2.1 Natural history of disease

Stages of disease

The natural history of disease refers to the progression of a disease in an individual over time. This includes all relevant phenomena from before initiation of the disease (the stage of susceptibility) until its resolution (Figure 2.1). In the period following exposure to the causal factor, the individual enters a stage of subclinical disease (also called the preclinical phase). For infectious agents, this corresponds to the incubation period during which the agent multiplies within the body but has not yet produced discernible signs or symptoms. For noninfectious diseases, this corresponds to the induction period between a causal action and disease initiation.

Figure 2.1 Stages in the natural history of disease and levels of prevention.

The stage of clinical disease begins with a patient’s first symptoms and ends with resolution of the disease. Be aware that the onset of symptoms marks the beginning of this stage, not the time of diagnosis. The time-lag between the onset of symptoms and diagnosis of disease can be considerable. Resolution of the disease may come by means of recovery or death. When recovery is incomplete the individual may be left with a disability.

Incubation periods of infectious diseases vary considerably. Some infectious diseases are characterized by short incubation periods (e.g., cholera has a brief 24- to 48-hour incubation period). Others are characterized by intermediate incubation periods (e.g., chickenpox has a typical incubation period of 2–3 weeks). Still others are characterized by extended incubation periods (e.g., the median incubation period of acquired immunodeficiency syndrome (AIDS) can be measured in decades). Table 2.1 lists incubation periods for selected infectious diseases. Note that even for a given infectious disease, the incubation period may vary considerably. For example, the incubation period for human immunodeficiency virus (HIV) and AIDS ranges from 3 to more than 20 years.

Table 2.1 Incubation periods for selected infectious diseases.

Source: Benensen (1990).

Induction periods for noninfectious diseases also exhibit a range. For example, the induction period for leukemia following exposure to fallout from the atomic bomb blast in Hiroshima ranged from 2 to more than 12 years (Cobb et al., 1959). As another example, Figure 2.2 illustrates the empirical induction periods for bladder tumors in industrial dyestuff workers (Case et al., 1954). Variability in incubation is due to differences in host resistance, pathogenicity of the agent, the exposure dose, and the prevalence and availability of cofactors responsible for disease.

Figure 2.2 Number of years after starting work and onset of urinary bladder tumors in industrial dyestuff workers (Source: Case et al., 1954).

Understanding the natural history of a disease is essential when studying its epidemiology. For example, the epidemiology of HIV/AIDS can only be understood after identifying its multifarious stages (Figure 2.3). Exposure to HIV is followed by an acute response that may be accompanied by unrecognized flu-like symptoms. During this acute viremic phase, prospective cases do not exhibit detectable antibodies in their serum, yet may still transmit the agent. During a lengthy induction, CD4+ lymphocyte counts decline while the patient is still free from symptoms. The risk of developing AIDS is low during these initial years, but increases over time as the immune response is progressively destroyed, after which AIDS then may express itself in different forms (e.g., opportunistic infections, encephalitis, Kaposi’s sarcoma, dementia, wasting syndrome).

Figure 2.3 Natural history and progression of HIV/AIDS (Source: Cotton, 1995).

A slightly more sophisticated view of the natural history of disease divides the subclinical stage of disease into an induction period and a latent period (Figure 2.4). Induction occurs in the interval between a causal action and the point at which the occurrence of the disease becomes inevitable. A latent period follows after the disease becomes inevitable but before clinical signs arise. During this latent phase, various causal factors may promote or retard the progression of disease. The induction and promotion stages combined are referred to as the empirical induction period (Rothman, 1981). This more sophisticated view better suits the consideration of multi-factored disease, where multiple factors must act together to result in a cause.

Figure 2.4 Induction period, latent period, and empirical induction period.

Stages of prevention

Disease prevention efforts are classified according to the stage of disease at which they occur (Figure 2.1). Primary prevention is directed toward the stage of susceptibility. The goal of primary prevention is to prevent the disease from occurring in the first place. Examples of primary prevention include needle-exchange programs to prevent the spread of HIV, vaccination programs, and smoking prevention programs.

Secondary prevention is directed toward the subclinical stage of disease, after which the individual is exposed to the causal factor. The goal of secondary prevention is to prevent the disease from emerging or delay its emergence by extending the induction period. It also aims to reduce the severity of the disease once it emerges. Treating asymptomatic HIV-positive patients with antiretroviral agents to delay the onset of AIDS is a form of secondary prevention.

Tertiary prevention is directed toward the clinical stage of disease. The aim of tertiary prevention is to prevent or minimize the progression of the disease or its sequelae. For example, screening and treating diabetics for diabetic retinopathy to avert progression to blindness is a form of tertiary prevention.

2.2 Variability in the expression of disease

Spectrum of disease

The epidemiologic iceberg

Dog bite injuries provide another example. In 1992 and 1994, there were 20 deaths due to dog bites annually. However, by relying solely on death certificate information, many additional serious dog bite injuries go undetected. For each fatal dog bite there were 670 dog bite hospitalizations, 16 000 emergency department visits for dog bites, 21 000 medical visits to other clinics, and 187 000 non-treated bites (Weiss et al., 1998; Figure 2.5). With recognition of this problem, more effective animal control and surveillance programs can be put into place to prevent future dog bite injuries.

Figure 2.5 Epidemiologic iceberg: annual number of dog bite injuries in the United States, 1992–1994 (Based on Weiss et al., 1998).

2.3 Causal models

Definition of cause

Component cause model (causal pies)

Rothman’s (1976) causal pies helps clarify the contribution of causal components in disease etiology. Figure 2.6 displays two causal mechanisms for a disease. Let us assume these are the only two mechanisms that cause this ailment. Wedges of each pie represent components of each causal mechanism, corresponding to risk factors we hope to identify. Each pie represents a sufficient causal mechanism, defined as a set of factors that in combination makes disease occurrence inevitable. Each casual component (wedge) plays an essential role in a given causal mechanism (pie); a specific disease may result from a number of different causal combination mechanisms.

Figure 2.6 Two sufficient causal mechanisms (“pies”).

A causal factor is said to be necessary when it is a component cause member of every sufficient mechanism. In other words, the component cause is necessary if the disease cannot occur in its absence. In Figure 2.6, Component A is a necessary cause, since it is evident in all possible mechanisms—the disease cannot occur in its absence. For example, the tubercular bacillus Mycobacterium tuberculosis is a necessary cause of tuberculosis. However, it is not sufficient by itself to cause disease: it is common for a person to harbor the Mycobacterium in their body while remaining disease-free. Some individuals are not susceptible to tuberculosis; they are resistant. Therefore, there are complementary factors that enable disease to manifest. Examples of complementary factors for the manifestation of tuberculosis include familial exposure, immunosuppression, genetic susceptibility, poor nutrition, overcrowding, and high environmental loads of the agent.

Causal components that do not occur in every sufficient mechanism yet are still essential in some cases are said to be contributing component causes. For example, cigarette smoking is a contributing but not a necessary cause of lung cancer, since it contributes to the cause of the (vast majority) lung cancer, but is not necessary in every case. (Approximately 5–10% of lung cancer cases occur in nonsmokers.) Likewise, high serum cholesterol, while neither necessary nor sufficient as a cause of coronary heart disease, is an indispensable component of many such causal processes. In Figure 2.6, B, C, and D are nonnecessary contributing causal components.

Component causes that complete a given causal mechanism (pie) are said to be causal complements. In Figure 2.6, for example, the causal complements of factor A in Mechanism 1 is (B + C). In mechanism 2, the causal complement of factor A is D. Factors that work together to form sufficient causal mechanism are said to interact causally.^a

Causal interactions have direct health relevance. For example, when a person develops an infectious disease, the causal agent must interact with the causal complement known as “susceptibility” to cause the disease. When considering hip fractures in elderly patients, the necessary element of trauma interacts with the causal complement of osteoporosis to cause the hip fracture. In similar veins, smoking interacts with genetic susceptibility and other environmental factors in causing lung cancer, and dietary excesses interact with lack of exercise, genetic susceptibility, atherosclerosis and various clotting factors to cause heart attacks. Causal factors rarely act alone.

Causal pies demonstrate that individual risk is an all-or-none phenomenon. In a given individual, either a causal mechanism is or is not completed. This makes it impossible to directly estimate individual risk. In contrast, the notion of average risk is a different matter. Average risk can be estimated directly as the proportion of individuals regarded as a member of a recognizable group that develops a particular condition. For example, if one in ten smokers develop lung cancer over their lifetime, we can say that this population has a lifetime risk for this outcome of one in ten.

The effects of a given cause in a population depend on the prevalence of causal complements in that population. The effect of phenylketanines, for instance, depends not only on the prevalence of an inborn error of metabolism marked by the absence of phenylalanine hydroxylase, but depends also on the environmental prevalence of foods high in phenylalanine. Similarly, the effects of falls in the elderly depend not only on the opportunity for falling, but also on the prevalence of osteoporosis. The population-wide effects of a pathological factor cannot be predicted without knowledge of the prevalence of its causal complements in the population.

Hogben’s (1933) example of yellow shank disease in chickens provides a memorable example of how population effects of a given causal agent cannot be separated from the prevalence of its causal complements. The trait of yellow shank in poultry is a condition expressed only in certain genetic strains of fowl when fed yellow corn. A farmer with a susceptible flock who switches from white corn to yellow corn will perceive the disease to be caused by yellow corn. A farmer who feeds only yellow corn to a flock with multiple strains of chickens, some of which are susceptible to the yellow shank condition, will perceive the condition to be caused by genetics. In fact, the effects of yellow corn cannot be separated from the genetic makeup of the flock, and the effect of the genetic makeup of the flock cannot be separated from the presence of yellow corn in the environment. To ask whether yellow shank disease is environmental or genetic is like asking whether the sound of a faraway drum is caused by the drum or the drummer—one does not act without the other. This is what we mean by causal interaction.

Causal web

The causal web is a metaphor that emphasizes the interconnectedness of direct and indirect cause of disease and ill-health. Direct causes are proximal to the pathogenic mechanism. Indirect causes are distal or “upstream” from the disease causing mechanism. Figure 2.7 depicts the well-established causal web for myocardial infarction (heart attack). The direct cause (pathogenic mechanism) of myocardial infarction is coronary artery blockage and subsequent death of the heart muscle. However, this disease also has indirect factors upstream from this direct cause when one considers the social and environmental factors that lead to hyperlipidemia, obesity, a sedentary lifestyle, arteriosclerosis, coronary stenosis, and ultimately to the coronary artery blockage.

Figure 2.7 Causal-web model for myocardial infarction.

Levels of cause in a causal web may broadly be classified as:

• Macro-level (indirect causes, such as social, economic, cultural, and evolutionary determinants)
  
• Individual-level (intermediate-level cause, such as personal, behavioral, and physiological determinants)
  
• Micro-level (direct cause at the organ, cellular, and molecular level).

Consider, for example, the cause of early childhood mortality in non-industrialized countries. In this example, macro-level causes encompass broad social, economic, and cultural conditions that lead to a paucity of clean water, food, shelter, and sanitation. Individual-level causes include child-care practices that expose children to pathogens, malnutrition, and dehydration. Micro-level causes include the immediate pathophysiologic interaction between malnutrition and the pathogenic respiratory and gastrointestinal agents that ultimately lead to death (Millard, 1994).

The relative contribution of these various levels of cause in epidemiology and public health have been the subject of considerable and sometimes contentious debate, with advocates for each level claiming particular and profound benefits for their way of addressing problems. In practice, however, advocating one or another level may hinder achieving the most practical solution for preventing a given public health problem. Maintaining fragmented methods of research into the various levels of cause can only obstruct our understanding and ultimately delay effective prevention measures (Savitz, 1997).

Agent, host, and environment

Causal components can be classified as agent, host, or environmental factors (Figure 2.8). Agents are biological, physical, and chemical factors whose presence, absence, or relative amount (too much or too little) are necessary for disease to occur (Table 2.2). Host factors include personal characteristics and behaviors, genetic predispositions, and immunologic and other susceptibility-related factors that influence the likelihood or severity of disease. Host factors can be physiological, anatomical, genetic, behavioral, occupational, or constitutional. Environmental factors are external conditions other than the agent that contribute to the disease process. Environmental factors can be physical, biological, social, economic, or political in nature.

Figure 2.8 Agent, host, and environment.

Table 2.2 Types of disease-causing agents.

The sexual transmission of HIV in a population can be viewed in terms of agent, host, and environmental determinants (Figure 2.9). Agent factors that influence HIV transmission include the prevalence of the agent in the environment and the phenotype of the agent. Examples of host factors include the coexistence of reproductive tract infections (especially genital ulcers), availability of antiretroviral therapies that decrease the HIV load in the population, prevalence of risky sexual behaviors, and use of condoms. Environmental factors include the rate of sexual partner exchange, presence of unregulated commercial sex facilities, presence of “crack houses,” sexual norms, and so on (Royce et al., 1997).

Figure 2.9 Agent, host, and environmental factors associated with the sexual transmission of HIV.

Over time, an epidemiologic homeostasis may form as agent, host, and environmental factors reach equilibrium. When an element contributing to the epidemiologic equilibrium is disturbed, the population may experience an increase or decrease in disease occurrence. For example, an epidemic may arise from any of the following:

• introduction of a new agent into the population
  
• increases in the ability of an agent to survive in the environment
  
• increases in an agent’s ability to infect the host (infectivity)
  
• increases in the ability of the agent to cause disease once inside the host (pathogenicity)
  
• increases in the severity of the disease caused by the agent once it has established itself in the host (virulence)
  
• increases in the proportion of susceptibles in the population
  
• environmental changes that favor growth
  
• environmental changes that favor transmission of the agent
  
• environmental changes that compromise host resistance.

Causal forces can strengthen, weaken, or cancel-out each other, tipping the epidemiologic balance in favor of the host or in favor of the disease causing agent (Figure 2.10).

Figure 2.10 Agent, host, and environmental homeostasis and imbalance.

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