assessing the influence of psychosocial factors on health and disease. Increasingly, epidemiologists and biostatisticians are working together to provide models of disease occurrence which can be used to predict trends of disease in the future

CHAPTER 38 INFECTIONS

CHAPTER 38 INFECTIONS
Practice of Geriatrics
CHAPTER 38 INFECTIONS
Mira Cantrell, M.D., and Dean C. Norman, M.D.
Epidemiology
Pathogenesis of Infection in the Elderly
Factors Peculiar to Infections in the Elderly
General Approach to the Management of Infection in the Elderly
EPIDEMIOLOGY
Infections have a major impact on the elderly, particularly those who are more disabled and institutionalized. Many infections occur more frequently in the elderly, and most of these have greater morbidity and mortality rates in the old than in the young (Table 38-1 and Table 38-2).1,2 and 3 Since many of these illnesses are preventable or curable, it is imperative that geriatricians have a good understanding of the diagnosis, treatment, and prevention of infection in aging adults.

TABLE 38-1 MORTALITY RATE OF INFECTIONS IN ELDERLY COMPARED TO YOUNG

TABLE 38-2 EXCESS MORBIDITY OF INFECTIONS IN ELDERLY

PATHOGENESIS OF INFECTION IN THE ELDERLY
The risk and severity of infection are directly related to the virulence and inoculum of the pathogen and inversely related to the integrity of the host defenses.

Virulence
Approximately 40% of acute care hospital beds are occupied by patients in the geriatric age category, and 5% of elderly patients reside in long-term care institutions. Thus, the risk of exposure to nosocomial pathogens such as gram-negative bacilli is increased in this population. In the acute care setting it has been established that the risk per day of hospitalization among older acute care patients for developing a nosocomial infection is 1.5 times that of the young.4 Similarly, the risks of developing a nosocomial urinary tract infection (threefold increase), bacteremia (fivefold increase), pneumonia (threefold increase), or wound infection (twofold increase) increase with age.5 The risk of colonization and infection with gram-negative bacilli is also high in the nursing home population.6,7 Moreover, the widespread and in some cases inappropriate use of antimicrobial agents, along with often inadequate infection control procedures has had a dramatic impact on the microbial flora. For example, studies demonstrate that patients treated with antibiotics in a nursing home may become colonized by Clostridium difficile (the pathogen most often associated with antibiotic-associated colitis).8,9 Methicillin-resistant Staphylococcus aureus (MRSA) infections also occur in long-term care facilities, and vancomycin-resistant Enterococcus (VRE) poses a new threat.
Inoculum
Older adults are more likely to be exposed to higher inocula (quantity) of pathogens for a variety of reasons. For example, in the case of bacterial pneumonia the elderly are more likely to aspirate oropharyngeal flora secondary to central nervous system disorders, oversedation, or placement of feeding nasogastric tubes; pressure sores remove skin, which is an important physical barrier against bacterial colonization; and the use of chronic indwelling bladder catheters allows colonization of the lower urinary tract with potential pathogens.
Host Defenses
As alluded to earlier, the skin and mucosal epithelial lining are important physical barriers to infection. The epidermis thins with age, and this thinning is exacerbated by chronic diseases and malnutrition. Other important changes in the skin include decreases in Langerhans cells, interleukin-1 production, and production and response to epidermal thymocyte-activating factor. These changes, coupled with poor perfusion, further increase the risk of damage to the skin and the subsequent development of soft tissue infection such as cellulitis and infected decubitus ulcers. Mucosal surfaces are also adversely affected by age, disease, and lifestyle (e.g., cigarette smoking with loss of the ciliary action of the epithelial cells of the upper respiratory tract and possibly reduction of secretory immunoglobulins).
Primary immunity (also called natural immunity) consists of phagocytosis, complement, and natural killer cells. Age in itself may have little effect on this form of immunity, which does not depend on prior exposure to pathogens (antigens) to be effective (hence the term primary). However, acute and chronic diseases, especially malnutrition, may compromise these defense mechanisms.
Secondary immunity (also called acquired immunity) refers to immune function that is activated only after prior exposure to a pathogen (antigen). This arm of the immune system requires a complex interaction between thymus-derived cells (T lymphocytes or T cells), bursa-derived cells (B lymphocytes or B cells), and antigen-presenting macrophages. T cells are most adversely affected by aging, during which there is a qualitative loss of function that parallels the involution of the thymus and the reduction of thymic hormones, which occurs by middle age. Two subsets of T cells, the CD45RO+ and the CD45RA, change most dramatically with age. The first is a predominantly naive subset, while the second consists predominantly of memory cells. With advancing age, the percentage of memory cells increases in relation to naive cells as the naive cells undergo a transition to memory cells. This altered ratio contributes to age-related changes in T-cell function including a decreased proliferative response to mitogens, production of and response to interleukin-2 and anti-CD-3 monoclonal antibody. T cells are necessary to enhance B-cell function. Although B cells are the cells responsible for antibody production, the diminished antibody response to vaccines that is observed with aging is due to defects in helper T-cell function and possibly B-cell function. Secondary immunity is also compromised by chronic diseases, malnutrition, and immunosuppressive agents.10
Other factors leading to increased morbidity and mortality for infectious diseases in the elderly include low physiologic reserve, presence of chronic underlying diseases, delays in diagnosis due to atypical clinical presentations leading to therapeutic delays, higher rates of adverse antibiotic and other drug interactions, and complications resulting from invasive diagnostic procedures.
FACTORS PECULIAR TO INFECTIONS IN THE ELDERLY
Etiology
Pathogens infecting older persons are different and more diverse than those infecting younger adults. Community-acquired pneumonia in young persons is most often due to Mycoplasma pneumoniae and Streptococcus pneumoniae. However, in aging adults, Mycoplasma is uncommon, and although S. pneumoniae causes 40% to 60% of cases of pneumonia, a variety of bacterial organisms including Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Branhamella catarrhalis, and Haemophilus sp as well as mixed flora (including anaerobes) account for many cases of lower respiratory infection in this population. A variety of Legionella sp cause a variable number of cases of pneumonia in the elderly depending on geographic location and immune status; Chlamydia pneumoniae causes a still undefined number of pneumonias in the elderly.
Urinary tract infections (UTIs) in the general population occur almost exclusively in sexually active women and are caused by Escherichia coli in over 85% of cases. In contrast, UTIs occur frequently in both elderly women and men, and the cause is frequently uropathogens other than E. coli (e.g., Klebsiella sp, Proteus sp, and Enterococcus sp). Moreover, polymicrobial bacteriuria is common in patients with indwelling bladder catheters.
The elderly are more likely to be in institutions and account for an increasing percentage of acute care hospital inpatients. They are therefore more likely to be exposed to nosocomial pathogens such as aerobic gram-negative bacilli and S. aureus as well as to multidrug-resistant pathogens including MRSA and VRE.
Viral illnesses also have a major impact on the elderly. Although rhinovirus infection (the “common cold”) decreases with age, respiratory viruses such as influenza virus cause very high morbidity and mortality in older adults, and there is a risk of hospitalization of about 1 per 300 and a risk of death of 1 per 1500 during influenza outbreaks.11 Respiratory syncytial virus12,13 as well as influenza virus may cause outbreaks of respiratory illness in nursing homes. Varicella-zoster virus is another important pathogen that is manifest in the elderly in the form of herpes zoster. This infection carries with it the dreaded potential complication of postherpetic neuralgia, which also occurs almost exclusively in the geriatric age group (see later)
Diagnosis
CLINICAL MANIFESTATIONS
The diagnosis and therapy of infections in the elderly present unique problems that are reviewed here briefly. Aside from prevention, early diagnosis with rapid institution of antimicrobial therapy is the mainstay of treatment for reducing the appallingly high morbidity and mortality of infection in the aged. Unfortunately, infection may present in an atypical manner in a significant number of cases (e.g., blunted or absent fever response in 20% to 30% of patients). This is particularly true in the old-old (i.e., persons 75 years old or older) and in long-term care institutions, in which residents are typically frail, suffer from multiple diseases, and are cognitively impaired.
There are basically four factors that contribute to the atypical presentation of infection in the elderly compared to the young. These include underreporting of illness, which may cause delay in bringing an elderly patient to medical attention, and different pathogens (which was discussed earlier). Underreporting of illness is an important problem in the cognitively impaired elderly patient, who may not complain or may be unable to communicate information about symptoms. Furthermore, even noncentral nervous system infections may result in compromising cognition in elderly patients. The presence of coexisting diseases such as chronic bronchitis, which may mask acute pneumonia, or rheumatoid arthritis, which can confound the presence of septic arthritis, may compound difficulties in making the diagnosis of infection. Finally, altere physiologic responses to infection, or for the manner to any acute illness, are due to man factors including the decremental biologic changes of normal aging, which may be exacerbated by lifestyle. For example, age-related changes in chest wall expansion and lung tissue elasticity, which may be made worse by smoking, contribute to a diminished cough reflex. A weakened cough has the double negative effect of contributing to a decline in pulmonary host defenses and making the diagnosis of respiratory infection more difficult.
Another example of an altered physiologic response to infection in older persons that deserves special mention is the often-observed blunted fever response.14,15 Although fever is the cardinal sign of infection, the traditional definition of fever (oral temperature of 100.4° to 101°F or 38° to 38.3°C) may not be sensitive enough to diagnose infection in elderly patients. We have found in a nursing home population that baseline body temperatures are approximately 1°F below those of a normal young person and that with infection, despite a rise in temperature comparable to that seen in the young, the maximum temperature may be below the traditional definition of fever. However, we also found that a temperature of 100°F (37.8°C) coupled with a decline in functional status is highly indicative of infection in this population.16,17
The presence or absence of fever—aside from facilitating or inhibiting the diagnosis of infection—has other implications. The presence of fever (as defined by an oral temperature of 101°F) is highly specific for the presence of a serious, usually bacterial, infection.18,19 Moreover, when the syndrome of fever of unknown origin (FUO) occurs in elderly persons, it typically signifies a treatable condition such as intra-abdominal infection, infective endocarditis, temporal arteritis, or other rheumatologic condition.20,21 A blunted fever response to infection frequently portends a poor prognosis.22 This may be relevant to the mounting evidence that fever may play an important role in host defenses.15,23
In summary, an acute infection in the elderly may present with either typical clinical manifestations or subtle findings. Signs and symptoms pointing to a specific organ system infection may be lacking. Thus, an infection should be sought in any elderly person with an unexplained acute to subacute (days to weeks) decline in functional status.
LABORATORY TESTS
It is more difficult and hazardous to perform invasive diagnostic tests in the elderly, particularly if they are frail and unable to cooperate. Furthermore, waning cellular immunity with age makes skin testing less reliable (e.g., for tuberculosis), whereas increased nonspecific immunoglobulin production may give false-positive serologic test results (e.g., positive rheumatoid factor). Also, radiologic procedures may be difficult to interpret in older adults because of biologic changes with age and age-related disorders (e.g., changes secondary to chronic congestive heart failure or obstructive pulmonary disease may confound the diagnosis of pneumonia). Finally, colonization of normally sterile sites by bacteria such as the age-related gastric colonization by Helicobacter pylori may make it difficult to assess the role of this pathogen in gastrointestinal disease in the elderly.24 Similarly, colonization of the bladder in elderly persons who are often completely asymptomatic may make it difficult to assess the clinical significance of a positive urine culture.
Still, basic laboratory studies such as a white blood cell (WBC) count with a differential remain the cornerstone of laboratory diagnosis. A high WBC count with a left shift, regardless of a patient’s hydration status, is highly suggestive of a developing infectious process.
Antimicrobial Therapy
PHARMACOLOGY
A detailed description of the pharmacology of antibiotics is beyond the scope of this chapter, and the reader is referred to a more comprehensive review.25 Briefly, oral absorption, tissue penetration, hepatic metabolism, and volume of distribution are either minimally or variably affected by age. In the pharmacology of antibiotics age affects mainly renal clearance. This is not a trivial effect because the majority of antibiotics are cleared predominantly by this mechanism. Therefore, drugs that are cleared predominantly by the kidneys, such as the aminoglycosides and vancomycin, require serial monitoring of the patient’s clinical status, renal function, and serum drug levels because they are associated with low therapeutic indices and potential serious adverse side effects (i.e., nephrotoxicity and ototoxicity). It has been demonstrated that reliance on simple serum creatinine measurements or formulas predicting creatinine clearance based on serum creatinine levels are inadequate in seriously ill elderly patients with an infection.25,26
SPECIFIC DRUGS
Table 38-3 lists some of the antibiotics more frequently used for treating infection in the elderly as well as their spectrum of action and potential indications. The list is not exhaustive and summarizes only some of the antibiotics believed by the authors to be particularly relevant for use in the elderly.

TABLE 38-3 SOME IMPORTANT ANTIBIOTICS FOR INFECTION IN THE ELDERLY

GENERAL APPROACH TO THE MANAGEMENT OF INFECTION IN THE ELDERLY
The diagnostic approach should take into consideration the setting in which the infection occurs. Community-acquired infections are more likely to be found in the respiratory tract, urinary tract, or abdomen. More than 80% of infections in nursing homes are pneumonias, urinary tract infections, and soft tissue infections (acronym, PUS). Hospital-acquired infections commonly comprise aspiration pneumonia involving nosocomial flora, catheter-associated urinary tract infections, and intravenous catheter-associated septic thrombophlebitis.
Empirical therapy with broad-spectrum antibiotics is often indicated pending culture results in seriously ill frail elderly patients with an infection. In general, this therapy should include a broad-spectrum beta-lactam antibiotic. The more toxic aminoglycosides should be avoided in the elderly unless the risk of death from sepsis outweighs the risk of ototoxicity and nephrotoxicity. Therapy should be altered to more narrow-spectrum agents based on the culture data.27,28 Because of cost considerations, patients should be switched to oral antibiotics as soon as possible.
Home intravenous antimicrobial therapy may be given to selected elderly patients who have stable infections if they and their caregivers are motivated to participate in this form of therapy.29
Despite some questions about cost-effectiveness and reimbursement for this kind of treatment, a significant number of infected elderly patients may benefit from this therapeutic option. Broad-spectrum cephalosporins with long half-lives and limited toxicity such as ceftriaxone are the antibiotics most frequently used in home intravenous therapy.
Specific Infections
PNEUMONIA
Pneumonia or influenza is the leading infectious cause of mortality in the elderly and the fourth leading cause of mortality in those over age 75. Moreover, compared with younger adults, the elderly have a five- to tenfold increased risk of developing pneumonia. One study showed that the risk was highest in those with coexisting alcoholism, followed in order by chronic obstructive pulmonary disease, immunosuppressive therapy, cardiovascular disease, and institutionalization.30
The majority of pneumonias are secondary to micro- or macroaspiration of oral pharyngeal flora in patients with compromised host defenses (e.g., diminished cough reflex, waning cellular immunity). The causes of pneumonia differ significantly from those in the young depending on the clinical setting (see earlier section on etiology). Data on the etiology of pneumonia in long-term care facilities are limited, and the available information is based primarily on sputum culture results, which are not definitive in establishing the actual etiologic pathogen.31 Nevertheless, it is estimated that, compared to community-acquired pneumonia, of which 40% to 60% of cases are caused by S. pneumoniae, pneumonia occurring in the nursing home frequently results from mixed causes. Moreover, in nursing homes there is an increased likelihood of isolating aerobic gram-negative bacilli such as Klebsiella sp and E. coli from the sputum. Fortunately, multiple drug-resistant pathogens such as Pseudomonas aeruginosa are infrequently found as respiratory pathogens unless the patient has recently been in an acute care facility or has been taking broad-spectrum antibiotics. Hospital-acquired pneumonia in the elderly is more likely to be caused by mixed flora, usually oral aerobic and anaerobic flora. In people over the age of 65, the risk of oropharyngeal colonization by staphylococci and aerobic gram-negative bacilli increases with decreasing functional status and increasing level of care.32 Therefore, it is not surprising that a significant proportion of cases involve these pathogens, again usually in mixed infections.
The diagnosis of pneumonia in debilitated elderly patients may be difficult.28 Cough and fever may be diminished or absent. Tachypnea and tachycardia are sensitive but not specific findings. Older patients may present simply with altered mental status or a decline in functional status. Physical examination usually does not reveal signs of consolidation and may be confusing in aging patients with coexisting congestive heart failure or chronic obstructive pulmonary disease. The chest radiograph along with the history and physical examination are important in establishing a diagnosis of pneumonia in the elderly patient. The chest radiograph typically shows a patchy pattern of bronchopneumonia but may be initially negative or difficult to interpret in patients with coexisting pulmonary disease. Following hospitalization, the pulmonary infiltrates may become worse in approximately half the patients. Moreover, resolution of the infiltrates typically takes longer in elderly patients than in younger ones.
Higher mortality rates for pneumonia in the elderly should not discourage aggressive therapy given that in one large study of community-acquired pneumonia (excluding nursing home cases) 2-year mortality rates for pneumonia patients discharged from the hospital were similar in both old and young.33 Management of pneumonia in the elderly requires hospitalization in most cases because of the higher mortality and more frequent complications, difficulties in establishing both the diagnosis and the precise cause, severity of the illness (which may be masked by the clinical presentation), and the need to monitor therapy. Pneumonia in nursing home patients with mild to moderate illness may be managed in the nursing home only if sufficient resources are available (e.g., staff, laboratory support, administration of intravenous fluids and antibiotics).
In all cases, an effort should be made to obtain sputum for a Gram’s stain smear and bacterial culture, and for a smear and culture for mycobacteria if tuberculosis is suspected. Older patients may be unable to provide an optimal sputum specimen (less than 10 epithelial cells and more than 25 polymorphonuclear cells per low-power field), but more invasive procedures such as transtracheal aspiration, shielded bronchoscopy, and transbronchial biopsy should be reserved for patients who are at high risk of unusual or opportunistic infections (e.g., those with immunosuppressed status) or who fail to respond to initial antimicrobial therapy and show clinically deteriorating signs. Other routine laboratory tests, including blood cultures (positive in about 5% to 10% of cases), serum electrolytes, complete blood count, and renal function tests, should also be performed. Monitoring of arterial blood gases is important for assessing adequate gas exchange and acid-base balance. At a minimum, measurement of oxygen saturation with a pulse oximeter should be performed, and an electrocardiogram should be obtained initially to evaluate any potential cardiac complications of pneumonia. Additionally, skin testing for tuberculosis and, in certain geographic areas, assessment for fungal infection (e.g., coccidioidomycosis) should be performed in elderly patients with pneumonia. Finally, diagnostic thoracocentesis for pleural fluid smear, culture, pH, leukocytes, glucose, protein, and cytologic examination as well as pleural biopsy should be considered in patients who have no coagulopathy and who can cooperate with the procedure. This is especially appropriate for patients who have large pleural effusions or in whom the effusion does not improve with therapy.
Antimicrobial therapy for pneumonia in the elderly should be based on the results of the tests just mentioned. In view of the severity of the illness, early empirical therapy with broad-spectrum antibiotics is advised for most older patients with pneumonia; adjustments are made when the culture data become available.28 It is the authors’ recommendation that for clinically stable elderly patients with community-acquired pneumonia, treatment should be started according to the Gram’s stain results. If the sputum specimen is of “poor” quality, empirical therapy with any one of the following antibiotics should be considered: parenteral second- or third-generation cephalosporin, ampicillin-sulbactam, or ticarcillin-clavulanate. In mildly ill patients, oral ciprofloxacin, with or without ampicillin to ensure adequate coverage of S. pneumoniae, may be considered. Clinically unstable patients—those with nosocomial-acquired pneumonia, who have recently begun taking antibiotics or who are immunosup pressed—should receive empirical therapy consisting of a parenteral third-generation cephalosporin plus either aztreonam, quinolone, or an aminoglycoside. Aminoglycosides should be avoided if possible. Erythromycin should be part of the therapeutic regimen if Legionnaire’s disease is suspected.
The prevention of pneumonia is best accomplished by reducing the risk of aspiration whenever possible (e.g., avoiding sedating medications, alcohol, and nasogastric tubes [Table 38-4]). Vaccination with the current pneumococcal vaccine is now strongly recommended despite some past questions about its efficacy. Influenza vaccination is very important in preventing influenza pneumonia as well as secondary bacterial pneumonia (see next paragraph).

TABLE 38-4 PREVENTION OF PNEUMONIA

INFLUENZA
Although other respiratory viruses such as respiratory syncytial virus are capable of infecting older persons, influenza has had the greatest impact by far, and much of the excess morbidity and mortality ascribed to influenza outbreaks has occurred in people at the extreme ends of the age scale.11 It should be kept in mind that in addition to damaging respiratory epithelial cells, decreasing the effectiveness of cell-mediated immunity, and causing upper and lower viral respiratory infection and secondary bacterial bronchitis and pneumonia, influenza may exacerbate and worsen chronic underlying medical conditions. This activity accounts in part for the high hospitalization rates of the elderly observed during influenza outbreaks in the community.
The virus undergoes antigenic changes (usually “drift,” although an actual “shift” occurs about every 10 years), and manufacturers of vaccines must take these changes into account annually. Thus, vaccinations must be given yearly. The precise efficacy of the influenza vaccine has not been established in the elderly, but it appears to be at least 60% effective in reducing the incidence of influenza infection. In addition to patients with special health problems and health care professionals who interact regularly with patients at high risk for influenza, the vaccine is recommended for all persons aged 65 and older. Amantadine and presumably rimantadine are effective for the early treatment of influenza (within 48 hours of exposure) and for prophylaxis against influenza A (not influenza B). The efficacy of amantadine is better established in the literature than that of rimantadine. Both are usually given in a reduced dosage of 100 mg orally per day in elderly persons. However, in the case of amantadine, which is cleared by the kidneys, even this dose may be too high for some debilitated elderly persons, and the dose must be adjusted downward based on creatinine clearance.7,34
TUBERCULOSIS
Mycobacterium tuberculosis infection occurs disproportionately in the older population and is associated with higher mortality rates in this population. Among all cases of tuberculosis in the United States, 26% occur in people over the age of 65, in whom the morbidity rate is 60%. Although the majority (80%) of all cases are diagnosed in community dwellers, the incidence rate is three to four times higher in those residing in nursing homes. The association between the tuberculous pathogen and the aged may exist in part because the majority of elderly people have been exposed to tuberculosis at an earlier age (when tuberculosis infection was quite common in the general population) but were able to eliminate or control the infection at that time. However, the waning of cell-mediated immunity with age as well as the presence of coexisting chronic illnesses, which may further compromise host defenses, may allow for “reactivation” of this infection in the geriatric age group. Although reactivation of preexisting infection is the usual pathogenesis of tuberculosis in the elderly, it should be emphasized that outbreaks of primary infection with active pulmonary tuberculosis have been well described in long-term care institutions.7,35
The diagnosis of tuberculosis should be considered in any elderly individual who has a cough, chronic fatigue, night sweats, unexplained fever, weight loss, or gradual or subacute decline in functional status. Unfortunately, a proper diagnosis may be difficult to ascertain because of subtle or unusual clinical features and atypical chest x-ray findings are common. Moreover, skin testing for tuberculosis is often unreliable in the elderly because reactivity to the tuberculin antigen (purified protein derivative [PPD]) wanes with age. Nevertheless, elderly patients with unexplained pulmonary infiltrates should undergo skin testing with PPD as well as with control antigens to exclude cutaneous anergy, and multiple sputum specimens for acid-fast bacteria smears and mycobacterial culture should be collected. In patients with significant pleural effusion, a pleural biopsy and culture should be attempted, and in patients with suspected miliary tuberculosis, a transbronchial biopsy and culture may be indicated.
Uncomplicated (drug-susceptible) pulmonary tuberculosis can be treated with 6 months of isoniazid 300 mg/day and rifampin 600 mg/day plus pyrazinamide 30 mg/kg/day for the first 2 months (intensive phase) of treatment, or, alternatively, 9 months of daily isoniazid (300 mg) and rifampin (600 mg) can be given. If the sputum smear and culture remain negative and drug resistance is unlikely, therapy can be shortened from 9 to 4 months. Elderly patients should also receive 25 mg/day of pyridoxine to reduce the risk of peripheral neuropathy associated with isoniazid.35
Due to a substantial increase in the incidence of multidrug-resistant tuberculosis (MDR-TB), the Centers for Disease Control recently published new recommendations for treatment of tuberculosis. In persons with a high likelihood of acquiring multidrug-resistant tuberculosis, the recommendations for treatment include three treatment options with four drug regimens consisting of isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin. However, most elderly patients do not require this type of treatment because of the low risk of drug resistance in this population group.
PRESSURE SORES
Pressure sores develop from the interaction of external factors with the patient’s own internal factors. Major external factors are pressure, shearing forces, friction, and moisture. Major internal factors include the patient’s overall skin condition, mobility, nutritional state, and underlying medical or surgical condition. Most patients with pressure sores are in the geriatric age group, and those over the age of 70 account for two thirds of all patients with bed sores. Although the prevalence of pressure sores is highest in patients residing in long-term care facilities, the incidence is highest in patients in acute care hospitals. More than 60% of patients with pressure sores develop them in hospitals, 18% in nursing homes, and another 18% at home. It is significant that the majority of pressure sores develop during the first 2 weeks of hospitalization.
Since pressure sores are wounds that are chronically contaminated, lowering the bacterial count may facilitate healing. Healing wounds typically show no anaerobic bacteria, whereas nonhealing wounds show the highest counts of both aerobic and anaerobic organisms.36
A local bactericidal effect can be achieved by using conservative measures consisting of cleansing, disinfection, and debridement. The use of topical antibiotics for this purpose remains controversial. Although they may lower bacterial counts, they penetrate poorly through devitalized tissue. Topical antibiotics can cause localized tissue sensitivity and promote the relatively rapid emergence of resistant organisms (especially the Pseudomonas species).
When cellulitis, osteomyelitis, or sepsis is present, treatment with systemic antibiotics directed against a mixed population of aerobic and anaerobic bacteria is mandatory. The most commonly found bacteria are S. aureus, gram-negative rods, and Bacteroides fragilis. A combination of clindamycin or metronidazole (for anaerobic coverage) with a quinolone, an aminoglycoside, a third-generation cephalosporin, or aztreonam (for coverage of gram-negative bacilli) provides an effective treatment. Ticarcillin-clavulanic acid and ampicillin-sulbactam also provide good coverage for the variety of organisms found in pressure sores. A decision about the use of antibiotics for infections associated with pressure sores frequently must be made empirically pending the results of meaningful cultures (blood cultures, tissue biopsy). Swab cultures of the necrotic debris are of little value. If the exact wound microbiology is sought, a biopsy of the viable tissue interface should be performed.
Sepsis associated with pressure sores carries a mortality rate of approximately 50%. It is even higher in patients over the age of 60 and in those who have multiple ulcer sites. Wound debridement may be associated with transient bacteremia but appears to have no serious consequences. Osteomyelitis occurs in 26% of patients with nonhealing pressure sores; the diagnosis should be confirmed by radionuclide scintigraphy of the bone and bone biopsy.37 Septic arthritis may also be seen and is frequently associated with a sinus tract leading from an ulcerous lesion.
The possibility of tetanus infection should be considered in patients with deep necrotic lesions that are becoming progressively larger and are resistant to local and systemic treatment. Because many elderly patients have not received adequate tetanus immunization, administration of tetanus toxoid should be considered.
URINARY TRACT INFECTIONS
Urinary tract infections (UTIs) are the most common type of infection and the most frequent cause of gram-negative bacillary sepsis in the elderly.
The frequency of bacteriuria in ambulatory patients over the age of 65 is 10% to 30% in women and 5% to 10% in men. These figures increase to 15% to 20% in elderly men and 25% to 50% in elderly women residing in long-term care facilities. Bacteriuria in the elderly is typically caused by a variety of gram-negative organisms. E. coli is responsible for the majority of episodes, but organisms such as Proteus, Klebsiella, Pseudomonas species, and, less frequently, Citrobacter and Providentia species are increasing in importance. Bacteriuria, especially when it is associated with chronic indwelling catheter use, is polymicrobial and often includes group D streptococcus (Enterococcus sp).38
Asymptomatic bacteriuria in the elderly is a well-described phenomenon. It is defined by a finding of 105 or more colony-forming units (CFU)/mL bacteria in urine, is not associated with clinical signs and symptoms of infection, and is frequently transient or intermittent. Often pyuria is lacking as well. The available data on the long-term sequelae of asymptomatic bacteriuria are conflicting. However, there is general agreement among clinicians that in the absence of chronic urinary obstruction, asymptomatic bacteriuria in aging adults should not be treated with antibiotics.39,40
An uncomplicated, symptomatic community-acquired UTI can present with fever, dysuria, frequency, and urgency, or, less typically, as weakness and fatigue, anorexia, or change in mental status. Once the diagnosis has been made, the choice of antimicrobial agent will depend on the urine bacteriology, clinical status of the patient, and pharmacokinetic properties of the agent chosen as well as patient tolerance of the drug. The antimicrobials most commonly used today are as follows: trimethoprim-sulfa-methoxazole (TMP/SMZ); first-generation cephalosporins such as cephradine, cefazolin, cefadroxil, and cephalexin; quinolones; and clavulanic acid combinations with amoxicillin or ticarcillin. Ampicillin and amoxicillin provide good coverage for enterococcal infections. Treatment is usually given for 7 to 14 days with the goal of alleviating the symptoms and sterilizing the urine. Single-dose treatment of uncomplicated urinary tract infections in the elderly is not recommended because it carries an unacceptably high relapse rate.
Complicated UTIs are associated with structural or functional abnormalities of the urinary tract. These infections are frequently caused by organisms that are resistant to different antibiotics. Hence, culture and sensitivity data are essential for the appropriate management of a complicated UTI. Empirical therapy requiring parenteral antibiotics for these infections should include third-generation cephalosporins, aztreonam, quinolones, or aminoglycosides. Complicated UTIs may be recurrent because of either relapse or reinfection and may require prolonged treatment of 4 to 6 weeks, usually with an oral agent such as quinolone, TMP-SMZ, or a cephalosporin.41,42 and 43
Patients with chronic indwelling urinary catheters invariably have infected urine and often present with polymicrobial bacteriuria. The rate of acquisition of bacteria after the catheter has been inserted is 7% to 8% per day. After a period of 3 to 4 weeks, virtually 100% of patients become bacteriuric. Characteristically, the microbial flora changes during the period of catheterization, averaging 2.0 species changes per month. However, antimicrobial treatment is reserved only for patients who develop clinical signs of infection. About 20% of these patients develop symptomatic urinary tract infection within 1 year. Routine surveillance of urine cultures in patients with indwelling urinary catheters is not necessary or cost-effective. Urine cultures should be obtained in all patients with indwelling catheters who show clinical signs of infection or changes in mentation or functional status. When a urine sample is to be obtained from a patient with an indwelling catheter, it should be done by using a needle and syringe, aspirating the specimen through the aspiration port after the port has been thoroughly cleaned with an iodophor agent. Treatment of catheter-associated infections in patients who are clinically stable can be accomplished by using oral quinolones, TMP/SMZ, or amoxicillin-clavulanic acid. In unstable patients who have a septic presentation, a combination of parenteral ampicillin with either aztreonam, a third-generation cephalosporin, quinolone, or an aminoglycoside, or imipenem plus cilastatin provides good coverage for most polymicrobial flora.44,45
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Yoshikawa TT, Norman DC: Approach to fever and infection in the nursing home. J Am Geriatr Soc 1996; 44:74–82.

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Castle S: Age-related changes in host defenses. In Yoshikawa TT, Norman DC (eds): Antimicrobial Therapy in the Elderly Patient. New York, Marcel Dekker, 1994, pp. 9–22.

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Couch RB, Kasel A, Glezen WP, et al: Influenza: Its control in persons and populations. J Infect Dis 1986; 153(3):431–440.

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Osterweil D, Norman DC: An outbreak of an influenza-like illness in a nursing home. J Am Geriatr Soc 1990; 38:659–662.

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Norman DC, Toledo SD: Infections in elderly persons. An altered clinical presentation. Clin Geriatr Med 1992; 8:713–719.

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Norman DC, Yoshikawa TT: Fever in the elderly. Infect Dis Clin North Am 1996; 10:93–100.

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CHAPTER 34 CARDIAC DISORDERS (cont’)

ELECTROCARDIOGRAPHIC FINDINGS AND ARRHYTHMIAS
Abnormal resting ECGs are common in the elderly. The most frequently observed abnormalities in this patient population include nonspecific ST-T-wave changes, atrial fibrillation, premature atrial and ventricular contractions, first-degree atrioventricular block, and left axis deviation.72,73 In the absence of structural cardiac disease, these abnormalities, with the exception of atrial fibrillation, have little prognostic value. However, if underlying cardiac disease exists, the corresponding ECG changes are associated with increased morbidity and mortality in the elderly.74 Duration of the P wave and PR interval increases with age owing to an increase in the left atrium size and conduction time through the atrium and the atrioventricular (AV) node, respectively. First-degree AV block has been reported in 3% to 4% of healthy older volunteers, which is a significantly higher prevalence than that noted in young men.75 Left axis deviation is one of the most common variations in the ECG seen in the elderly and may reflect the increase in left ventricular mass that occurs with aging. With advanced age, the mean amplitude of the QRS complex decreases despite an increase in the prevalence of other ECG findings of left ventricular hypertrophy. Electrocardiographic findings of left ventricular hypertrophy in elderly patients lack sensitivity but have excellent specificity. Evidence of left ventricular hypertrophy on ECG is an independent risk factor for cardiovascular morbidity and mortality. The prevalence of right and left bundle branch block increases with age; the prevalence of right bundle branch block is reported to be 3.4% in men aged 40 years and older. Left bundle branch block is found less frequently than right bundle branch block in elderly persons; when found, it usually indicates the presence of a cardiovascular disease.73 Abnormalities involving the ST-T wave have been reported in 16% of subjects aged 70 years and older73 and were associated with clinical heart disease in the majority of these patients.
Bradyarrhythmias
Bradycardia results from either decreased automaticity of the sinus node or a block in the conduction system. The decline in parasympathetic function that occurs with aging is associated with a reduction in sinus arrhythmias and sinus bradycardia, usually seen after the fourth decade of life. Bradycardias, however, are common after age 60 because of the increased prevalence of ischemic heart disease, degenerative changes of the sinus node and conduction tissue, autonomic and baroreceptor abnormalities, and increased sensitivity to various drugs that affect the conduction system.
Sinoatrial Exit Block
Sinoatrial exit block refers to a failure of the sinus impulse to propagate from the sinus node to the surrounding atrial tissues. This abnormality is fairly common in the elderly owing to autonomic imbalance, degeneration of the sinus node tissue, and the effects of medications (digoxin, calcium channel blockers, beta-blockers, and class I antiarrhythmic preparations). Asymptomatic patients need no specific treatment except for discontinuing the involved medication, although a pacemaker is required in symptomatic patients.
Sick Sinus Syndrome
Sick sinus syndrome comprises a constellation of abnormalities of impulse initiation and conduction, including sinus bradycardia, tachy-bradycardia syndromes, atrial fibrillation with slow ventricular response, sinus arrest or sinus exit block, and combinations of these disorders. Not uncommonly, atrioventricular conduction abnormalities are associated with the sinus abnormalities. Sick sinus syndrome occurs most commonly in the elderly and may be caused by ischemic or rheumatic heart diseases, aging with degeneration and fibrosis of the sinus node, cardioactive drugs, hypothyroidism, and increased vagal tone. Treatment of sick sinus syndrome consists of removing the responsible drug, treating the underlying disease, or permanent pacing. In some patients with the tachy-bradycardia syndrome, administration of drugs that control the tachycardia, such as beta-blockers, calcium channel blockers, or digitalis, may be needed after a permanent pacemaker has been placed. The development of atrial fibrillation is common in elderly patients with sick sinus syndrome and increases in patients treated with permanent ventricular pacing. With atrial pacing, atrial fibrillation develops in a much lower percentage, and atrial pacing is considered the treatment of choice in these patients. Newer dual chamber pacemakers with the capability of detecting supraventricular tachycardia and converting it to ventricular pacing mode have facilitated the management of patients with the tachy-bradycardia syndrome.
Atrioventricular Block
Atrioventricular block is a pathologic delay or complete block of atrial impulse conduction to the ventricle. The blocked atrial impulse that occurs during the ventricular compensatory period should be exempted from this definition. The site of the block can be in the atrium, atrioventricular node, or the His-Purkinje system. The causes of atrioventricular block that are almost exclusive to the elderly include degeneration and calcification of the conduction system. Other conditions that are common but not exclusively present in the elderly include drug effects, ischemic heart disease, amyloidosis, myocarditis, and collagen vascular diseases. The ECG sign of first-degree AV block is prolongation of the PR interval. Second-degree AV block (type I Wenckebach block) produces a gradual prolongation of the PR interval in successive beats with a periodic drop in the QRS complex, whereas second-degree AV block (type II Wenckebach) is manifested by an intermittent QRS drop without antecedent PR prolongation. In third-degree AV block, or complete heart block, there is a complete dissociation between the atrium and the ventricle. The site of the block can be in or below the AV node. In the former, the QRS complexes are usually narrow, and the ventricular escape rate is sufficient to maintain adequate cardiac output and blood pressure. If the block site is below the AV node, the QRS complexes are usually wide and are associated with a slow ventricular rate. Symptomatic patients with AV block should be treated with a permanent pacemaker after excluding an offending drug as a cause of the block.
Tachyarrhythmias
Tachyarrhythmias originate in the atrium or the ventricle from enhanced automaticity, reentry, or triggered activity or any combination of these mechanisms. Enhanced automaticity produces a gradual onset and increase in the rate of arrhythmia followed by a gradual decrease when the arrhythmia terminates. In contrast, arrhythmia caused by reentry usually begins and terminates abruptly. Reentry tachycardias are frequently precipitated, and sometimes terminated, by premature atrial or ventricular complexes. Reentry requires the presence of two electrophysiologically different conduction pathways with a unidirectional block in one of them. Examples of reentry include ventricular and supraventricular tachycardia, atrial flutter, typical and atypical AV node reentry, and sinoatrial reentrant tachycardia.
Triggered activity represents abnormal automaticity in the cardiac tissue. It is commonly caused by drug toxicity such as that due to digoxin or quinidine. Examples of triggered activity include atrial fibrillation, ventricular tachycardia, and probably torsades de pointes.
MULTIFOCAL ATRIAL TACHYCARDIA
Multifocal atrial tachycardia is a rhythm characterized by the presence of at least three P-wave morphologies, variable durations of the PR interval, and an irregular ventricular rhythm. It is commonly seen in elderly patients who have chronic obstructive lung disease. The mechanism that underlies this rhythm is most likely triggered activity. Effective therapies include beta-blockers and verapamil; digitalis may exacerbate the condition.
JUNCTIONAL TACHYCARDIA
Junctional tachycardia is a manifestation of triggered activity and is most commonly encountered in elderly persons following cardiac surgery (especially valvular surgery) or with digoxin toxicity. It is characterized by a supraventricular QRS morphology at a rate ranging from 70 to 200 beats/minute; frequently AV dissociation is present. This disturbance usually resolves with improvement of the primary disorder or discontinuation of the offending drug.
ATRIOVENTRICULAR REENTRY TACHYCARDIA
It is estimated that 60% of patients with supraventricular tachycardia referred for electrophysicologic studies have AV node reentry. This arrhythmia is seen primarily in young and middleaged patients, although it may present initially in elderly patients. The onset and termination of the tachycardia is abrupt and is frequently followed by sinus tachycardia. Typical AV node reentry is manifested by a short RP interval with retrograde conduction occurring over the rapid pathway and is the most prevalent form. The rare atypical AV node reentry form produces a long RP interval with retrograde conduction over the slow pathway. Acute treatment with carotid massage should be performed carefully in elderly patients and only after ruling out the presence of carotid disease. Pharmacologic treatment includes the use of adenosine, digoxin, verapamil, and class I antiarrhythmic medications. Electrical cardioversion should be carried out promptly in elderly patients who are hemodynamically unstable. Radiofrequency ablation of the reentry pathways is indicated for chronic or frequent AV node reentry tachycardia that is not controlled by medical therapy; this is an effective and safe treatment in elderly patients.76
ATRIAL FIBRILLATION
Atrial fibrillation is the most common cardiac arrhythmia in the elderly; it has a prevalence in patients older than 65 that approaches 5% and increases with advancing age. In a study of 2101 unselected nursing home patients with a mean age of 81 years, the prevalence of atrial fibrillation was found to be 13%.77 This arrhythmia is an important cause of morbidity and mortality in elderly persons, in whom stroke is a major complication. An estimated 75,000 strokes occur annually in patients with this disease, accounting for one third of embolic events in patients older than 65 years. In the majority of patients with atrial fibrillation there is underlying cardiovascular disease, although valvular heart disease is usually not present. Atrial fibrillation unassociated with underlying heart disease is referred to as “lone atrial fibrillation” and usually occurs in patients under 50 years of age. The disorder is considered benign unless other cardiovascular disorders are present. The mechanism of atrial fibrillation is thought to be either abnormal automaticity in one or more ectopic areas in the atrium or multiple microreentry wavelets presenting simultaneously. Symptoms of atrial fibrillation include palpitations, anxiety, fatigue, dizziness, heart failure, stroke, and syncope.
Treatment of atrial fibrillation should be directed toward achieving the following goals: (1) control of the ventricular rate, (2) restoration and maintenance of the sinus rhythm, and (3) prevention of systemic embolism. Controlling the ventricular response may be achieved by using medications that slow conduction through the AV node including digitalis, beta-blockers, and calcium channel blockers (Table 34-4). Special attention should be given to monitoring the side effects of drugs, and measurement of the digoxin serum level may be beneficial in elderly patients who have a high AV node sensitivity to medications and subnormal renal function. Spontaneous conversion of the atrial fibrillation occurs in 20% of patients, and restoration of sinus rhythm is usually successful in approximately 90% of patients with the use of chemical or electric cardioversion. Prior to an attempted conversion, 3 weeks of anticoagulation therapy is necessary whether the conversion procedure is pharmacologic or electrical. Some authorities do not think that anticoagulation is necessary before an attempt at conversion if the onset of atrial fibrillation occurred 48 hours or less before presentation. The use of transesophageal echocardiography to detect an atrial clot and determine whether anticoagulation is necessary prior to cardioversion remains controversial. The recommendation of the American College of Chest Physicians (ACCP) Consensus Conference on Antithrombolytic Therapies78 is that echocardiographic findings should not determine the use of anticoagulation therapy prior to cardioversion of atrial fibrillation.

TABLE 34-4 EFFECTIVE DRUGS FOR RATE CONTROL IN ATRIAL FIBRILLATION

The benefit of antiarrhythmic therapy to prevent recurrence of atrial fibrillation is controversial, and no conclusive study has demonstrated that the risk of death or stroke is decreased with antiarrhythmic drugs. Some studies have actually demonstrated an increased mortality with the use of these drugs in patients with atrial fibrillation. Therefore, antiarrhythmic therapy should be used cautiously and is justified in elderly patients only when the symptoms are prominent and fail to respond to other types of therapy, and when the proarrhythmic effects of the antiarrhythmic drugs are low. The specific antiarrhythmic drug used depends on an individualized assessment of the risks and benefits of therapy and the severity of the underlying heart disease (Table 34-5).79

TABLE 34-5 CONSIDERATIONS IN EVALUATION OF ANTIARRHYTHMIC DRUGS FOR ATRIAL FIBRILLATION

The risk of stroke in patients with nonvalvular atrial fibrillation is more than fivefold higher than that of patients with sinus rhythm. Increased risk of stroke occurs in patients with atrial fibrillation whether the arrhythmia is chronic or paroxysmal. Associated independent risk factors for stroke include advancing age, history of hypertension, diabetes, or a prior stroke or transient ischemic attack (TIA). Other risk factors for strokes considered important in patients with atrial fibrillation are a history of heart failure and the presence of CAD.
In five multicenter randomized studies of patients with nonvalvular atrial fibrillation and a mean age of over 65 years, warfarin decreased the risk of stroke by a mean of 68% (range 50% to 79%) and the risk of death by a mean of 33% (range 9% to 51%).78,79 In these studies warfarin therapy was not associated with an increase in incidence of cerebral hemorrhage. Two of the multicenter studies assessed the benefits of aspirin, and in one study a significant reduction in strokes was noted, although no benefit was found in patients over 75 years of age. In another multicenter randomized study, the Stroke Prevention in Atrial Fibrillation II Study (SPAF-II),80 the use of aspirin was found to be equivalent to that of warfarin in preventing strokes. Also, an increase in significant intracerebral hemorrhage was noted in patients 75 years or older who were treated with warfarin. On close analysis of this study, however, it is evident that 40% of the thromboembolic events in the warfarin group occurred when the patients were either off warfarin or when the international normalized ratio (INR) was below the therapeutic range. Such findings are thought to explain the higher incidence of events in the warfarin group in this study compared to the results of other trials, which favored warfarin. Furthermore, most cases of intracerebral hemorrhage in this study occurred when the patient’s INR was elevated above the therapeutic level. Another study, the European Atrial Fibrillation Trial,81 which was a secondary preventive study, compared warfarin (Coumadin) with aspirin in preventing the occurrence of recurrent stroke or TIA in patients with nonvalvular atrial fibrillation. This study found aspirin to be of no benefit, whereas a reduction of 30% was noted with warfarin. The most recent study (SPAF-III),82 which assessed the benefit of a fixed low-dose warfarin and aspirin combination in elderly patients who were at high risk for stroke, found that the combination therapy was not beneficial in reducing stroke. Therefore, given the information from the many studies available, most authorities favor anticoagulation over antiplatelet therapy in the treatment of elderly patients with nonvalvular atrial fibrillation. More specific guidelines for the management of anticoagulation in patients with atrial fibrillation have been formulated by the ACCP Consensus Conference on Antithrombotic Therapies (Table 34-6).78

TABLE 34-6 RECOMMENDATIONS FOR ANTICOAGULATION IN PATIENTS WITH ATRIAL FIBRILLATIONa

ATRIAL FLUTTER
Atrial flutter is the second most common supraventricular tachycardia seen in the elderly patients. It is usually associated with organic heart disease and is commonly found in elderly patients with chronic obstructive lung disease and in those who have recently had surgery. Atrial flutter is believed to be a macro-reentry mechanism located in the right atrium. The goals of treatment and the management of patients with atrial flutter are similar to those of atrial fibrillation. In regard to the use of anticoagulation in patients with atrial flutter, the ACCP Consensus Conference on Antithrombotic Therapies78 recommends following the same guidelines as those used when managing patients with atrial fibrillation.
VENTRICULAR TACHYCARDIA
Ventricular ectopy, including premature ventricular contractions and ventricular tachycardias, are common in the elderly and are associated with increased mortality in patients who have underlying heart disease. In elderly patients without heart disease, as in younger patients, ventricular ectopy is usually a benign finding. Patients at the highest risk for increased mortality are those with nonsustained ventricular tachycardia and abnormal left ventricular function (see earlier section, Acute Myocardial Infarction, for treatment of ventricular arrhythmias).
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