Chapter 5: Emergence and Global Spread of Infection

Epidemiology, the study of the distribution of determinants of disease and injury in human populations, is a discipline that includes both infectious and noninfectious diseases. Most epidemiologic studies of infectious diseases have concentrated on the factors that influence acquisition and spread, because this knowledge is essential for developing methods of prevention and control. Historically, epidemiologic studies and the application of the knowledge gained from them have been central to the control of the great epidemic diseases, such as cholera, plague, smallpox, yellow fever, and typhus.

An understanding of the principles of epidemiology and the spread of disease is essential to all medical personnel, whether their work is with the individual patient or with the community. Most infections must be evaluated in their epidemiologic setting. For example, what infections, especially viral, are currently prevalent in the community? Has the patient recently traveled to an area of special disease prevalence? Is there a possibility of nosocomial infection from recent hospitalization? What is the risk to the patient's family, schoolmates, and work or social contacts?

The recent recognition of emerging infectious diseases has heightened appreciation of the importance of epidemiologic information. A few examples of these newly identified infections are cryptosporidiosis, hantavirus pulmonary syndrome, and severe acute respiratory syndrome (SARS) coronavirus disease. In addition, some well-known pathogens have assumed new epidemiologic importance by virtue of acquired antimicrobial resistance (eg, penicillin-resistant pneumococci, vancomycin-resistant enterococci, carbapenem-resistant enterobacteraciae, and multiresistant Mycobacterium tuberculosis).

Over the past two decades, powerful new molecular methods have been developed that have greatly enhanced the ability to even more clearly understand the origins, evolution and spread of a wide variety of infectious agents. This discipline is called molecular epidemiology. The fundamental methodologies are described in Chapter 4, and their specific applications are discussed in many other chapters throughout this book.

Factors that increase the emergence or reemergence of various pathogens include:

• Population movements and the intrusion of humans and domestic animals into new habitats, particularly tropical forests

• Deforestation, with the development of new farmlands and exposure of farmers and domestic animals to new arthropods and primary pathogens

• Irrigation, especially primitive irrigation systems, which fail to control arthropods and enteric organisms

• Uncontrolled urbanization, with vector populations breeding in stagnant water

• Increased long-distance air travel, with contact or transport of arthropod vectors and primary pathogens

• Social unrest, civil wars, and major natural disasters, leading to famine and disruption of sanitation systems, immunization programs, etc.

• Global climate change

• Microbial evolution, leading to natural selection of multiresistant agents (eg, methicillin-resistant staphylococci; new, highly virulent strains of influenza A virus). In some instances, these changes can be accelerated considerably by indiscriminate use of antiinfective agents.

There are other factors, of course, and all of these are discussed here as to their relative impacts on the specific infectious agents described in subsequent chapters.

The major general concerns for the future are that new, often unexpected, infectious diseases emerge (or in many cases simply reemerge) for any of the reasons detailed earlier. Although mortality rates declined dramatically during much of the 20th century (Figure 5–1), an alarming upward trend has been occurring over the last 24 years. The general global nature of the problem is illustrated in Figure 5–2.

Infectious diseases of humans may be caused by exclusively human pathogens such as Shigella; by environmental organisms such as Legionella pneumophila; or by organisms that have their primary reservoir in animals such as Salmonella.

Noncommunicable infections are those that are not transmitted from human to human and include: (1) infections derived from the patient's normal flora, such as peritonitis after rupture of the appendix; (2) infections caused by the ingestion of preformed toxins, such as botulism; and (3) infections caused by certain organisms found in the environment, such as clostridial gas gangrene. Some diseases transmitted from animals to humans (zoonotic infections), such as rabies and brucellosis, are not transmitted between humans, but others such as plague may be transmitted at certain stages. Noncommunicable infections may still occur as common-source outbreaks, such as food poisoning from an enterotoxin-producing Staphylococcus aureus–contaminated chicken salad or multiple cases of pneumonia from extensive dissemination of Legionella through an air-conditioning system. Because these diseases are not transmissible to others, they do not lead to secondary spread.

Communicable infections require an organism to be able to leave the body in a form that is directly infectious or to be able to become so after development in a suitable environment. The respiratory spread of the influenza virus is an example of direct communicability. In contrast, the malarial parasite requires a developmental cycle in a biting mosquito before it can infect another human. Communicable infections can be endemic, which implies that the disease is present at a low but fairly constant level, or epidemic, which involves a level of infection higher than that usually found in a community or population. In some infections, such as influenza, the infection can be endemic, persisting at a fairly low level from season to season. Introduction of a new strain, however, may result in epidemics, as illustrated in Figure 5–3. Communicable infections that are widespread in a region, sometimes worldwide, and have high attack rates are termed pandemic.

An important consideration in the study of the epidemiology of communicable organisms is the distinction between infection and disease. Infection involves multiplication of the organism in or on the host and may not be apparent, for example, during the incubation period, or latent when little or no replication is occurring (eg, with herpesviruses). Disease represents a clinically apparent response by, or injury to, the host as a result of infection. With many communicable microorganisms, infection is much more common than disease, and apparently healthy infected individuals play an important role in disease propagation. Inapparent infections are termed subclinical, and the individual is sometimes referred to as a carrier. The latter term is also applied to situations in which an infectious agent establishes itself as part of a patient's flora or causes low-grade chronic disease after an acute infection. For example, the clinically inapparent presence of S aureus in the anterior nares is termed carriage, as is a chronic gallbladder infection with Salmonella serotype Typhi that can follow an attack of typhoid fever and result in fecal excretion of the organism for years.

With some infectious diseases such as measles, infection is invariably accompanied by clinical manifestations of the disease itself. These manifestations facilitate epidemiologic control, because the existence and extent of infection in a community are readily apparent. Organisms associated with long incubation periods or high frequencies of subclinical infection, such as human immunodeficiency virus (HIV) or hepatitis B virus, may propagate and spread in a population for long periods before the extent of the problem is recognized. This makes epidemiologic control more difficult.

The incubation period is the time between the exposure to the organism and the appearance of the first symptoms of the disease. Generally, organisms that multiply rapidly and produce local infections, such as gonorrhea and influenza, are associated with short incubation periods (eg, 2-4 days). Diseases such as typhoid fever, which depend on hematogenous spread and multiplication of the organism in distant target organs to produce symptoms, often have longer incubation periods (eg, 10 days to 3 weeks). Some diseases have even more prolonged incubation periods because of slow passage of the infecting organism to the target organ, as in rabies, or with slow growth of the organism, as in tuberculosis. Incubation periods for one agent may also vary widely depending on route of acquisition and infecting dose; for example, the incubation period of hepatitis B virus infection may vary from a few weeks to several months.

Communicability of a disease in which the organism is shed in secretions may occur primarily during the incubation period. In other infections, the disease course is short but the organisms can be excreted from the host for extended periods. In yet other cases, the symptoms are related to host immune response rather than the organism's action and, thus, the disease process may extend far beyond the period in which the etiologic agent can be isolated or spread. Some viruses can integrate into the host genome or survive by replicating very slowly in the presence of an immune response. Such dormancy or latency is exemplified by the herpesviruses, and the organism may emerge long after the original infection and potentially infect others.

The inherent infectivity and virulence of a microorganism are also important determinants of attack rates of disease in a community. In general, organisms of high infectivity spread more easily, and those of greater virulence are more likely to cause disease than subclinical infection. The infecting dose of an organism also varies with different organisms and, thus, influences the chance of infection and development of disease.

Various transmissible infections may be acquired from others by direct contact, by aerosol transmission of infectious secretions, or indirectly through contaminated inanimate objects or materials. Some infections, such as malaria, involve an animate insect vector. These routes of spread are often referred to as horizontal transmission, in contrast to vertical transmission—from mother to fetus. The major horizontal routes of transmission of infectious diseases are summarized in Table 5–1 and discussed in the following text.

Respiratory Spread

Many infections are transmitted by the respiratory route, often by aerosolization of respiratory secretions with subsequent inhalation by other persons. The efficiency of this process depends, in part, on the extent and method of propulsion of discharges from the mouth and nose, the size of the aerosol droplets, and the resistance of the infectious agent to desiccation and inactivation by ultraviolet light. In still air, a particle 100 μm in diameter requires only seconds to fall the height of a room; a 10 m particle remains airborne for about 20 minutes, smaller particles even longer. When inhaled, particles with a diameter of 6 μm or more are usually trapped by the mucosa of the nasal turbinates, whereas particles of 0.6 to 5.0 μm attach to mucous sites at various levels along the upper and lower respiratory tract and may initiate infection. These “droplet nuclei” are most important in transmitting many respiratory pathogens (eg, M tuberculosis).

Respiratory secretions are often transferred on hands or inanimate objects (fomites) and may reach the respiratory tract of others in this way. For example, spread of the common cold may involve transfer of infectious secretions from nose to hand by the infected individual, with transfer to others by hand-to-hand contact and then from hand to nose by the unsuspecting victim.

Salivary Spread

Some infections, such as herpes simplex and infectious mononucleosis, can be transferred directly by contact with infectious saliva through kissing. Transmission of infectious secretions by direct contact with the nasal mucosa or conjunctiva often accounts for the rapid dissemination of agents, such as respiratory syncytial virus and adenovirus. The risk of spread in these instances can be reduced by simple hygienic measures such as handwashing.

Fecal–Oral Spread

Fecal–oral spread involves direct or finger-to-mouth spread, the use of human feces as a fertilizer, or fecal contamination of food or water. Food handlers who are infected with an organism transmissible by this route constitute a special hazard, especially when their personal hygienic practices are inadequate. Some viruses disseminated by the fecal–oral route infect and multiply in cells of the oropharynx and then disseminate to other body sites to cause infection. However, organisms that are spread in this way commonly multiply in the intestinal tract and may cause intestinal infections. They must, therefore, be able to resist the acid in the stomach, the bile, and the gastric and small intestinal enzymes. Many bacteria and enveloped viruses are rapidly killed by these conditions, but members of the Enterobacteriaceae and unenveloped viral intestinal pathogens (eg, enteroviruses) are more likely to survive. Even with these organisms, the infecting dose in patients with reduced or absent gastric hydrochloric acid is often much smaller than in those with normal stomach acidity.

Skin-to-Skin Transfer

Skin-to-skin transfer occurs with a variety of infections in which the skin is the portal of entry, such as the spirochete of syphilis (Treponema pallidum), strains of group A streptococci that cause impetigo, and the dermatophyte fungi that cause ringworm and athlete's foot. In most cases, an unapparent break in the epithelium is probably involved in infection. Other diseases may be spread through fomites such as shared towels and inadequately cleansed shower and bath floors. Skin-to-skin transfer usually occurs through abrasions of the epidermis, which may be unnoticed.

Bloodborne Transmission

Bloodborne transmission of infection through insect vectors requires a period of multiplication or alteration within an insect vector before the organism can infect another human host. Such is the case with the mosquito and the malarial parasite. Direct transmission from human to human through blood has become increasingly important in modern medicine because of the use of blood transfusions and blood products and the increased self-administration of illicit drugs by intravenous or subcutaneous routes using shared nonsterile equipment. Hepatitis B and C viruses, as well as HIV, were frequently transmitted in this way before the institution of blood screening tests.

Genital Transmission

Disease transmission through the genital tract has emerged as one of the most common infectious problems, and reflects changing social and sexual mores. Spread can occur between sexual partners or from the mother to the infant at birth. A major factor in these infections has been the persistence, high rates of asymptomatic carriage, and frequency of recurrence of organisms such as Chlamydia trachomatis, cytomegalovirus (CMV), herpes simplex virus, and Neisseria gonorrhoeae.

Eye-to-Eye Transmission

Infections of the conjunctiva may occur in epidemic or endemic form. Epidemics of adenovirus and Haemophilus conjunctivitis may occur, and are highly contagious. The major endemic disease is trachoma, caused by Chlamydia, which remains a common cause of blindness in developing countries. These diseases may be spread by direct contact via ophthalmologic equipment or by secretions passed manually or through fomites such as towels.

Zoonotic Transmission

Zoonotic infections are spread from animals, where they have their natural reservoir, to humans. Some zoonotic infections such as rabies are directly contracted from the bite of the infected animal, whereas others are transmitted by vectors, especially arthropods (eg, ticks, mosquitoes). Many infections contracted by humans from animals are dead-ended in humans, whereas others may be transferred between humans once the disease is established in a population. Plague, for example, has a natural reservoir in rodents. Human infections contracted from the bites of rodent fleas may produce pneumonia, which may then spread to other humans by the respiratory droplet route.

Vertical Transmission

Certain diseases can spread from mother to fetus through the placental barrier. This mode of transmission involves organisms such as rubella virus that can be present in the mother's bloodstream and may occur at different stages of pregnancy with different organisms. Another form of transmission from mother to infant occurs by contact during birth with organisms such as group B streptococci, C trachomatis, and N gonorrhoeae, which colonize the vagina. Herpes simplex virus and CMV can spread by both vertical methods, as it may be present in blood or may colonize the cervix. In addition, CMV may be transmitted by breast milk, a third mechanism of vertical transmission.

The characterization of epidemics and their recognition in a community involve several quantitative measures and some specific epidemiologic definitions. Infectivity, in epidemiologic terms, equates to attack rate and is measured as the frequency with which an infection is transmitted when there is contact between the agent and a susceptible individual. The disease index of an infection can be expressed as the number of persons who develop the disease divided by the total number infected. The virulence of an agent can be estimated as the number of fatal or severe cases per total number of cases. Incidence, the number of new cases of a disease within a specified period, is described as a rate in which the number of cases is the numerator and the number of people in the population under surveillance is the denominator. This is usually normalized to reflect a percentage of the population that is affected. Prevalence, which can also be described as a rate, is primarily used to indicate the total number of cases existing in a population at risk at a point in time.

The prerequisites for propagation of an epidemic from person to person are: (1) a sufficient degree of infectivity to allow the organism to spread; (2) sufficient virulence for an increased incidence of disease to become apparent; and (3) sufficient level of susceptibility in the host population to permit transmission and amplification of the infecting organism. Thus, the extent of an epidemic and its degree of severity are determined by complex interactions between parasite and host. Host factors such as age, genetic predisposition, and immune status can dramatically influence the manifestations of an infectious disease. Together with differences in infecting dose, these factors are largely responsible for the wide spectrum of disease manifestations that may be seen during an epidemic.

The effect of age can be dramatic. For example, in an epidemic of measles in an isolated population in 1846, the attack rate for all ages averaged 75%; however, mortality rate was 90 times higher in children less than 1 year of age (28%) than in those 1 to 40 years of age (0.3%). Conversely, in one outbreak of poliomyelitis, the attack rate of paralytic polio was 4% in children 0 to 4 years of age, and 20% to 40% in those 5 to 50 years of age. Gender may be a factor in disease manifestations; for example, the likelihood of becoming a chronic carrier of hepatitis B is twice as high for males as for females.

Prior exposure of a population to an organism may alter immune status and the frequency of acquisition, severity of clinical disease, and duration of an epidemic. For example, measles is highly infectious and attacks most susceptible members of an exposed population. However, infection gives solid lifelong immunity. Thus, in unimmunized populations in which the disease is maintained in endemic form, epidemics occur at approximately 3-year intervals when a sufficient number of nonimmune hosts has been born to permit rapid transmission between them. When a sufficient immune population is reestablished, epidemic spread is blocked and the disease again becomes endemic. When immunity is short-lived or incomplete, epidemics can continue for decades if the mode of transmission is unchecked, which accounts for the present epidemic of gonorrhea.

Prolonged and extensive exposure to a pathogen during previous generations selects for a higher degree of innate genetic immunity in a population. For example, extensive exposure of Western urbanized populations to tuberculosis during the 18th and 19th centuries conferred a degree of resistance greater than that among the progeny of rural or geographically isolated populations. The disease spread rapidly and in severe form, for example, when it was first encountered by Native Americans. An even more dramatic example concerns the resistance to the most serious form of malaria that is conferred on people of West African descent by the sickle cell trait. These instances are clear cases of natural selection—a process that accounts for many differences in racial immunity.

Occasionally, an epidemic arises from an organism against which immunity is essentially absent in a population and that is either of enhanced virulence or appears to be of enhanced virulence because of the lack of immunity. When such an organism is highly infectious, the disease it causes may become pandemic and worldwide. A prime example of this situation is the appearance of a new major antigenic variant of influenza A virus against which there is little, if any, cross-immunity from recent epidemics with other strains. The 1918 to 1919 pandemic of influenza was responsible for more deaths than World War I (>20 million). Subsequent but less serious pandemics have occurred at intervals because of the development of strains of influenza virus with major antigenic shifts (see Chapter 9). Another example, acquired immunodeficiency syndrome (AIDS), illustrates the same principles but also reflects changes in human ecologic and social behavior.

A major feature of serious epidemic diseases is their frequent association with poverty, malnutrition, disaster, and war. The association is multifactorial and includes overcrowding, contaminated food and water, an increase in arthropods that parasitize humans, and the reduced immunity that can accompany severe malnutrition or certain types of chronic stress. Overcrowding and understaffing in day-care centers or institutions for the mentally impaired can similarly be associated with epidemics of infections.

In recent years, increasing attention has been given to hospital (nosocomial) epidemics of infection. Hospitals are not immune to the epidemic diseases that occur in the community; and outbreaks result from the association of infected patients or persons with those who are unusually susceptible because of chronic disease, immunosuppressive therapy, or the use of bladder, intratracheal, or intravascular catheters and tubes. Control depends on the techniques of medical personnel, hospital hygiene, and effective surveillance.

Control of Epidemics

The first principle of control is recognition of the existence of an epidemic. This recognition is sometimes immediate because of the high incidence of disease but, often, the evidence is obtained from ongoing surveillance activities, such as routine disease reports to health departments and records of school and work absenteeism. The causative agent must be identified, and studies to determine route of transmission (eg, food poisoning) must be initiated.

Measures must then be adopted to control the spread and development of further infection. These methods include: (1) blocking the route of transmission, if possible (eg, improved food hygiene or arthropod control); (2) identifying, treating, and, if necessary, isolating infected individuals and carriers; (3) raising the level of immunity in the uninfected population by immunization; (4) making selective use of chemoprophylaxis for subjects or populations at particular risk of infection, as in epidemics of meningococcal infection; and (5) correcting conditions such as overcrowding or contaminated water supplies that have led to the epidemic or facilitated transfer.

Immunization is the most effective method of providing individual and community protection against many epidemic diseases. Immunization can be active, with stimulation of the body's immune mechanisms through administration of a vaccine, or passive, through administration of plasma or globulin containing preformed antibody to the agent desired. Active immunization with living attenuated organisms generally results in a subclinical or mild illness that duplicates, to a limited extent, the disease to be prevented. Live vaccines generally provide both local and durable humoral immunity. Killed or subunit vaccines, such as influenza vaccine and tetanus toxoid, provide immunogenicity without infectivity. They generally involve a larger amount of antigen than live vaccines, and must be administered parenterally with two or more spaced injections and subsequent boosters to elicit and maintain a satisfactory antibody level. Immunity usually develops more rapidly with live vaccines, but serious overt disease from the vaccine itself can occur in patients whose immune responses are suppressed. Live attenuated virus vaccines are generally contraindicated in pregnancy because of the risk of infection and damage to the developing fetus. Recent developments in molecular biology and protein chemistry have brought greater sophistication to the identification and purification of specific immunizing antigens and epitopes, and to the preparation and purification of specific antibodies for passive protection. Thus, immunization is being applied to a broader range of infections.

Prophylaxis or therapy of some infections can be accomplished or aided by passive immunization. This procedure involves administration of preformed antibody obtained from humans, derived from animals actively immunized to the agent, or produced by hybridoma techniques. Animal antisera induce immune responses to their globulins that result in clearance of the passively transferred antibody within approximately 10 days, and carry the risk of hypersensitivity reactions such as serum sickness and anaphylaxis. Human antibodies are less immunogenic and are detectable in the circulation for several weeks after administration. Two types of human antibody preparations are generally available. Immune serum globulin (gamma globulin) is the immunoglobulin G fraction of plasma from a large group of donors that contains antibody to many infectious agents. Hyperimmune globulins are purified antibody preparations from the blood of subjects with high titers of antibody to a specific disease that have resulted from natural exposure or immunization; some examples include hepatitis B immune globulin, rabies immune globulin, and human tetanus immune globulin. Details of the use of these globulins can be obtained from the chapters that discuss the diseases in question. Passive antibody is most effective when given early in the incubation period.

Epidemiology is, clearly, the cornerstone for understanding all infectious diseases. The principles, when applied wisely, serve to understand the nature and spread of pathogens, facilitate their recognition, and suggest means of control. The latter may variously involve direct therapeutic maneuvers, prevention through selective chemoprophylaxis or immunization, implementation of environmental controls, and public education. These approaches vary among specific agents, but knowledge of their usefulness is highly important, whether dealing with a single ill patient or an entire community.