The Millennium in Infectious Diseases: Focus on the Last Century 1900-2000

Vincent A. Fulginiti, MD

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In This Article

The Millennium Years: 1900-2000

Society was undergoing gradual but progressive change during this period. Hospitals were begun, clinics to treat the poor were established, and better public health strategies were employed as understanding of infectious disease increased. Public health departments began to be developed and functioned to improve the healthy practices of the communities they served, courses of hygiene were introduced into schools, and medical care began to absorb and practice new discoveries as they were introduced. Infectious diseases were still rampant and, by today's standards, intolerable in morbidity and mortality. One interesting aspect of the loss to society by infectious diseases is the list of "persons of leadership" lost to the scourges of this millennium, including some in the century under focus.[10] Monarchal leaders, US Presidents, other world rulers, authors, journalists, musicians, composers, physicians, scientists, and many others point out by their prominence just what was happening in society in their times. For each leader, there were millions afflicted with the same infectious diseases that met similar fates. But there were remarkable achievements, incremental in improving general health and welfare, and monumental in some areas, such as the diagnosis, treatment, and prevention of disease.

One construct to understand both the magnitude of infectious diseases in the 20th century and the millennial changes in incidence is to look at the "baseline" annual morbidity of a variety of diseases.[25,33] Table 1 gives a snapshot of the yearly frequency of selected infectious diseases between their height in the 20th century and 1998.[33]

Perusal of these figures for the 20th century baseline indicates the plight of early childhood and that among susceptible adults. The incidence figures do not tell the whole story, as mortality and permanent disability for these diseases was significant. Smallpox, measles, diphtheria, tetanus, and pertussis all exacted a high death toll on those affected.[1,2,5,6,10,12,30] One need only examine paralytic polio and the congenital rubella syndrome to recognize the long-lasting effects on the thousands affected during the millennium. These diseases are only those amenable to vaccine prevention. Others, such as yellow fever, malaria, cholera, and tuberculosis, were equally rampant.[1,6,24] Influenza exacted its toll in the great epidemic of 1918 and on lesser-scale, but no less morbid, epidemics in 1957 and 1968.[1,16,34] No matter how viewed, these data paint a dismal picture of life in the early part of the 20th century, and for some persisted far into that century. But the data also illustrate that application of the expanding knowledge base, in this case related to development and use of vaccines, has a remarkable effect on improved health.

How did this come about? There was an increasing interest in exploring biology in a systematic way as opposed to theorizing.[6,14,15,16,19,21,22,25,27] As a result, remarkable breakthroughs occurred as scientists, chemists, and physicians all contributed to incremental understanding of basic biologic mechanisms, and, specific to infectious diseases, understanding of the nature of bacteria, fungi, parasites, and viruses, and of pathogenesis and epidemiology of the various infectious resulting from these organisms. Additionally, more was learned about the immune capacity and response of humans, which eventually led to strategies for prevention of many previous scourges, and even elimination of some. Examples of some of the epochal discoveries and their application follows.

The diphtheria bacillus had been discovered in the 1800s, and Emil Von Behring was awarded the Nobel Prize (the first awarded) in 1901 for the development of diphtheria antitoxin.[19] Ehrlich and Morgenroth discovered antibodies and complement in 1899 and hypothesized that they neutralized antigens on bacteria, despite prevalent theories about antitoxic effects.[35] Metchnikoff had discovered the phagocyte and its role in immunity.[6] Although earlier insight by Semmelweiss had identified the mechanism of transmission of puerperal sepsis, his discovery was largely ignored, but in the 20th century the concept was revived and handwashing and sterilization more commonly employed, aided by Lister's contributions of the benefits of sterilization of surgical instruments and supplies.

After Antoni Von Leeuwenhock's discovery of the microscope in the 1600s, use of this instrument in the 19th and 20th centuries was uncovering organisms in diseases previously of unknown causation, although some errors still occurred since the concept of viruses was largely unknown and isolation of bacteria from patients with such diseases as mumps led to the faulty idea that the disease was bacterial in origin.[6] European scientists added yearly to the understanding of infectious disease and immunity, and Americans were soon to follow. Discoveries such as the chemical structure of bacterial capsules, the linking of antitoxins and, ultimately, antibodies to immunity were giant steps forward in understanding pathogenesis and immunity.[35]

Jenner's epochal use of cowpox to prevent smallpox, discovered in 1798, and Pasteur's use of rabies-infected tissue as a vaccine in 1885, paved the way for the concept of active immunity conferred by injection of infectious material, live or killed, to stimulate the host to 'remember' the antigen and ward the agent off when exposed.[1,2,6,34] But, not until the discovery by Enders, Weller, and Robbins in the 1950s did vaccine application reach proportions undreamed of previously.[19,36] Their contribution was the discovery that tissue culture could be infected with polio virus, which led to subsequent manufacture of polio, measles, mumps, and rubella vaccines, among other live agents now safely propagated in vitro. Yellow fever vaccine had been developed earlier in the century by inoculation of eggs, and other live virus vaccines were of animal derivation, as was vaccinia. The ability to grow viruses in vitro spawned a new era in vaccine development that we are still exploring today.

Modern knowledge of the immune mechanism derives from the work of countless scientists, each contributing incremental increase in our knowledge.[35] Landmarks include: discovery of anaphylaxis by Theobold Smith; expansion of experimental immunology by Landsteiner and Heidelberger; the demonstration of transfer of hypersensitivity by lymphocytes by Chase; the production of leukocyte chimeras by Medawar, Brent, and Billingham; the delineation of hypogammaglobulinemia by Bruton; and further delineation by Talmage, Broder, Good, Kempe, Claman, Cooper, Stiehm, Hong, Fulginiti, Pearlman and many others of immunologic disorders; Von Pirquet's discovery of allergy and of the role of immunologic function in responses to infectious diseases; Prausnitz and Kustner's discovery of passive transfer of reaginic antibody; and the massive information about lymphocytes and their function in cellular immunity by many investigators and clinicians.

Following on Ehrlich's contribution of arsenic compounds for the treatment of syphilis, Gerhard Domagk ushered in the modern era of antimicrobials in 1935 with the discovery that prontosil was effective in streptococcal infections in experimental animals.[6] Soon afterwards this effect was displayed in human disease. Examination of the biochemistry of prontosil led to the discovery of sulfonamides. Fleming's discovery of penicillin, initially largely ignored, was elaborated and expanded by Howard Florey and his colleagues. Diseases formerly deadly were cured as if by miracle; the change in management of diseases was phenomenal after the discovery and application of penicillin in America. Waksman continued the progress by discovery of a product from molds called streptomycin that revolutionized treatment of tuberculosis and other serious infections that had not yielded to sulfonamides or penicillin. Rapidly thereafter, new antimicrobials were discovered, leading to the modern era of designer-developed antibiotics.

As one can see, these remarkable discoveries, and others not enumerated here, had 2 major effects: (1) they changed the concept of infectious disease causation, pathogenesis, epidemiology, and host response to infection; and (2) they opened up an era of effective diagnosis and therapy. We shall see how these important changes have led to elimination of some diseases, dramatic reduction in others (Table 1), and reduced morbidity and mortality for most.

Smallpox has been eliminated worldwide since 1977. The effort was spearheaded by the collaborative approach of the World Health Organization, the Centers for Disease Control and Prevention, a number of critical individuals such as Henry Kempe, Gordon Meikeljohn, D.A. Henderson, and W. Foege (and many others), and a number of countries where the disease was endemic. Case definition was followed by massive vaccination until no new cases occurred in that area; the cumulative effect in a given country was eventual elimination of disease. The last patient known to have smallpox from natural exposure was in 1977, although laboratory-acquired disease has occurred after that.

Polio has been eliminated from the entire Western Hemisphere and in many other parts of the world. Eradication of paralytic disease is in sight.[9] Measles, mumps and rubella have been reduced almost to nonexistence in the United States (see Table 1). This has come about by massive immunization efforts early on, followed by routine immunization in a 2-dose regimen, aided by mandatory school immunization laws, and a specific effort aimed at young children who previously had been missed by many programs.[13] Some predict elimination of measles in the near future, but an earlier effort with a 1990 deadline was thwarted by occurrence of the disease in children under the age of 2 who had not been immunized.

The incidence of pertussis has been reduced dramatically, but efforts to eliminate the disease have been stymied by several factors, including less than 100% efficacy of the vaccine, reservoirs in adults, and an active antivaccine campaign by the variously designated Dissatisfied Parents Together or National Vaccine Information Center. The latter have given rise to excessive attention to the undesirable effects of pertussis vaccine, resulting in the refusal of some parents to have their children immunized. A low level of persistent occurrence of the diseases has resulted, and mini-epidemics -- largely among nonimmunized children -- have been seen. Introduction of a chemically altered vaccine that has reduced the side effects associated with whole bacterial products promises to gain wider acceptance and, it is hoped, will eliminate this disease sometime during this next millennium.

Not all diseases had similar patterns. In 1918, influenza virus infection devastated the world with one of the worst pandemics in history. Each year influenza took its toll, especially among the infirm in society, but not nearly in the proportions of the 1918 epidemic. But, in 1957 and 1968, significant epidemics of disease occurred subsequent to antigenic shift in the organism. Influenza vaccines had been developed from egg-grown virus early in the millennium, and continuous improvement in manufacture resulted in virus-antigen products that were devoid of egg antigens, hence producing effective protection without some of the side effects observed with the egg-grown products. But the vaccine is only partially protective and the virus undergoes antigenic drift, ie, slight changes in its outside coat, enough to escape protection for some persons in the population. Antigenic shift, a major change in external antigens, renders the population at large exposed to a virus for which most have no protection.

In the latter part of the 20th century, the world encountered new threats to health in the form of persistent old, emerging, re-emerging and "new" infectious diseases.[11,18,23,42,43,44] Despite the gains made in vaccine-preventable diseases, others, such as gonorrhea, syphilis, herpes, and hepatitis, remained a problem and in some populations actually increased in frequency. Malaria is still prevalent worldwide, and the anopheles mosquito is estimated to infect as many as 400 million persons a year. Among all "new" diseases, the rather sudden appearance of AIDS caused by infection with a newly emerged retrovirus, HIV, became one of the most pressing infectious diseases problems in the world. The spread of this infection and subsequent disease was both remarkable and alarming. From small foci throughout the world, this virus has infected more than 30 million and has killed 16 million. Africa remains a hotbed for this infection/disease, and several countries are facing decimation of their populations.

Britain experienced a novel infection of the central nervous system (CNS) caused by a new type of infectious agent, the prion.[37] This is a small protein structure capable of replication like a virus and producing what had formerly been termed "slow virus infections" -- ie, after initial infection a very long incubation period ensued with then devastating CNS manifestations emerging, most often leading to death. This rare disease was known as a variant of Creutzefeld-Jacob Disease, but because the primary hosts were beef cattle in England, it became widely known as "Mad Cow Disease" (scientifically, bovine spongioform encephalopathy). The prion causing bovine spongioform encephalopathy has been linked convincingly with the variant CJD by epidemiologic evidence. Significant disruption of the cattle industry occurred with destruction of enormous numbers of beef herds, and some countries banned import of beef from England for fear of prion contamination of the meat from such cattle.[17,37]

Other emergent diseases included: Legionella pneumonia, from a water-borne bacterium; tick-transmitted Lyme disease; Hantavirus infection from exposure to rat urine; toxic shock syndrome originally caused by toxin-producing Staphylococcus aureus, and additionally from Group A beta-hemolytic streptococci; a group of viral hemorrhagic illnesses (eg, Marburg virus infection, Ebola virus disease); monkeypox infection in man, previously thought not transmissible in that direction; nibah virus encephalitis (from contact with infected pigs); Helicobacter pylori infection, a cause of GI ulcer disease; and infant botulism caused by spore-contaminated foods, such as honey. These are examples of newly identified syndromes. In addition, other diseases thought to be quiescent, such as tuberculosis, malaria, cholera, re-emerged in many parts of the world. Surgeon General Stewart in 1969 was so optimistic about the deployment of then-effective antibiotics and vaccines that he declared; "The war against infectious diseases has been won!"

Although antimicrobials changed the course of many infectious diseases, microbial resistance became a major problem in the last decades of the 20th century. More details of this phenomenon will be described later.

Thus, as the 20th century ended, one could count the many blessings, both intellectually and practically. Intellectually, many scientists and clinicians had contributed to deep understanding of basic biology and human physiology, providing both the framework and tools for increased knowledge in the future. Practically, great reduction in morbidity and mortality resulted from application of the scientific information in the clinical arena.[28] Despite these advances, many problems remained, and we will explore both the benefits and troubles in the 21st century that were inherited from the 20th.

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