Natural History of Disease

Stage of Disease

Screen Shot 2015-12-26 at 8.46.43 PMThe 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. 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.

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 disability.

Incubation periods of infectious diseases vary considerably. Some infectious diseases are characterized by short incubation periods. Others are characterized by intermediate incubation periods. Still others are characterized by extended incubation periods. 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.

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. 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.

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 identify its multifarious stages. 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 increase 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).

Screen Shot 2015-12-26 at 9.29.53 PMA slightly more sophisticated view of the natural history of disease divides the subclinical stage of disease into an induction period and a latent period. 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 the disease. The induction and promotion stages combined are referred to as the empirical induction period. This more sophisticated view better suits the consideration of multi-facored disease, where multiple factors must act together to result in a cause.

Stage of Prevention

Disease prevention efforts are classifed according to the stage of disease at which they occur. Primary prevention is directed toward the stage of susceptibility. The goal of primary prevention is to prevent the disease from occuring in the first place. Examples of primary preventiion 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.


Variability in The Expression of Disease

Spectrum of Disease

Diseases often display a broad range of manifestations and severities. This is referred to as the spectrum of disease. Both infectious and noninfectious diseases exhibit spectrums. When considering infectious diseases, there is a gradient of infection. As an example, HIV infection ranges from inapparent, to mild (e.g., AIDS-related complex), to severe (e.g., wasting syndrome). As an example of a noninfectious disease's spectrum, consider that coronary artery disease exists in as asymptomatic form (atherosclerosis), transient myocardial ischemia, and myocardial infarctions of various severities.

The epidemiologic iceberg

The bulk of a health problem in a population may be hidden from view. This phenomenon, referred to as the "epidemiologic iceberg", applies to infectious, noninfectious, acute, and chronic diseases alike.

Uncovering disease that might otherwise be "below sea level" by screening and better detection often allows for better control of health problems. Consider that for every successful suicide attempt there are dozens of unsuccessful attempts and a still larger number of people with depressive illness that might be severe enough to have them wish to end their lives. With appropriate treatment, individuals with suicidal tendencies would be less likely to have suicidal ideation and be less likely to attempt suicide. As another example: reported cases of AIDS represent only the tip of HIV infections. With proper antiretroviral therapy, clinical illness may be delayed and transmission averted.


Causal Models

Definition of Cause

A cause of a disease event is an event, condition or characteristic that preceded a disease without which the disease event either would not have occurred at all or would not have occurred until some later time. On a population basis, we expect that an increase in the level of a causal factor in inhabitants will be accompanied by an increase in the incidence of disease in that population, caeteris parabus (all other things being equal). We also expect that if the causal factor can be eliminated or diminished, the frequency of disease or its severity will decline.

Component cause model (causal pies)

Most diseases are caused by the cumulative effect of multiple causal components acting ("interacting") together. Thus, a causal interaction occurs when two or more causal factors act together to bring about an effect. Causal interactons apply to both infectious and noninfectious diseases and explains, for example, why two people exposed to the same cold virus will not necessarily experience the same outcome: one person may develop a cold while the other person may experience no ill effects.

Rothman's causal pies helps to clarify the contribution of causal components in disease etiology. Figure 2.6 displays two causal mechanisms for a disease. 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 componet (wedge) plays an essential role in a given causal mechanism (pie); a specific disease may result from a number of different causal combination mechanisms.Screen Shot 2015-12-28 at 6.19.20 PM

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. Causal components that do not occur in every sufficient mechanism yet are still essential in some cases are said to be contributing component causes. 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.

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 excess 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 (10%). 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. Simiarly, 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 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 mulltiple 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.

Agent, Host, and Environment

Causal components can be classified as agent, host, or environmental factors. Agent are biological, physical, and chemical factors whose presence, absence, or relative amount (too much or too little) are necessary for disease to occur. Host factors include personal characteristics and behaviros, genetic predispositions, and immunologic and other susceptibility-related factors that influence the likelihoood 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.