EPIDEMIOLOGY OF VIRAL DISEASES

Introduction

Viral disease epidemiology is the study of the determinants, dynamics and distribution of viral diseases in populations. The risk of infection or disease in a population is determined by characteristics of the virus, the host and the host population, as well as behavioral, environmental and ecological factors that affect virus transmission from one host to another. Epidemiology attempts to meld these factors into a unified whole.

The foundations of epidemiology predate the microbiological and virological sciences, starting with Hippocrates, the Greek physician and father of medicine, who in the fourth century BC made important epidemiologic observations on infectious diseases. John Snow is called the father of modern epidemiology because he developed excellent quantitative methods while studying the source of a cholera outbreak at the Broad Street pump in London in 1849. Snow was followed by William Farr, who in the 1870s advanced the use of vital statistics and clarified many of the principles of risk assessment and retrospective and prospective studies. Their vision is reflected in the fast-changing science of epidemiology which is now supported by advanced computer technology, sophisticated statistical methods and very sensitive and specific diagnostic systems.

Assessment of Disease Occurrence and Outcome

By introducing quantitative measurements of disease trends, epidemiology has come to have a major role in improving our understanding of the overall nature of disease and in alerting and directing disease control activities. Epidemiology is also effective in: (1) clarifying the role of particular viruses and viral variants as the cause of disease; (2) clarifying the interaction of viruses with environmental determinants of disease; (3) determining factors affecting host susceptibility; (4) unraveling modes of transmission; and (5) field testing of vaccines and antiviral drugs.

The comparison of disease experience between populations is expressed in the form of rates. The terms incidence rate and prevalence rate are used to describe quantitatively the frequency of occurrence of infection or disease in populations. Incidence rate is defined as the ratio of new cases occurring in a population to the size of the population during a specified period of time. Prevalence rate is the ratio of the total number of cases occurring in a population to the size of the population during a specified period of time. Seroprevalence rate relates to the occurrence of antibody to a particular virus in a population. Because viral antibodies, especially neutralizing antibodies, often last a lifetime, seroprevalence rates usually represent cumulative experience with the virus. The term case-fatality rate is used to indicate the percentage of subjects with a particular disease that die from the disease. All these rates may be affected by various attributes that distinguish one individual from another: age, sex, genetic constitution, immune status, nutritional status and various behavioral and medical care and patient management parameters. The most widely applicable attribute is age, which may encompass immune status as well as various physiological variables.

An infectious disease is characterized as endemic when there are multiple or continuous chains of transmission resulting in continuous occurrence of disease in a population over a period of time. Epidemics are peaks in disease incidence that exceed the endemic baseline or expected rate of disease. The size of the peak required to constitute an epidemic is arbitrary and is related to the background endemic rate and the anxiety that the disease arouses (e.g. a few cases of rabies is regarded as an epidemic, whereas a few cases of influenza is not). A pandemic is a worldwide epidemic.

Epidemiologic Studies

Case control studies and cohort studies

There are two basic analytic techniques used to investigate relationships between cause and effect and to evaluate risk factors of disease. These are the case-control study and the cohort study. In the case-control study, investigation starts after the disease has occurred – it is a retrospective study, going back in time to determine causative events. Although this kind of study does not require the creation of new data or records, it does require careful selection of the control group, matched to the test group so as to avoid bias. The retrospective case-control study lends itself to quick analysis and is relatively inexpensive to carry out. In the cohort study, the prospective study, investigation entails the gathering of new data to identify cause–effect relationships. This kind of study is expensive and does not lend itself to quick analysis as groups must be followed until disease is observed. However, when cohort studies are successful, proof of cause–effect relationship is often incontrovertible.

Molecular epidemiologic studies

The term molecular epidemiology is used to denote the use of any of a large number of molecular biological methods in support of epidemiologic investigations. For example, with herpesviruses, restriction endonuclease mapping provides a means of identification of unique viral genotypes – in an epidemiologic study recognized as the first based upon viral molecular characterization, the source of herpes simplex virus 1 causing disease in a hospital newborn nursery was traced to one persistently infected nurse rather than any of several other possible shedders. With rotaviruses and bluetongue viruses, polyacrylamide gel electrophoresis of the segmented viral RNA is used epidemiologically, for example to unravel outbreaks involving multiple viral variants. Partial sequencing is rapidly becoming the most commonly used molecular epidemiologic method: partial sequencing of poliovirus isolates recovered from patients indicates whether they are wild-type (even local or introduced wild-type), attenuated vaccine type, or a vaccine type that has reacquired neurovirulence during human passage. Panels of monoclonal antibodies are used similarly to distinguish virus variants for epidemiologic purposes; they have been particularly useful in elucidating host-range and geographic variants of rabies virus.

Seroepidemiologic studies

Seroepidemiology is useful in public health investigations and in research to determine the prevalence or incidence of particular infections, to evaluate control and immunization programs, and to assess past history when a ‘new’ virus is discovered. When paired serum specimens are obtained from individuals several weeks apart, the initial appearance of antibody in the second specimen or a rise in antibody titer indicates recent infection. Likewise, the presence of specific immunoglobulin M (IgM) antibody in single serum samples, indicating recent infection, may be used in seroepidemiologic studies. Correlation of serologic tests with clinical observations makes it possible to determine the ratio of clinical to subclinical infections.

Sentinel studies

Because of advanced diagnostic/serologic methods, sentinel studies can yield many valuable data in timely fashion about impending disease risks. For example, sentinel chicken flocks are set out for the early detection of the presence of arboviruses such as St Louis encephalitis virus in the southern and western United States. These flocks are bled and tested weekly for the presence of virus or antiviral antibody; they provide an early warning of the levels of virus amplification that occur before epidemics.

Vaccine trials

The immunogenicity, potency, safety and efficacy of vaccines are first studied in laboratory animals, followed by small-scale closed trials, and finally in large-scale open trials. Such studies employ epidemiologic methods, rather like those of the cohort (prospective) study. In most cases, there is no alternative way to evaluate new vaccines, and the design of trials has now been developed so that they yield maximum information with minimum risk and cost.

Virus Transmission among Individuals

Viruses survive in nature only if they are able to be transmitted from one host to another, whether of the same or another species. Transmission cycles require virus entry into the body, replication and shedding with subsequent spread to another host.

Virus entry

Portals of virus entry into the body include the skin, respiratory tract, intestinal tract, oropharynx, urogenital tract and conjunctiva. In some cases, viruses use a particular portal of entry because of particular environmental or host behavior factors and in other cases because of specific viral ligands and host cell receptors. In many cases, disruption of normal host defense mechanisms leads to entry that might otherwise be thwarted; for example, papillomaviruses may enter the deep layers of the skin via abrasions, acid-labile coronaviruses may enter the intestine protected by the buffering capacity of milk, and influenza viruses may enter the lower respiratory tract because a drug has dampened cilial action of the respiratory epithelium.

Virus shedding

The exit of virus from an infected host is just as important as entry in maintaining its transmission cycle. All portals used by viruses to gain entry are used for exit. The important elements in virus shedding are virus yield (from the standpoint of the virus, the more shedding the better) and timeliness of yield (again, the earlier the shedding the better). Viruses that cause persistent infections often employ remarkable means to avoid host inflammatory and immune responses so as to continue shedding. For example, the epidemiologically important shedding of herpes simplex viruses 1 and 2 that perpetuates the viruses in populations requires recrudescence of persistent ganglionic infection, centrifugal viral genomic transit to peripheral nerve endings and productive infection of mucosal epithelium, all in the face of established host immunity.

Modes of Virus Transmission

Virus transmission may be horizontal or vertical. The vast majority of transmission is horizontal, that is between individuals within the population at risk. Modes of horizontal transmission of viruses can be characterized as direct contact, indirect contact, common vehicle, airborne, vector-borne, iatrogenic and nosocomial. Vertical or transplacental transmission occurs between the mother and her fetus or newborn. Some viruses are transmitted in nature via several modes, others exclusively via one mode (Table 1 ).

Table 1.

Examples of virus transmission patterns

Infectious agent/disease	Mode of transmission	Portal of entry
Influenza virus/influenza	Contact/direct/indirect via droplets and aerosol	Respiratory tract
Rhinoviruses/common cold	Contact/direct/indirect via droplets, aerosols and fomites	Respiratory tract
Rubella virus/congenital rubella	Contact/direct/indirect via droplets, aerosol	Respiratory tract
	Vertical/congenital	Transplacental
Rotaviruses/diarrhea	Contact/direct/indirect via fomites	Intestinal tract (oral)
Poliovirus/poliomyelitis	Contact/direct	Intestinal tract (oral)
Norwalk virus/diarrhea	Common vehicle/fecal contamination of water	Intestinal tract (oral)
Hepatitis A virus/hepatitis	Common vehicle/fecal contamination of food	Intestinal tract (oral)
New-variant Creutzfeldt–Jakob disease prion/prion disease (spongiform encephalopathy)	Common vehicle/bovine spongiform encephalopathy prion contamination of beef or beef products	Intestinal tract (oral)
Herpes simplex virus/genital herpes	Contact/direct (sexual)	Genital tract
Human immunodeficiency virus 1/acquired immunodeficiency syndrome (AIDS)	Contact/direct (sexual), contact/direct (blood), vertical/congenital	Genital tract, bloodstream, transplacental, at birth and via breast feeding
Rabies virus/rabies	Zoonotic/contact/direct (saliva)	Skin (bite wound)
Russian spring summer encephalitis virus/encephalitis	Zoonotic/arthropod-borne	Skin (tick bite)
Dengue viruses/dengue	Zoonotic/arthropod-borne	Skin (mosquito bite)
Sin Nombre and related viruses	Zoonotic/contact/direct (rodent urine, saliva and feces)	Respiratory tract
Lassa virus	Zoonotic/contact/direct (rodent urine, saliva and feces)	Respiratory tract and intestinal tract (oral)
Ebola and Marburg viruses	Zoonotic/index cases unknown; secondary cases contact/direct/nosocomial and iatrogenic	Index cases unknown, likely respiratory tract or skin and mucous membranes; secondary cases, contact and iatrogenic (injection)
Leukemia viruses/leukemias (proven only in animals)	Vertical/germ-line	Transmitted as genetic trait

Direct contact transmission involves actual physical contact between an infected subject and a susceptible subject [e.g. kissing (Epstein–Barr virus, the cause of mononucleosis), biting (rabies), coitus (sexually transmitted viral diseases)]. Indirect contact transmission occurs via fomites, such as shared eating utensils, improperly sterilized surgical equipment or improperly sterilized nondisposable syringes and needles. Common vehicle transmission pertains to fecal contamination of food and water supplies (e.g. Norwalk virus diarrhea). Common vehicle transmission commonly results in epidemic disease. Airborne transmission typically results in respiratory infections (and less typically in intestinal infections), but these infections may also be transmitted by direct and indirect contact. Airborne transmission occurs via droplet nuclei (aerosols) emitted from infected persons during coughing or sneezing (e.g. influenza) or from environmental sources. Large droplets settle quickly, but microdroplets evaporate forming dry droplet nuclei (less than 5 nm in diameter) which remain suspended in the air for extended periods. Droplets may travel only a meter or so whereas droplet nuclei may travel much longer distances. Vector-borne transmission involves the bites of arthropod vectors (e.g. mosquitoes, ticks, sandflies). Iatrogenic transmission involves health care procedures, materials and workers (e.g. physicians, nurses, dentists). Nosocomial transmission pertains to infections acquired while a patient is in hospital.

Vertical or transplacental transmission occurs from mother to fetus prior to or during parturition. Certain retroviruses are vertically transmitted in animals via the integration of viral DNA directly into the DNA of the germ-line of the fertilized egg. Other viruses are transmitted to the fetus across the placenta, yet others are transmitted when the fetus passes through the birth canal. Another vertical transmission route is via colostrum and milk. Vertical transmission of a virus may or may not be associated with congenital disease (i.e. disease that is present at birth) which may be lethal (and the cause of abortion or stillbirth) or the cause of congenital abnormalities. The herpesviruses, especially cytomegaloviruses, and rubella virus cause important congenital diseases.

Common patterns of virus transmission

Enteric infections are most often transmitted by direct contact and by fomites in a fecal–oral cycle that may include fecal contamination of food and water supplies; diarrheic feces may also splash to give rise to aerosols. Respiratory infections are most often transmitted by the airborne route or by indirect contact via fomites in a respiratory cycle, i.e. virus is shed in respiratory secretions and enters its next host through the nares during inhalation. The respiratory cycle is responsible for the most explosive patterns of epidemic disease.

Perpetuation of Viruses in Nature

Perpetuation of a virus in nature depends on the maintenance of serial infections, i.e. a chain of transmission; the occurrence of disease is neither required nor necessarily advantageous.

Influence of the clinical status of the host

Infection without recognizable disease is called subclinical or clinically inapparent. Overall, subclinical infections are much more common than those that result in disease. Their relative frequency accounts for the difficulty of tracing chains of transmission, even with the help of laboratory diagnostics. Although clinical cases may be somewhat more productive sources of virus than subclinical infections, because the latter do not restrict the movement of the infected host, they can be most important as sources of viral dissemination. In most acute infections, whether clinically apparent or not, virus is shed in highest titers during the late stages of the incubation period, before the influence of the host immune response takes effect. Persistent infections, whether or not they are associated with episodes of clinical disease, also play an important role in the perpetuation of many viruses in nature. For example, prolonged virus shedding can reintroduce virus into a population of susceptibles all of which have been born since the last clinically apparent episode of infection. This is important in the survival of rubella virus in some isolated populations. Sometimes the persistence of infection, the production of disease and the transmission of virus are dissociated; for example, togavirus and arenavirus infections have little adverse effect on their reservoir hosts (arthropods, birds and rodents) but transmission is very efficient. On the other hand, the persistence of infection in the central nervous system, as with measles virus in subacute sclerosing panencephalitis (SSPE), is of no epidemiological significance, since no infectious virus is shed from this site.

Influence of virulence of the virus

The virulence of the infecting virus may directly affect the probability of its transmission. The classic example of this is rabbit myxomatosis. In Australia, mosquito-borne transmission of myxoma virus was found to be most effective when infected rabbits maintained highly infectious skin lesions for several days before death. Highly virulent strains of the virus were found to kill rabbits so quickly that transmission did not occur, and naturally attenuated strains were found to produce minimal lesions that healed quickly and did not permit transmission. Virus strains at either extreme of this virulence spectrum were found not to survive in nature, but virus strains of intermediate virulence have circulated for many years.

Influence of host population immunity

With most viruses, endemic or epidemic transmission leads to a level of immunity in the host population that affects or even interrupts further transmission. The ‘herd immunity’ effect is countered in some cases by viral antigenic variation. For example, influenza viruses undergo genetic variations (‘shift’ and ‘drift’) such that persons immune to previously circulating virus strains are susceptible to new strains. Assessing these genetic changes is the main objective of laboratory-based surveillance programs, which in turn are used to decide the formulation of new influenza vaccines.

Influence of population size

It is self-evident that the long-term survival of a virus requires that it be continuously transmitted from one host to another. In general, for rapidly and efficiently transmitted viruses such as many respiratory viruses, local survival of the virus requires that the susceptible host population be very large. A virus may disappear from a population because it exhausts its potential supply of susceptible hosts as they acquire immunity to reinfection with the same virus. Depending on duration of immunity and the pattern of virus shedding, the critical population size varies considerably with different viruses and with different host species. The most precise data on the importance of population size in acute nonpersistent infections come from studies of measles. Persistence of measles virus in a population depends on a continuous supply of susceptible children. Analyses of the incidence of measles in large cities and in island communities have shown that a population of about half a million persons is needed to ensure a large enough annual input of new susceptible hosts, by birth or immigration, to maintain measles virus in the population. Because infection depends on respiratory transmission, the duration of epidemics of measles is correlated inversely with population density. If a population is dispersed over a large area, the rate of spread is reduced and the epidemic will last longer, so that the number of susceptible persons needed to maintain transmission chains is reduced. On the other hand, in such a situation a break in the transmission chain is much more likely. When a large proportion of the population is initially susceptible, the intensity of the epidemic builds up very quickly and attack rates are almost 100% (virgin-soil epidemic).

Influence of zoonotic transmission cycles

Because most viruses are host-restricted, most viral infections are maintained in nature within populations of the same or related species. However, there are a number of viruses that may have multiple hosts and spread naturally between several different species of vertebrate host, e.g. rabies and eastern equine encephalitis viruses. The term zoonosis is used to describe multiple-host infections that are transmissible from animals to man. The zoonoses, whether involving domestic or wild animals or arthropods, usually represent important problems only under conditions where humans are engaged in activities involving close contact with animals or exposure to arthropod habitats.

Influence of arthropod transmission cycles

Many viral zoonoses are caused by arboviruses. Arboviruses have two classes of host, vertebrate and invertebrate. Over 500 arboviruses are known, of which about 100 cause disease in humans and 40 in domestic animals; some of these are transmitted by ticks, some by mosquitoes and yet others by phlebotomine flies (sandflies) or Culicoides spp. (midges). Arthropod transmission may be mechanical, where the arthropod acts as a ‘flying pin’, or more commonly, biological, involving replication of the virus in the arthropod vector. The arthropod vector acquires virus by feeding on the blood of a viremic person or animal. Replication of the ingested virus, initially in the arthropod's gut, and its spread to the salivary glands takes several days; the interval varies with different viruses and is influenced by ambient temperature. Virions in the salivary secretions of the vector are injected into animal hosts during subsequent blood meals. Most arboviruses have localized natural habitats in which specific receptive arthropod and vertebrate hosts are involved in the viral life cycle. Vertebrate reservoir hosts are usually wild mammals or birds; humans are rarely involved in primary transmission cycles, although the exceptions to this generalization are important (e.g. Venezuelan equine encephalitis, yellow fever and dengue viruses). Humans are in most cases infected incidentally, for example by the geographic extension of a reservoir vertebrate host and/or a vector arthropod. Ecological changes produced by human activities disturb natural arbovirus life cycles and have been incriminated in the geographic spread or increased prevalence of arbovirus diseases.

Mathematical Modeling

From the time of William Farr, who studied epidemic disease problems in the 1870s, mathematicians have been interested in ‘epidemic curves’ and secular trends in the incidence of infectious diseases. With the development of computer-based mathematical modeling techniques, there has been a resurgence of interest in the population dynamics of infectious diseases. There has also been a resurgence in controversies surrounding the use of models: critics say ‘for every model there is an equal and opposite model’. Models are used to determine: (1) patterns of disease transmission; (2) critical population sizes to support the continuous transmission of viruses with short and long incubation periods; (3) the dynamics of endemicity of viruses that become persistent in their hosts; and (4) the variables in age-dependent viral pathogenicity. Computer modeling also provides useful insights into the effectiveness of disease control programs. Much attention has been given to modeling the future of the acquired immunodeficiency disease (AIDS) epidemic in the United States and the rest of the world. Such models usually start with historical data on the introduction of the etiologic virus, HIV1, proceed to the present stage of the epidemic where the disease has become well established in many countries and in fewer subject to prevention and treatment strategies, and then proceed to project its course into the future. During the first 10 years of the AIDS epidemic in the United States, African countries and then in Asian countries most models underestimated developing trends; more recently models have become more accurately predictive.

Implications for Disease Prevention

Knowledge of the epidemiology and modes of transmission of infectious diseases is critical to the development and implementation of prevention and control strategies. Data on incidence, prevalence and mortality contribute directly to the establishment of priorities for prevention and control programs whereas knowledge of viral characteristics and modes of transmission are used in deciding prevention strategies focusing on vaccine development and delivery, environmental improvements, enhancement of nutritional status, improvement in personal hygiene and behavioral changes.

See also:

EMERGING AND RE-EMERGING VIRUS DISEASES; HUMAN IMMUNODIFICIENCY VIRUSES (RETROVIRIDAE) | Molecular Biology; HUMAN IMMUNODIFICIENCY VIRUSES (RETROVIRIDAE) | Anti-retroviral Agents; HUMAN IMMUNODIFICIENCY VIRUSES (RETROVIRIDAE) | General Features; INFLUENZA VIRUSES (ORTHOMYXOVIRIDAE) | General Features; INFLUENZA VIRUSES (ORTHOMYXOVIRIDAE) | Molecular Biology; INFLUENZA VIRUSES (ORTHOMYXOVIRIDAE) | Structure of Antigens; PATHOGENESIS | Animal Viruses; PATHOGENESIS | Plant Viruses; VACCINES AND IMMUNE RESPONSE; ZOONOSES.