Emerging Infectious Diseases

Vaccination Is Not Immunization Vaccine Risks Exposed

Vaccines Have Serious Side Effects

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A cursory glance at the current offerings in your local bookstore or video rental store brings into focus the preoccupation of the public and the press with new infectious agents. Several times a year, it seems, we hear about a new virus or bacterium that arises in a particular location and causes severe illness or death in a population. Newly described pathogens are referred to as emerging pathogens. Some of the emerging pathogens that have been described since the early 1970s appear in Table 17-4. These new pathogens are thought to have emerged within the recent past. HIV is an example of a newly emerged pathogen.

In other instances, diseases that were no longer causing widespread infection suddenly began to infect an ever-larger number of individuals. These are referred to as "re-emerging"

Emerging pathogens recognized since 1973



















1997 1999

Rotavirus Hepatitis C

Cryptosporidium parvum Ebola virus

Legionella pneumophilia Hantavirus Campylobacter jejuni

Human T-lymphotrophic virus I (HTLV-1) Toxin-producing strains of

Staphylococcus aureus Escherichia coli 0157 :H 7 HTLV-II

Borrelia burgdorferi HIV

Helicobacter pylori Hepatitis E Guanarito virus Encephalitozzon hellem Vibrio cholerae 0139 Bartonella henselae Sabia virus

Human herpes virus-8 TSE causing agent Influenza A subtype H5N1 Influenza A subtype H9N2 Nipah virus West Nile virus

Major cause of infantile diarrhea globally

Non-A, non-B hepatitis commonly transmitted via transfusions

Acute chronic diarrhea

Ebola haemorrhagic fever

Legionnaires' disease

Haemorrhagic fever with renal syndrome

Enteric diseases distributed globally

T-cell lymphoma

Toxic shock syndrome

Haemorrhagic colitis Hairy cell leukemia Lyme disease AIDS

Peptic ulcers

Enteric non-A, non-B hepatitis

Venezuelan haemorrhagic fever

Conjunctivitis, disseminated disease

New strain of epidemic cholera

Cat scratch disease

Brazilian haemorrhagic fever

Associated with Kaposi sarcoma in AIDS patients

New variant of Creutzfeldt-Jakob disease (mad cow disease)

Avian influenza

New strain of human influenza



SOURCE: Adapted from M. F. Good et. al., 1988, Annual Review of Immunology, Vol. 6.

infectious diseases. The re-emergence of these diseases should not be surprising if we consider that bacteria can adapt to living in almost any environment. If they can adapt to living at the high temperatures of the thermal vents deep within the oceans, it is not difficult to accept that they can evolve to evade antimicrobial drugs. (An additional risk from intentionally disseminated diseases is discussed in the Clinical Focus.)

Tuberculosis is a well-known re-emerging disease. Fifteen years ago, public health officials were convinced that tuberculosis would soon disappear as a major health consideration in the United States. Then, because of a number of events, including the AIDS epidemic, thousands of infected individuals developed TB strains resistant to the conventional battery of antibiotics. These individuals then passed on the newly emerged, antibiotic-resistant strains of M. tuberculosis to others. While the rate of infection with M. tuberculosis in the United States increased sharply during the early part of the 1990s, by 1995 the incidence had begun to decline again. However, the worldwide incidence of the disease is still in creasing, and the World Health Organization predicts that, between 1998 and 2020, one billion more people will become infected and over 70 million will die from this disease if preventive measures are not adopted.

Another re-emerging disease is diphtheria. This disease was almost non-existent throughout Europe in recent years because of vaccination; in 1994, however, scattered cases were reported in some of the republics of the former Soviet Union. By 1995, there were over 50,000 cases reported in the same region, and thousands died from diphtheria infection. The social upheaval and instability that came with the breakup of the Soviet Union was almost certainly a major factor in the re-emergence of this disease, because of the resultant lapses in public health measures—perhaps most important was the loss of immunization programs. Since 1995, immunization programs have been re-established and the trend has reversed, with only 13,687 cases of diphtheria reported in Russian republics in 1996, 6932 in 1998, and 1573 in 2000.

Other diseases have appeared seemingly from nowhere and, as far as we know, are new pathogens. These include



The Threat of Infection from Potential Agents of Bioterrorism

The use of human pathogens as weapons has a long history. Lord Jeffery Amherst used smallpox against native American populations before the Revolutionary War, and there are reports of attempts to spread plague and anthrax in both the distant and recent past. A few years ago, members of a dissident cult in Oregon introduced salmonella into the salad bars of several restaurants in an attempt cause sickness and death. The more recent discovery of anthrax spores mailed to congressmen and news offices accelerates our interest in possible agents of bioterrorism.

Pathogens and toxins with potential for use as weapons are called "select agents" and include bacteria, bacterial toxins, and certain viruses (see table). The threat from such agents depends on both the severity of the disease it causes and the ease with which it can be disseminated. For example, Ebola virus causes a fulminating hemorraghic disease, but

Category A agents of bioterrorism

Anthrax (Bacillus anthracis) Botulism (Clostridium botulinum toxin) Plague (Yersinia pestis) Smallpox (Variola major) Tularemia (Francisella tularensis) Viral hemorrhagic fevers (filoviruses [e.g., Ebola, Marburg] and arenaviruses [e.g., Lassa, Machupo])

spread of the virus requires direct contact with infected fluids. More worrisome are pathogens that can be spread by aerosol contact, such as anthrax, and toxins that can be added to food or water supplies, such as botulinum toxin.

It is ironic that one of the most feared bioterrorism agents is smallpox, the target of the first vaccine. Smallpox is caused by the virus Variola major; 30% or more of those infected with this virus die within a month of exposure. Survivors may be horribly scarred. Smallpox can spread rapidly, even before symptoms are visible. As described in Chapter 1, the vaccine for smallpox is a virus ( Vaccinia) related to variola, which in most cases causes a localized pustule that resolves within 3 weeks. Smallpox disappeared as a consequence of widespread vaccination—the last reported case of natural infection was in 1977. As the disease was eradicated, vaccination was discontinued. In the United States, vaccination ceased in 1972. Production of the vaccine ceased and the remaining doses were put into storage.

Reasons for discontinuing smallpox vaccination include side effects that affect approximately 40 individuals per million vaccinees. These can be life threatening and take the form of encephalitis or disseminated skin infection. In addition, recently vaccinated individuals can spread the virus to others, especially those with compromised immunity. The occasional negative reactions to vaccinia can be treated by the administration of immu-noglobulin isolated from sera of persons previously vaccinated, but this so-called

Vaccina IG, or VIG, is no longer produced and little remains available. Facing the threat of smallpox as a bioterrorism agent means that vaccination must be reconsidered. It is unlikely that the vaccine produced today will be the same one used earlier. Vaccine was produced by infection of the scarified skin of calves and virus was collected by scraping the infected area. Most likely a new vaccine candidate will be produced under controlled conditions in a tissue-cultured cell line that is certified free of any contaminating viruses. Furthermore, the actual virus used may be a more highly attenuated form of vaccinia. Stocks of VIG must be replenished before a mass vaccination effort is begun.

Most of the viruses on the select agent list are not easy to disseminate. Agents of bioterrorism prepared in a form that allows easy dispersal are referred to as weaponized. While nightmare scenarios include customized viral agents engineered in the laboratory, the more likely weaponized pathogens are bacteria. An accidental release of anthrax (Bacillus anthracis) in Sverdlovsk in the former Soviet Union infected 79 persons, of whom 68 died, pointing to the deadly potential of this organism. In late 2001, mail containing anthrax (see the accompanying figure) infected a number of persons in multiple postal centers as the letters progressed to their destinations, giving a glimpse of how widely and rapidly a bioweapon might be spread through modern infrastructure.

Bacillus anthracis is a common veterinary pathogen, and like smallpox was the subject of early vaccine efforts, in this case by Louis Pasteur. Human infection was found mainly in those working with hair or hides from animals, especially goats. Infection occurs via three different routes:

■ Inhalation causes severe flu-like illness with high mortality unless diagnosed and treated immediately such pathogens as the widely publicized Ebola virus and Legionella pneumophilia, the bacterial causative agent for Legionnaires' disease. Ebola was first recognized after an outbreak in Africa, in 1976. By 1977, the virus that causes this disease had been isolated and classified as a filovirus, a type of RNA virus that includes Marburg virus, a close relative of Ebola. Ebola causes a particularly severe haemorrhagic fever that kills more than 50% of those infected. Because of the with antibiotics such as penicillin, doxycycline or ciprofloxacin.

■ Cutaneous exposure results in skin lesions with characteristic black deep eschar. Cutaneous anthrax has a 20% mortality if untreated, but usually responds to antibiotics.

■ Gastrointestinal exposure results in ulcers in the ileum or cecum, bloody diarrhea, and sepsis, and is nearly always fatal because of difficulty in diagnosis.

B. anthracis is particularly deadly because the bacillus forms spores that are quite stable to heat, dryness, sunlight, and other factors that normally limit pathogen viability. It is relatively simple to induce spore formation, and it is spores that are used as bioweapons. Primate studies suggest that inhalation of 2500 to 55,000 spores will cause fatal disease, although the number is controversial. Victims may have flu-like symptoms; a chest x-ray will reveal a characteristic widening of the mediastinum, and blood smears will show gram-positive bacilli. Since prompt diagnosis and treatment is required for survival it is essential that medical personnel recognize the disease.

A vaccine has been developed for anthrax, but its use has been limited to the military. The present preparation is a filtrate from cultures of a non-spore-forming strain of B. anthracis. Newly proposed vaccines take advantage of the information gained from basic studies of the mechanism used by the organism to infect target cells, as well as our understanding of the structure and function of anthrax-derived proteins. The major protein involved in infection is the so-called protective antigen, or PA, which pairs with either edema factor (EF) or lethal factor (LF) to cause productive infection. Antibodies that target the binding site on PA for either LF or EF are being developed as the next generation of vaccines against anthrax.

The threat from select agents of bioter-rorism, like that from emerging diseases, is being addressed by careful attention to unusual infection events, and by increased study of agents that lend themselves to weaponization. Research to determine the efficacy of various treatments and the windows of immunity that result from administration of antitoxins have risen to top priority in the U.S. following the events of September 11, 2001.

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Letters to congressmen and news agencies that contained anthrax spores. Courtesy of the Federal Bureau of Investigation.

severity of disease and the rapid progression to death after the initial appearance of symptoms, this virus has received a great deal of attention. However, while the risk of death is very high if you are infected with Ebola, it is fairly easy to control the spread of the virus. Through isolation of infected individuals, hospital workers and medical personnel can be protected. In such ways, the spread of Ebola virus has been contained during the two most recent outbreaks.

Another emerging disease recently described is Legionnaires' disease, a virulent pneumonia first reported in 221 individuals who had attended an American Legion convention in Philadelphia in 1976. Of the 221 afflicted, 34 died from the infection. The organism causing the disease was not known, but further investigation led to the identification of a bacterium that was named Legionella pneumophilia. This bacterium proliferates in cool, damp areas and can be found in the condensing units of large commercial air-conditioning systems. The air-conditioning system can produce an aerosol that contains the bacteria, thus spreading the infection throughout the area served by the unit. This was determined to be the source of the bacteria at the 1976 convention in Philadelphia. Because the hazard of such aerosols is now recognized, improved design of air-conditioning and plumbing systems has greatly reduced the incidence of the disease.

In 1999, a new virus emerged in the Western Hemisphere. West Nile virus was first isolated in Uganda in 1937, but until recently it was not found outside Africa and western Asia. In 1999, West Nile virus was found in the New York City metropolitan area and by summer 2002, incidence of West Nile virus was reported in all but a few states in the Northwest, indicating a rapid spread of this virus in a short period of time. West Nile virus belongs to a group of viruses known as flaviruses, a group of viruses spread by insects, usually mosquitoes. The most common reservoir of the virus is birds. Crows are particularly sensitive to infection by this virus. Mosquitoes bite an infected bird and, most commonly, the virus-infected mosquito passes the virus to another bird. However, on occasion, the mosquito bites a human, infecting that individual with the virus. Since West Nile is not contagious between humans, it cannot be spread among human populations. In all but a small proportion of humans, West Nile infection does not cause disease. Only in individuals with compromised immune function is the virus a health hazard. Because this virus can cross the blood-brain barrier in compromised individuals, it can cause life threatening encephalitis or meningitis and this is the usual cause of death. Between 1999 and 2001, West Nile caused 18 deaths and sickened 131 others. By September 6, 2002, 954 cases of West Nile had been reported to CDC and 43 people had died in the year 2002. These statistics indicate that West Nile is spreading and is a virus to monitor carefully. Current public health control mechanisms include education of the public regarding mosquito control.

Why are these new diseases emerging and others re-emerging? One reason suggested by public-health officials is the crowding of the world's poorest populations into very small places within huge cities. Another factor is the great increase in international travel; it is now easy to traverse the globe in a very short time, making it possible for an individual to become infected on one continent and then spread the disease to another continent tens of thousands of miles distant. Other features of modern life that may contribute include mass distribution of food, which exposes large populations to potentially contaminated food, and unhygienic food preparation. The World Health Organization and the U. S. Center for

Disease Control both actively monitor new infections and work together closely to detect and identify new infectious agents and to provide up-to-date information for travelers to parts of the world where such agents may pose a risk.


■ Innate immune responses form the initial defense against pathogens. These include physical barriers, such as skin, as well as the nonspecific production of complement components and certain cytokines in response to infection by various pathogens.

■ The immune response to viral infections involves both humoral and cell-mediated components. Antibody to a viral receptor can block viral infections of host cells. However, a number of viruses, including influenza, are able to mutate their receptor molecules and thus evade the humoral antibody response (see Figure 17-6). Once a viral infection has been established, cell-mediated immunity appears to be more important than humoral.

■ The immune response to extracellular bacterial infections is generally mediated by antibody. Antibody can induce localized production of immune effector molecules of the complement system, thus facilitating development of an inflammatory response. Antibody can also activate complement-mediated lysis of the bacterium, neutralize toxins, and serve as an opsonin to increase phagocytosis. Some bacteria secrete protease enzymes that cleave IgA dimers, thus reducing the effectiveness of IgA in the mucous secretions. Other bacteria escape phagocytosis by producing surface capsules or proteins that inhibit adherence to phagocytes, by secreting toxins that kill phagocytes, or by their ability to survive within phagocytes. Host defense against intracellular bacteria depends largely on CD4+ T-cell-mediated responses.

■ Both humoral and cell-mediated immune responses have been implicated in immunity to protozoan infections. In general, humoral antibody is effective against blood-borne stages of the protozoan life-cycle, but once protozoans have infected host cells, cell-mediated immunity is necessary. Protozoans escape the immune response through several mechanisms. Some—notably, Trypanosoma brucei—are covered by a glycoprotein coat that is constantly changed by a genetic-switch mechanism (see Figure 17-12). Others (including Plasmodium, the causative agent of malaria) slough off their glycoprotein coat after antibody has bound to it.

■ Helminths are large parasites that normally do not multiply within cells. Because few of these organisms are carried by an affected individual, immune-system exposure to helminths is limited; consequently, only a low level of immunity is induced. Although helminths generally are attacked by antibody-mediated defenses, these may be ineffective. A cell-mediated response by CD4+ T cells plays a critical role in the response to Schistosoma.

■ Emerging and re-emerging pathogens include some that are newly described and others that had been thought to be controlled by public-health practices. Factors leading to the emergence of such pathogens include increased travel and intense crowding of some populations.

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