Exam #2

Disease Natural Selection

It is absolutely essential that we focus on the importance of natural selection and evolution in the emergence of diseases of man. a) Also, that we pay attention to the impact of ecosystem disruption on these processes. Modern medical science has added another ingredient to this equation - the overriding factor of scientific advances in the biomedicine, which has reshaped the human and microbial environment, and the selective pressures that impinge on these evolving systems. All infectious diseases are encounters between two different living systems, us and the microbe. Each system is subject to the laws of evolution and each system obeys its own rules of selection and survival. We must view disease as an evolutionary event for both parties, which is a dramatic departure from the old view of invasion of a static host by a resilient enemy. One of the end products of selective forces driving adaptations which ultimately become traits, is the establishment of a genetic equilibrium which is accompanied by genetic diversity within species.

Natural Ecosystems

It is within these natural ecosystems that human interference comes into play. By disturbing otherwise balanced ecosystems and their balanced genomes, human intervention disrupts this genetic harmony, dispersing species, and breaking up genetic patterns by which groups of species have become adapted to their environments. Under these conditions of environmental disturbance, those organisms that maintained a high degree of genetic diversity and reproductive ability can become widely dispersed and invade new environments. In the macroenvironment human activities such as the use of pesticides and fertilizers, water contamination or purification, and livestock treated with antibiotics have selected for different compositions of organisms in the microscopic world of soils, lakes, oceans and aquifers, to mention a few. An analogous situation is seen in the body's microenvironment where massive die -offs of bacterial populations occur when someone abruptly changes their diet or starts taking antibiotics.

Incubation Period Has Many Uses in Epidemiology

1) it helps to define the etiological agent in an epidemic 2) it helps to differentiate common source form propagated epidemics 3) it defines the period during which a person exposed to an infection is at risk of developing the disease 4) it helps to define the period of infectiousness 5) it provides a guide to the possible effectiveness of active or passive immunization, and 6) it gives clues as to the pathogenesis of the disease

Outbreak Decreases Whenever:

1) the number of susceptibles decreases because of attrition, immunization, treatment or getting the disease; 2) the source of infection is eliminated; 3) transmission is interrupted.

Three Essential Requirements for an Outbreak of an Infectious Disease

1) the presence or introduction of infectious agent (human, animal, arthropod, food, water, air, etc.); 2) an adequate number of susceptibles; and 3) an effective means of transmission

Intrauterine or Transplacental Transmission

A number of viruses can transmit from maternal to fetal blood via the placenta (e.g -CMV, HBV, HSV and others)

More Disease Mechanisms

Large doses of endotoxin cause vascular collapse and death Unlike exotoxins, endotoxins are heat stable, and are not convertible to protective toxoids for use in vaccines. Some examples of the effects of the EXOTOXINS : diptheria toxin inhibits protein synthesis and causes necrosis of the epithelium, heart muscle, kidney and nerves; a) Clostridium difficile produces a necrotizing toxin that leads to antibiotic associated colitis; b) tetanus toxin increases excitation of the neurons of the spinal cord; c) botulinum toxin blocks the release of acetylcholine, shutting down nerve function; d) staph aureus exotoxin stimulates gut motility. Disease agent ‐induced immunopathologic lesions are related to the formation of immune complexes that can impact on a number of host organs directly (kidney) or indirectly via the immune reactions to the disease agent and its antigens and to antigen/antibody complexes. In strep infections antibodies develop that cross react with human heart muscle, leading to myocarditis.

Incubation Period

You will recall that the incubation period is the period of time between exposure to a source of infection and the point at which the first symptoms of clinical illness appear. Incubation period varies with: 1) the nature and dosage of the organism 2) the portal of entry 3) the type of infection (localized versus systemic) 4) the mechanism responsible for tissue injury (invasiveness, toxin, immunopathology, etc.) 5) the immune status of the host (incubation period will be longer in a partially immune person) 6) other unknown factors individual to the host.

Epidemiologists Warned You

Prime example: the antibiotic vancomycin used to be the major drug used to treat the enterococci which carry with them a mortality as high as 42%. In 1988 a vancomycin-resistant enterococcus emerged in a French hospital that soon transferred to Staphylococcus as well. a) This organism has spread today to many places on the globe. Not only do we see resistance to bacterial diseases, but also such diseases ass Malaria

Childhood and Infant Diseases

The high Group B Strep infection rate among children less than 1 month is related to contraction of the infection from the vaginal and rectal tissues of the mother during passage through the birth canal which can lead to between 40 and 70% infection rate in newborns thus exposed. For the same reason E. coli is a common cause of meningitis among newborns. Among adults with meningitis it was found that 40% are of nosocomial origin with a 35% mortality

The Bubonic Plague (Black Death)

The lack of large predatory species has filled the New England forests with rodents and deer. With high densities of these species comes high densities of their ectoparasites, including ticks. a) Ticks carry many infectious diseases and they are carried into human habitation zones on the bodies of rodents which are attracted to human areas by the availability of food. Among these disease agents is Borrelia burgdorferi which has adapted quite nicely to these new environmental parameters. Historically with bubonic plague we witnessed one or another kind of social disruption before each major outbreak. a) In the preceding decades, population growth in Europe had led to the decimation of woodlands to make room for farming and the need for lumber in the major urban centers. With the freeing of the serfs, mass migration to urban centers occurred, creating a lower class in the cities. Unhygienic conditions in the inner cities coupled with the abandonment of the farms was a deadly combination as plague-carrying woodland rats invaded the cities. a) The ensuing contact between woodland rats and urban rats solidly introduced plague into the cities. The BLACK DEATH followed.

Routes of Transmission

The major routes of infection of bacterial diseases are many and varied. Many organisms are capable of using multiple routes of transmission. For most bacterial pathogens, regardless of the route of infection they use to gain access to the tissues of the host, receptors on the surfaces of at least some of the target cells are required for infection to take place. Their success in reaching man depends on the number of organisms present, the size of released particles (larger particles remain suspended for shorter periods of time and travel shorter distances than smaller particles), the force with which they are propelled into the environment (sneezes are better than coughs which are better than speaking), the temperature and humidity of the air, the presence of air currents and the distance to the host.

Immune Response

The most effective mechanism for bacterial spread is via the bloodstream. When this happens, the bacteria can remain free in the plasma (pneumococci, anthrax and leptospirosis), exist intracellularly within monocytes (blood macrophages) - seen with brucellosis, leprosy, tuberculosis and others - or remain in association with neutrophils - a long list of bacteria can do this. When bacteria are in the blood it is referred to as bacteremia which may be a transient condition with little or no systemic response, such as that following a dental extraction in a healthy person.

Hospitals Promote Change

The net effect of these intense selective forces in the hospital is to produce nosocomial infections that tend to be more severe and difficult to treat than we find in the community. This is particularly true because the main mode of transmission in the hospital are nurses and other health care personnel who serve as vectors or carriers of the organisms to immune-impaired patients. The main targets for these kinds of infections in the hospitals are the newborn, the very old, AIDS and cancer patients. The more care a patient requires, the greater the risk for infection of the patient with one of these microbes. Studies have shown that the teaching hospitals associated with major universities generally have the highest rates and most serious forms of nosocomial infections. BUT- why should hospitals that use the most up-to-date. a) State-of-the-art techniques for sterilization and antibiotic usage be the epicenter of the most serious diseases? It is probably that the very intensity of the sanitation and disinfection practices of such hospitals selects for the most robust and virulent organisms. While nosocomial infections in hospitals in general range around 1 to 2%, teaching hospitals report rates as high as 10%!

Host

The occurrence of infection depends on exposure to a source of infection and on susceptibility of the host. On the other hand, the development of disease in an infected person depends in large part on factors intrinsic to the host - although properties of the disease agent itself will play a significant role in this regard as well. The actual exposure to a pathogenic agent depends on characteristics of the human host which result in contact with sources of infection in the environment or that promote person to person spread. The behavioral pattern of the individual at different ages opens the way to varying degrees and types of exposures in different seasons, cultures and geographic locations. Personal habits such as iv drug abuse or sexual promiscuity are strong determinants of exposure.

Sexually Transmitted Infection

The old term "venereal disease" referred to the 5 classic infections clearly transmitted by sexual intercourse (gonorrhea, syphilis, chancroid - caused by Hemophilus ducreyi, lymphogranuloma venereum - caused by Chlamydia trachomatis, and granuloma inguinale - caused by Calymmatobacterium granulomatis ). The newer term STDs (sexually transmitted diseases) is broader and applies to both hetero and homosexual activities, and encompasses all infections transmitted from person to person during sexual activity. Within this group, Chlamydia trachomatis has been identified as the cause of 50% of all nongonococcal urethritis. The presence of lesions caused by STDs increases dramatically the risk of acquiring HIV infection.

Environmental Control

The provision of safe air, water and food; the proper management of sewage and garbage; and the control of insect disease vectors are not only essential to good health but a legal right in most countries. How well these goals are accomplished depends on the economy, energy resources, political will and educational level of the country. As stated earlier, it is extremely difficult to control air quality, especially in open systems. Improvement in our water supply has had an enormous impact on infectious diseases, especially enteric infections. As human population density increases we will see a decline in water quality. Another very important control point has been improvement of our handling and disposal of sewage and garbage. a) Dumping human sewage into surface waters and the application of human fertilizer may have a great potentiating effect on the spread of infectious diseases

Respiratory Transmission

The respiratory route is the most important method of spread for the most common viral diseases of man, and is the least subject to control. Influenza virus relies heavily on this route of transmission, but the degree of transmissibility varies from one virus to another. As with other types of aerogenically transmitted organisms, transmission by the respiratory route is dependent upon the intensity and method of discharge from the mouth and nose, the size of the aerosol droplets created, and the resistance of the airborne virus to desiccation. Respiratory viruses can also be transmitted by contact with contaminated personal objects, by kissing or by direct deposition of large droplets produced by coughing and sneezing.

Disease Promotion

The severity of nosocomial infections may be enhanced in patients who are already ill with another disease or condition or who are immunocompromised. a) And of course, to make matters worse, antibiotic resistance in pathogens more often arises in the *hospital or related setting* than in any other part of the environment. In *prisons or in institutions for the mentally challenged* we encounter *low levels of personal hygiene and crowding* which promote the transmission of respiratory, intestinal and skin infections. Exposure in *meat-packing or slaughter houses and tanneries, or travel to developing countries*, may involve extreme risk for exposure to a long list of pathogens unique or more common in those environments. *Day Care Centers* and similar settings involving children pose a significant hazard for fellow children and for parents. a) This includes a robust list of pathogens. b) It should be noted that *in children, infection is much more common than is disease*. At the beginning of the HIV and other STDs epidemic, the environments of the brothel, bath houses and bars have provided opportunities for the efficient and rapid transmission of STDs in general. The "shooting gallery" used by iv drug abusers is an environment that has a high level of importance in transmission of a wide variety of disease agents.

Dengue is Caused by

Any of four related viruses: Dengue virus 1, 2, 3, and 4. For this reason, a person can be infected with a dengue virus as many as four times in his or her lifetime.

Common Source Outbreak

As mentioned earlier, epidemics can be classified from the standpoint of the source of infection. For example: a Common Source outbreak results from exposure of a group of people to a common source of infection such as a banquet at which a food borne epidemic occurred. This type of outbreak will give you a nice bell-shaped curve usually within the incubation period of the disease agent. Or, in the case of exposure on a continuing basis or over an extended period of time, will give you an extended epidemic curve

Pathogenesis

As mentioned earlier, most bacteria have specific attachment sites on epithelial surfaces. a) Examples of localized infections include diphtheria and strep infections of the throat, gonoccocal infection of the eye or urethra, and cholera and most salmonella infections of the intestine. Many of the gram negative bacteria have limited capacity to invade tissues and tend to remain localized. a) Some are able to invade in immunocompromised, debilitated or malnourished patients.

Acute Respiratory Infections

As mentioned earlier, these infections are the most common cause of morbidity in the world. a) In fact, it has been estimated that around 5 million children under the age of 5 die annually in the developing world from this group of diseases. The most common causes are Streptococcus pneumoniae and Hemophilus influenzae which together represent some 40% of the annual deaths in this age group. However, only 10% of acute respiratory infections in the world are caused by bacteria. a) By far most of these diseases are due to viruses.

Nosocomial Infections

As with the bacteria, hospitals and related environments provide unique populations and physical circumstances that promote transmission of some viral infections. Viruses are estimated to cause at least 5% of nosocomial infections. More than 24 different viruses have been documented as being transmitted in the nosocomial environment. Among these are HSV, HIV, hepatitis viruses, enteric viruses, respiratory viruses and others. Rabies virus has been transmitted via corneal transplant and Lassa, Marburg and Ebola have all been transmitted in this environment. Pediatric wards get hit by outbreaks of Respiratory syncytial virus

Best Incubators

Chronic care settings where infections tend to be smoldering and long-lasting serve as foci for the most intense selection of all, creating the most resistant and infectious organisms. Under circumstances in these environments, infections can last for weeks or months, and the mortality rate can approach 10%. In fact the most dangerous, multi-resistant microbes are more common in tertiary care centers than in acute care hospitals. This is true in part because long-term hospitalized patients at veteran's hospitals and homes for the elderly are often immunologically depressed and subjected to repeated bouts of infection. Researchers have recorded a 263% increase in hospital-acquired urinary tract infections alone over the past 10 years. There are many indiscriminate uses of antibiotics that contribute to the problems described. Treatment in anticipation of a postsurgical wound infection is one area of concern. a) There is a strong temptation to use antibiotics as insurance for high-risk surgical procedures that have not been approved for such treatment.

Four Cardinal Signs of Inflammation

warmth and redness due to vasodilation, swelling due to vasodilation and exudate, pain due to tissue distension, and the release of pain mediators.

Diarrhea

A second group of bacterial infections that are transmitted via the fecal-oral route are referred to as the food poisonings. a) This involves contamination of food by the feces of an infected person (for example an infected food handler), the animal source may be infected (for example Salmonella in chicken products), the organism may be present on the skin of the food handler (staph and strep), in the environment (staph), in the soil (Clostridium perfringens, C. botulinum), or in raw seafood (Vibrio parahemolyticus). Transmission of the enteric fevers and food poisonings are largely preventable. A clean source of water, proper chlorination or boiling of water, frequent hand washing, appropriate refrigeration of foods, and thorough cooking of foods are effective means of breaking the chain of infection. Some may be prevented by vaccination. In most developing countries even these simple precautions may be beyond the educational or economic reach of many people.

Vector

A vector is involved in transmission of a disease agent, the agent will be heavily influenced via its insect vector by environmental factors such as humidity, temperature, vegetation and other factors that impact directly on vector survival, breeding and feeding success. These and other environmental factors will also play a role in geographically limiting the vector and its disease agent.

Urinary Tract Infections

About 50-60% of patients with HIV in the U.S. have diarrhea at the onset of illness and initial diarrhea is seen in over 90% of AIDS patients in Africa and Haiti. A wide variety of organisms can be involved in these situations, of which Cryptosporidium is among the most important, accounting for diarrhea in 20% of AIDS patients in the U.S. and about 50% in Africa and Haiti. Acute Urinary Tract Infections: a) In various studies of acute urinary tract infections, E. coli has been implicated in 80% of infections. A recent study in a nosocomial unit showed that : a) 36% were due to E. coli, b) 17% to Pseudomonas mirabilis, c) 16% due to Enterobacter aerogenes and d) 10% due to Klebsiella pneumoniae. Risk factors that contribute to urinary tract infections in women include: a) sexual intercourse, b) diaphragm usage and c) voiding behavior. Urinary tract infection is the most common infectious disease of the elderly and is especially common in debilitated, institutionalized older persons.

Human Genetics

All of the people whose lives have been saved during childhood or adulthood by chemical treatments, would not have survived if their immune system had not been able to handle the infection. a) If these people had succumbed, only the people surviving based on their immune capability would have lived to reproduce and pass on their high level of immune vigor to their offspring. Before antibiotics and even today in some countries, pathogenic organisms have exerted strong selective pressure on human genetics. a) To use only two examples: Malaria kills many children whose suboptimal immune response to malaria is never passed on to their children. b) The same is true of cholera, which kills many children worldwide each year. With the advent of chemical agents to treat diseases, we have suppressed the evolution of our immune competence in dealing with pathogens. Boy, are we gonna be in trouble if that biomedical wall collapses. a) Antibiotics no longer rule - many disease agents have become and are becoming resistant to our best antibiotics. b) The continuing misuse of, and over reliance of the medical profession on, antibiotics ignores the reality that we are selecting for "Andromeda" strains of bacteria and viruses!!

Urinary Transmission

Although a wide variety of viruses have been shown to grow in human kidney cell culture, renal viral infections in humans are uncommon. A couple of the adenoviruses have been implicated in hemorrhagic cystitis in children and some evidence suggests that some of the hantaviruses may cause direct damage to kidney cells. While some viruses will exit the body in human urine, such as Ebola, hantavirus and others, this does not appear to be an important route for infection of other humans.

A Foodborne Outbreak - Case Study

An outbreak of an illness characterized by diarrhea, abdominal cramps and little or no fever involved 366 college students at a new dormitory on the campus of a major university. A quick assessment revealed that illness was confined to students who ate in 3 of the 6 dining halls that served food from a common kitchen to 3000 students. No other dorms were involved and the cases were sharply limited in time. The disease had a peak incubation period of 14 hours. Stool specimens were obtained from both ill and health students and from food handlers. Samples of leftover food were obtained for testing. Menus for the preceding evening revealed that the three dining halls in which all of the ill students had eaten offered a choice of fish, or roast beef and gravy, whereas the other three dining halls had a choice of hamburger or fish. Other food items were common to all 6 dining halls.

Power of the Doctors

Another dangerous group of bacteria are the Enterococci which are common inhabitants of the intestine of humans. a) These organisms show great inherent resistance to many antibiotics to begin with, and are easily transmitted between patients through simple nursing errors. b) Their inherent resistance to many of the broad spectrum antibiotics gives them a selective advantage over other organisms in any patient being treated with antibiotics. Today, entercocci are the 2nd or third most common cause of hospital acquired infections in the U.S. We must keep in mind that antibiotic resistance can be passed from a disease agent possessing it to a different one that does not. a) This can be accomplished by transfer of plasmids during conjugation between species of bacteria. While there are now some antibiotics which are supposed to eliminate the plasmids that carry resistance, many bacteria have evolved to circumvent this obstacle and become resistant to the effects of these kinds of antibiotics as well. It is obvious that antibiotics will be compromised as long as physicians ignore the power of antibiotics as selective forces in bacterial evolution.

Dummy

Another example is Kyasanur Forest disease, a classic example of human disruption of a wildlife environment leading to emergence of a new human disease. The disease first appeared in 1957 in India, caused by a virus that had previously infected only game animals and was transmitted by ticks. a) Human incursions into the Kyasanur Wildlife Refuge and destruction of habitat afforded the ticks opportunities to feed on people which resulted in a very severe and widespread epidemic and eventual establishment of the disease as endemic in local humans. These are of course only a few examples of the gross stupidity of human kind in regard to the potential for disease outbreaks, not to even mention the criminal destruction of our planetary environment and the species of animals with whom we share the planet. The rule is - you cannot disturb natural relationships without endangering your own species - DUMMY. Environmental disruption caused by logging, farming and war have had, and will continue to have, disastrous effects on the occurrence of human disease and the health of our planet.

Kids Promote Disease Change

Another example is the routine use of antibiotics to treat children simple because the feverish child "appears" to have a bacterial infection. a) Studies have shown that the use of antibiotics in such cases is no more effective than sugar pills in reducing the severity of illness. Can the medical profession apply effective and rational evolutionary principles to control of the most virulent bacteria? There are examples of where they have actually done so. a) In cystic fibrosis in children there has been recognition that transmission-related increases in virulence can be avoided by strict hygienic controls employed BFEORE antibiotics are fallen back on. Children and adults with cystic fibrosis are very susceptible to lung infections because of a greatly reduced ability to remove lung secretions. a) For example the organism, Pseudomonas cepacia, a plant pathogen which previously only caused rare infections in humans, has somehow shifted from plants to humans as a common cause of infection in cystic fibrosis patients. Chronic reliance on antibiotics has led to emergence of drug resistant forms. a) To limit spread of resistant Pseudomonas strains, there is strict limits placed on cystic fibrosis patients. b) And, by eliminating gatherings where rapid transmission between infected and uninfected patients could increase the virulence of the organism, physicians have begun to deal effectively with this dangerous problem

Propagated Epidemic

Another type of infectious disease epidemic curve results from a Propagated epidemic which is due to the spread of a disease agent from one host to another (human-to-human, animal-to-human or the involvement of an arthropod). In a propagated epidemic, the epidemic curve will depend on: 1) the number of susceptibles; 2) the degree of contact with an infected host; 3) the incubation period of the disease; 4) the mechanisms of transmission; 5) the portal of entry; and 6) the infectiousness of the causative agent.

1990's: The Golden Years for Bacteria

Antibiotic use has quietly shaped the nature and severity of many of our most important pathogens. For infectious diseases in general, we are losing the therapeutic race with pathogenic microbes. The 1990's are now recognized as the decade during which we witnessed the global resurgence of infectious disease, in large part because of drug resistance. Antibiotic resistance is one of the biggest public health challenges of our time. a) In 2013, CDC published a comprehensive analysis outlining the top 18 antibiotic-resistant threats in the U.S., titled Antibiotic Resistance Threats in the United States, 2013 (AR Threats Report). b) The report sounded the alarm to the danger of antibiotic resistance, stating that each year in the U.S., at least 2 million people get an antibiotic-resistant infection, and at least 23,000 people die.

Control Measures

Antibody analysis of sera taken at the time of the outbreak compared with those taken in the intensive study (2-3 weeks later) may not only confirm the diagnosis with a rising antibody titer, but may identify persons who were exposed, were infected, but did not become ill. The more intensive study may also require a more careful look at the environment, vectors or reservoirs. On the basis of the data from the intensive study, some control measures can usually be implemented. a) For example: immunization of susceptibles.

Vector-Borne Transmission

Both passive and active transfer of disease agents by vectors is a very important source of human infection in many parts of the world. Control of many of these vectors is extremely difficult especially in tropical and subtropical areas of the world. Much of the burden of avoidance in areas of intensive vector activity falls on the individual, and in areas of the world where people do not have the economic and educational wherewithal to initiate and maintain a plan of personal protection, vector borne diseases are rampant. In many of the industrialized countries, governmental efforts at vector control are significant and most often highly effective. a) Under these circumstances, personal protection will decline in importance except in special situations where intensive exposure takes place in isolated rural areas or in association with vectors that are difficult to control, such as ticks.

Flea Biting

By 1970 a major plague epidemic was raging throughout South Vietnam, but military censorship had prevented public dissemination of this information. Cultural traditions among rural Vietnamese including biting a flea found on one's body to kill it. a) This spread the plague to the lungs, leading to establishment of pneumonic plague. Pneumonic plague was spread human to human. a) This form of the disease carried a much higher mortality, especially among children. Before the war was over, the plague had spread to additional species of rodents and had spread to other areas of Southeast Asia. a) More critically, the plague has evolved to a form that could be carried in the pharyngeal tissues of man without causing symptoms - and we know quite well the epidemiological significance of symptomless carriers of disease. This story highlights very well the role of ecosystem disruption in encouraging emergence of new diseases and new variants of old diseases.

Human Papilloma Virus Infection

Can cause genital warts and cervical cancer. Annual physician visits for these conditions rose from 45,000 in 1966 to more than 50,000 in in 2010. Other vaginal infections have risen from 200,000/yr to 3 million/yr.

Vaccination

Careful protection of the body during the summer months, especially wearing long pants with cuffs tucked into high socks (nerd uniform), and the religious application of insect repellents are very important in prevention of tick bites. Intensive searching of the body, as well as domestic pets, is important in preventing Lyme disease, since the tick must remain attached to the skin for about 24 hr before it can transmit the organism. Vaccination is considered by many scientists to be the only reasonable approach for dealing with infectious diseases that lend themselves to vaccination. By using the body's natural defenses we can significantly retard development of drug resistance in bacteria and other disease agents.

RNA Virus Mutation Rates

Chronic infection in hepatitis demonstrates the attainment of an equilibrium between host and pathogen. a) Evolutionary changes within the host move the organism toward lowered pathogenicity (chronic versus acute) and helps explain how hepatitis victims become chronic carriers that neither kills them nor succumbs to an effective immune response. b) Unfortunately, the patient is always at risk of the organism causing cirrhosis or hepatocellular carcinoma. In theory, the constant accumulation of mutations that characterize RNA viruses should eventually diminish their fitness. a) Without sexual recombination, organisms like hepatitis, HIV and flu should become less fit over time. So high a mutation rate should be intrinsically risky and many of the RNA viruses should self-destruct. The mechanism supporting the vigor and success of the pathogenic RNA viruses is host immune attack! a) The vertebrate immune response is a potent selective force in the microevolution of disease agents, and it is destroying a certain proportion of the most mutated viral strains, eliminating the less fit subtypes.

Mother Nature Will Take Us Out

Civil strife, wars, natural disasters, deforestation, and other forms of economic, social and environmental breakdown are leading to loss of quality in the water and food supplies of the world, opening the way for emergence of an incredible array of diseases of man. This is occurring routinely and intensely in developing countries of the world. When we add to this situation, the massive movement of people around the globe, we begin to understand the concept of a "Global Community" and we are seeing excellent opportunities for transmission of these diseases to all of mankind.

In the Hands of Clinicians

Clinicians need to recognize that each time antibiotics are used they are exerting tremendous selective pressure against our natural flora as well as against the target organism. Our commensal organism normally help prevent colonization of our mouth, throat, vagina and intestine by unwanted bacteria and yeasts by competing with them for nutrients and attachment sites and by producing noxious chemicals that kill or disable the invaders. Understanding the often fragile ecological relationships among bacteria can help us prevent the major undesirable effects of antibiotic use. Hospitals continue to be the epicenters for development of new antibiotic-resistant strains of bacteria because of their continued reliance on broad-spectrum antibiotics and incomplete treatment regimens, particularly in ICUs. Even at the most prestigious hospitals, the ICU is the crucible for antibiotic-resistant bacteria. In the ICU bacterial infections are often life-threatening and sepsis especially poses a challenge to the infectious disease specialist. a) Often such conditions justifies the use of potent antibiotics, sometimes without the necessary antibiotic-sensitivity testing. b) However, this approach can quickly result in the emergence of antibiotic resistance .

Contact Transmissions

Contact transmission can be either direct or indirect by droplets that are too big to be truly airborne.

Dengue Fever

Dengue fever also provides an interesting model to illustrate emergence of a disease in previously unaffected areas of the world. Dengue fever also provides an interesting model to illustrate emergence of a disease in previously unaffected areas of the world. Dengue is a rapidly dispersing disease. a) It is a mosquito borne viral disease that originated in confined areas of the tropical and subtropical areas of the world . Dengue exemplifies how ecological disruption can create novel opportunities for very rapid spread and global dispersion of a disease vector and the disease itself. Dengue is thought to have originated in Tropical Asia but was quiet for the first half of the 20th century. a) Around 1950 it began a long resurgence that has yet to slow down. b) It is currently a major cause of death and hospitalization among children and when it first emerged it carried a mortality of 40%! Severe epidemics were first seen in the Philippines and Thailand in 1954, largely as a result of severe flooding and explosion of the mosquito populations. a) Today in this region of the world, Dengue causes over a million infections annually. b) In the late 1970s a very rapid spread of Dengue occurred to North and South America.

Dengue in the Western and Southern Hemispheres

Dengue's arrival in this hemisphere was announced in 1981 in the form of a major epidemic in Cuba with 300,000 infected and 116,000 hospitalized. As a result of ecological disturbances and poor flood control, we have produced worldwide an expanded habitat for mosquitoes. Several cases of Dengue have shown up along the U.S. Mexican border, with some cases contracted on the U.S. side. An important factor in the obstacles to wholesale movement of Dengue into the U.S. is the fact that Americans, unlike many people in the world, do not tolerate mosquito bites and we use screens and air-conditioning, both of which interfere with mosquito access to man. The CDC has isolated 16 newly recognized arboviruses from the newly introduced Aedes albopictus alone and as you know albopictus is a recent arrival in the U.S.

Breakbone Fever

Dengue's arrival in this hemisphere was announced in 1981 in the form of a major epidemic in Cuba with 300,000 infected and 116,000 hospitalized. Each year, up to 400 million people get infected with dengue. a) Approximately 100 million people get sick from infection, and 22,000 die from severe dengue. As a result of ecological disturbances and poor flood control, we have produced worldwide an expanded habitat for mosquitoes. Several cases of Dengue have shown up along the U.S. Mexican border, with some cases contracted on the U.S. side. An important factor in the obstacles to wholesale movement of Dengue into the U.S. is the fact that Americans, unlike many people in the world, do not tolerate mosquito bites and we use screens and air-conditioning, both of which interfere with mosquito access to man. The CDC has isolated 16 newly recognized arboviruses from the newly introduced Aedes albopictus alone and as you know albopictus is a recent arrival in the U.S.

Bacterial Genetics

Different bacteria adopt different solutions to resist antibiotics. a) Some of these adaptations include changes in the cell wall permeability that keep the antibiotic from penetrating the organism; b) some will alter their cell surface membranes and the binding site for the antibiotic; c) others might attack the antibiotic with enzymes; d) and other ploys abound. Bacteria can then use a variety of genetic packages to transfer antibiotic resistance, sometimes to multiple antibiotics, between and within bacterial species. a) These factors greatly accelerate bacterial evolution. One of the classic examples of the problems that can arise from this capability is that our resident E. coli can house such multi-drug resistant genes and serve as a reservoir for this kind of dangerous information for any pathogen that might happen along. There is a wealth of real-life examples that illustrate this danger quite clearly. An 84 year old woman was admitted from a nursing home with gastric bleeding. a) Blood culture showed Serratia marcescens, which at first appeared to be susceptible to all standard antibiotics.

Disease

Disease is generally a rare consequence of infection. The term virulence is the quantitative expression of the disease-producing potential of a pathogen and can be expressed as: the number of deaths and severe illnesses ÷ number of diseased. There are quite a few factors that may contribute to the virulence of a disease agent. a) For example: the production of a toxin, high invasiveness, the induction of an immune response that is harmful to the host, etc. While invasiveness is a key component in virulence, it does not always correlate with disease. Wide distribution of a pathogen in the body and its contact with many different kinds of cells , as well as its presence in the blood stream certainly may set the stage for disease, but it is not a guarantee of high virulence. a) For example, there is minimal host response elicited by millions of Mycobacterium leprae bacilli in the blood often without high virulence. Organisms that produce endotoxins and exotoxins are likely to produce severe disease since most bacterial toxins are harmful to host cells and evoke dramatic immune responses.

Bet On the Bacteria

During the 1950s, just about every major infection responded to penicillin and the newly discovered antibiotics, aureomycin and streptomycin. a) Within 10 years it was a common event to encounter a disease agent that was resistant to one or more of these chemicals. With the discovery of new and more powerful antibiotics like tetracycline in the 1960s, we saw the emergence of new resistance patterns among bacteria.

Preliminary Assessment 1

Each case of the disease is characterized according to key epidemiological factors (age, sex, ethnic group, occupation, home and work addresses, behavioral or cultural characteristics, recent travel, date of onset of disease, and functions attended by the patient and by others that are ill). A graph is constructed of the epidemic cases by date of onset - this immediately provides a clue on incubation period. Single exposures to the epidemic will be very useful in defining incubation period as well. A spot map showing the geographic location of cases can be quite helpful, particularly if there is a clustering of cases which may indicate a source of infection. These data are statistically analyzed to identify the persons at highest risk or some common denominator of risk. This step will help form a hypothesis on route of transmission.

RMSF- Signs and Symptoms

Early (1-4 Days) High fever Severe headache Malaise Myalgia Edema around eyes and on the back of hands Gastrointestinal symptoms (nausea, vomiting, anorexia)

Ecosystem Disruption and Disease

Evolution is the main shaping force in the establishment of new diseases. The emergence of new diseases must address evolutionary changes in pathogens, which underwrite their ability to jump species barriers into Humans. Moreover, the host will pose an evolutionary resistance to infection by the pathogen which will play a powerful role in the disease emergence. While there are exceptions to this rule, and circumstances under which the rule may not apply, we find that many disease agents tend to evolve toward less pathogenicity over long associations with a host. This "Happy Equilibrium" is one in which infection occurs without high pathology. Often, we witness that newly emerged diseases are associated with short, highly pathogenic and often fatal associations with their new host. a) Sometimes in these new associations with man, does a new pathogen last long enough in its association with humans and work out a routine mode of transmission to become endemic.

Disease Mechanisms

Exotoxins liberated by many of the gram-positive bacteria cause local cell and tissue injury (examples: Staphylococcus aureus, Streptococcus pyogenes, Corynebacterium diptheriae, Vibrio cholerae and Bacillus anthracis). The exotoxins cause little or no fever in the host, are excreted by living cells, are quite unstable to heat and consist of polypeptides. They are highly antigenic and result in high titers of antitoxin (antibodies) which can neutralize the toxin. Exotoxins can be rendered non-toxic and used in vaccines. Endotoxins are an integral part of the cell wall of gram-negative bacteria. They are liberated in soluble form during bacterial growth and death. Endotoxins are strong immunological adjuvants and induce macrophages to release potent fever-inducing cytokines . Lipopolysaccharide is the most important component of endotoxin. The following sequence of immunological events usually accompany exposure of a host to endotoxin: inflammation, cytotoxicity, wasting, organ failure, irreversible shock and death.

Gastrointestinal Transmission

Fecal -oral transmission is the second most important route of transmission of viruses and the gastrointestinal tract is the second great portal of entry of infection with viruses. While there are some viruses that can infect cells of the oropharnyx, those that target cells of the gastrointestinal system must be swallowed, resist the low pH of the stomach, resist the emulsifying effects of the bile salts, and find susceptible cells along the length of the intestine. The target cells may be the epithelial cells of the intestinal mucosa or the intestinal lymphatics. Of course, with many viruses that enter via the gut, their ultimate targets are cells of the deeper organs , such as the liver (Hep A, B, C, D, etc.), nerves (poliovirus), etc. The major enteric transmitted viruses are rotaviruses (diarrheal diseases), noraviruses (gastroenteritis), poliovirus, Echoviruses (diarrhea, respiratory and other illnesses), coxsackievirus (diarrhea, meningitis) and others. Unlike the respiratory viruses, the enteroviruses rarely produce disease as a result of their local multiplication in the gastrointestinal tract - as stated earlier, they are after cells outside the GI tract.

Characteristics of organisms that transmit through the environment

For spread of infection a sufficient number of organisms must enter and survive transport through the environment. Resistance to heat, UV light, drying and chemical agents are important survival factors for bacteria in nature. Some organisms, like Vibrio cholerae can survive for months in water, others, like Bacillus anthracis form resistant spores. Any organism, and there are many, that can multiply in some environmental medium (water, food, soil, milk, plants, etc.) has a real survival advantage. The capacity to infect a nonhuman host, or be transferred through an insect vector, offers alternative pathways for the persistence, spread and survival of a microorganism in the environment.

Resistance is Rampant

From the beginning of the antibiotic era just after WWII, antibiotics were considered the "cure-all" microbial diseases. Indiscriminant use of antibiotics has been rampant since their initial discovery. Penicillin-containing drinks, mouthwashes and soaps were available over-the-counter during the 1940's. Many organisms that cause important diseases have become resistant to our best drugs. Chronic overuse and misuse of therapeutic chemicals in general have selected for bacteria, viruses and other microorganisms with multidrug resistance.

Gonorrhea

Gonorrhea is a prime example. It first became resistant to penicillin in the 1970s and to tetracycline in the 1980s. This organism even went so far as to evolve into a penicillinase-producing strain which actually destroyed penicillin directly.

Epidemiology of Lyme Disease

Had this lesson been learned by CDC, it might have prevented or limited the spread of Lyme disease 30 years later in the U.S. Lyme disease another evolutionary window into how ecological disturbances and increased contact between humans and animals that we described earlier for New England can shape the success of an emerging disease. Worse yet, a disease closely related to Lyme disease with a migrating rash and arthritic conditions, was reported sporadically in Europe throughout the last century. Lyme disease was virtually unknown in the U.S. about 25 years ago, then in 1975 several children in Lyme and East Haddam, Connecticut reported to a local physician with various complaints including pain , fever and neurological symptoms. a) This physician subsequently identified more than a dozen cases locally and reported it to the CDC. b) Since that time Lyme disease has swept throughout New England, especially along the coast, and the U.S. beyond. This event was foreseeable!!! a) For many years it has been known that certain species of ticks native to America serve as reservoirs and vectors for a group of organisms of the genus Borrelia, which is assumed to have evolved as a parasite of ticks. b) Birds, mammals and now humans have served as opportunistic hosts who serve to amplify the spread of the organism to ticks. c) These hosts are not essential for propagation of the disease agent in nature.

Genital Transmission

Herpes, CMV, HBV, HIV and rubella (German measles) may be present in the cervical secretions of an infected woman and can infect infants during birth or sex partners during intercourse. CMV, HBV, and HIV are present in the semen and can be transmitted during homosexual or heterosexual intercourse. HSV and HPV are transmitted from perigenital lesions during intercourse or from oral lesions to genital tissues or vice versa. Several types of HPV (principally 16 and 18) are associated with penile and cervical cancers

Inflammation

Host anti-bacterial forces are able to limit the spread of many bacteria and at the subepithelial level, three important defense mechanisms are called into play against bacterial invaders: 1) tissue fluids containing antibody 2) the cleansing action of the lymphatic system leading into the lymph nodes 3) macrophages in the tissues and neutrophils in the blood (ingestion and destruction of bacteria). Each of these mechanisms depends on the inflammatory response for its action (an attraction to and an influx in tissue sites invaded by bacteria).

Epidemiology of Infectious Disease

Humans smugly thought that, at least in the industrialized countries, we would put infectious disease on the "back burner". During the past 25 years we have not only seen the emergence of dozens of diseases new to humans, but the reemergence of a host of diseases that we thought we had "put to bed". The growing pool of immunocompromised people, the iv drug abusers, street people and alcoholics have created a breeding ground for new or uncommon, and old, once common diseases that simply needed a "weak link" to reach human kind. The inherent danger here is that in these immunologically weak people, there is no all-important immunological "backup" to provide the essential assistance to drugs in destroying the disease agent. a) Moreover, some of these populations are the exact ones that will refuse to complete a round of treatment with some of our best drugs, putting those drugs in harm's way for the development of drug resistance in disease agents.

African Borrelia

In Africa, Borrelia duttoni causes African relapsing fever, and ticks carrying this agent often feed on burrowing rodents. a) Remember that Borrelia is a parasite of ticks, that is its primary host. b) In fact the organism is transmitted among ticks by trans ovarian transmission. c) Rodents merely serve as a primary source of blood for the larval, nymphal and adult ticks but because of this role, rodents also serve as an epicenter for human Lyme disease. Borrelia duttoni has changed its character in a big way because humans routinely encroached on its territory. a) Today, in some areas of its range, man has supplanted the rodent as the primary source of blood for the ticks that carry B. duttoni and the cycle has changed to tick-man-tick. b) AND, it is less pathogenic in man now. When ticks enter a new ecosystem they have an opportunity to feed on a new host. a) For reasons we discussed earlier, when a new disease agent enters humans for the first time it may be quite virulent. b) Since humans are not an integral part of the biology of the disease agent, it does not have to be kind to the human host and are under little pressure to become less virulent. Perhaps eventually Lyme will follow the path of duttoni and go tick-human-tick which will then impose some constraints on Lyme to be gentler with its new - PRIMARY BLOOD SOURCE

Genetic Combinations

In a country like Mexico where there is a high background level of toxin-producing bacteria, such as toxigenic E. coli, these die-offs of normal bacterial flora make way for colonization by organisms such as E . Coli and other pathogens. This is particularly true when the pathogen is resistant to the antibiotic in question. a) In addition to the microecological disturbances wreaked by antibiotic usage, it also permits the surviving organisms to acquire new combinations and types of adaptations through exchange of genetic material. On a macroenvironmental level, a disturbance in the number or variety of intermediate or definitive hosts of a pathogen may suddenly allow a microbe to increase the number and variety of hosts it is able to infect. Disturbances that have impacted on humans in the past have pushed surviving humans to breed outside genetic enclaves or their reproductively isolated groups. This expansion of a previously isolated genetic population can lead to acquisition of new genetic combinations. This process has occurred in human populations and has had significant medical consequences.

Gut Pathogens

In all countries children account for the lion's share of enteric illnesses and they are estimated to kill 13,000 children/day in many parts of Asia, Africa and Latin America. As stated earlier, enterotoxigenic E. coli is the most important cause of travelers' diarrhea. Diarrhea is increased in specialized settings. Ex) the importance of nosocomial diarrhea is being increasingly recognized. Most nosocomial diarrhea is caused by Clostridium difficile and various species of Salmonella. In extended care facilities for the elderly, about 1/3rd of patients experience significant bouts of diarrhea each year.

Countermeasures for Antibiotic Resistance

In fact, immune selective pressure can explain the sudden emergence of potent new viral subtypes from a formerly stable population. Paradoxically, if immunity were to be relaxed altogether, it is possible that the virus would accumulate such a high load of mutations that it would be weakened. a) Theoretically, if one allowed the virus to stabilize and then introduced a clone of immunologically active cells specific for the virus we might get viral elimination. b) No one is suggesting that we should suppress immune response in someone infected with any of the RNA viruses, this is all hypothetical. However, using this same thinking, it might be possible to avoid emergence of antibiotic resistance in bacteria, by applying a strategy of alternating between intense and relaxed selective pressure by using different antibiotics with different targets. a) This is worth thinking about because, drugs used against viruses, bacteria and cancer cells support rapid evolutionary change. We must not forget the huge impact of chemotherapeutic agents on host evolution as well. a) Since the beginning of the antibiotic era and with the increase in usage of chemical treatments for viruses, bacteria and other diseases, we have shifted our own evolution from resistance to disease to a state of relaxation of that resistance!

Jungle Fever

In modern times many of the newly emerged diseases have followed in the wake of human disturbance of new ecosystems. a) Such events lead to human exposure to the pathogens of seldom encountered species of animals, which harbor their own species of disease agents, most of which cannot cross species lines. Example: Oropuche fever emerged from the jungles of the Amazon Basin where the virus had been circulating among isolated jungle animals via biting flies. a) The building of the Amazon Highway disrupted the Amazon ecosystem and the disease found man. As stated earlier, the tropical regions of the world enjoy floral and faunal diversity that is many times greater than the temperate zones of the world. When widespread ecosystem disruption is perpetrated for example, through extensive logging and farming operations, such as we have seen in parts of Africa, Asia, Central and South America, this opens man up to inclusion in the cycles of many new disease agents, and the creation of major epizootics in which humans can become involved. When we add into this picture massive human migration within and between countries in association with these major ecological disturbances, we see the stage set for disease disasters. a) Especially if they reach big human population centers.

Generational Changes in Disease Agents

In practice, selective pressures by antibiotics must occur over long periods of time in order to provide a genetic advantage to any antibiotic resistant organism. This is why the emergence of antibiotic resistance usually occurs after a long course of drug therapy, especially if the dose was suboptimal to eradicate all of the infection. Natural selection is a particularly powerful force in the case of microorganisms because constant selection pressures exerted generation after generation have a cumulative effect. When even slight variations in the environment are continuously present over time, they may favor one type over another to a barely perceptible degree - for example at the rate of 1 -2% per generation. Such an advantage is equivalent to leaving behind 101 survivors for every 100 of a competitor after each generation. a) Even this slight advantage accrues rapidly. If a constant 1-2% advantage is compounded from generation to generation, a previously subordinate type may become the dominant form in only 30 generations. a) In human terms this amounts to about 800 years, but with microorganisms it could be a matter of hours.

Alexander Fleming

In the U.S. alone, drug resistance costs $200 billion annually. The real danger here is that the emergence of drug resistant microorganisms has forever changed the very nature of infectious disease agents. In 1942, shortly after his discovery of penicillin, Sir Alexander Fleming stated that bacteria would undoubtedly become resistant to his new drug. Even before he made this statement, the first drug resistance emerged in Staphylococcus.

More Environment

Inadequate refrigeration or a lack of reliable sources of energy to run such conveniences, coupled with poor or no food inspection, lead to many food ‐borne outbreaks of infectious disease. Even in the temperate zones warm weather promotes the success of a long list of pathogens. a) For example, epidemics of legionnaires disease depend on a chain of warm weather events. b) These include appropriate temperature and humidity for the organism to grow in water or soil, the contamination of a water‐cooling tower or air conditioning system, and airborne carriage of the agent to a susceptible human population. c) These events usually occur in temperate zones during the months of July and August and often involve closed environments (hospital, institution, club. Etc.). In the temperate zones, the colder months coincide with school seasons and bring many people into close contact in a closed environment which promotes the spread of respiratory infections. Specific environmental settings may have a huge impact over disease occurrence and its clinical patterns. For example, in hospitals, certain types of skin, wound and urinary tract infections are common because of invasive procedures that offer unique opportunities for transmission to vulnerable sites on susceptible people.

Helicobacter pylori

Increasingly recognized as an important cause of gastritis, peptic ulcer disease and gastric cancer. This organism can be eliminated in 80-90% of infections by treatment with pepto-bismol and antibiotics, and now such treatment is routinely recommended for gastric ulcers

Localized Infections

Many bacterial infections produce disease through the cells with which they first come in contact. These cells are often in the skin or epithelial surfaces, and in some infections remain confined to these sites.

Epidemiology of Viral Diseases

Many of the factors that influence the epidemiology of bacterial diseases are also important in the epidemiology of viral diseases, as well as diseases caused by other classes of agents. We will briefly discuss some of the unique components in the epidemiology of viral diseases. I will first talk about the novel aspects of routes of transmission of viral diseases. As with bacteria many viruses have more than one route of transmission that they may employ. Unlike many of the bacteria, all viruses are intracellular parasites for all or much of their stay in the vertebrate host. The sequence of events in transmission of a virus involves release of the virus from the cell, exit of the virus from the body, transport through the environment in a viable form, and appropriate entry into a susceptible host.

Zoonoses

Many zoonoses are difficult to control without rigorous sentinel systems in place. In the U.S. we have such sentinel systems in place and operative at local, state and federal levels, so we are able to keep a close eye on disease activities in animal populations. However, the occasional outbreaks of plague, Hantavirus, Lyme and Ehrlichiosis, only to mention a few, indicates that these diseases are always out there and will break through in foci. In many other countries in the world, little or no control or warning of the presence and potential danger of zoonoses is operative.

Infections of the CNS

Meningitis is a pretty common clinical syndrome caused by bacteria, viruses, fungi and protozoa. The clues that suggest bacterial involvement are: a) neutrophils in the CSF, b) low CSF glucose and high CSF protein c) in about 75 % of cases, bacteria present in a gram-stained sample of CSF. The etiologic agents that will produce meningitis in different age groups will vary by geographic location, time of year and socioeconomic level. The age group experiencing the highest rates of meningitis range between one month and 2 years of age, but the causes of the disease vary according to age groups. a) For example, Group B Strep causes most of the meningitis in children <1 month of age; Hemophilus influenzae is the most important cause after 1 month of age. b) Neisseria meningitidis is third most important cause after 1 month of age; and Streptococcus pneumoniae came in third within this age.

Systemic Infections

Microorganisms that escape local host defenses and make it into the lymphatic and circulatory systems. As mentioned earlier, several bacteria are able to survive and even multiply within macrophages - a mobile cell that will help transport an organism all over the body. In other cases, such as in plague, the disease agent will multiply within the lymph node and spread via the lymphatics.

Food Supply

Milk and food must be protected against contamination at their source, during transport and storage and in their preparation for consumption. Our food supply in the U.S. is not as safe as it was before importation of foods from tropical areas of the developing world where standards for growing, handling, processing and storage are not as strong as ours. Supermarkets in the States are now selling food products from all over the world that have been imported rapidly and may be contaminated with pathogens. During some parts of the year, 75% of many fruits and vegetables that we consume are harvested outside the country and delivered within days of harvest to grocery stores and restaurants in the U.S. Irradiation of foods may provide a significant degree of protection from these hazards, but the public education will be necessary to acclimate them to this method of food treatment.

Arthropod Borne Infections

Mosquitoes, fleas, flies, ticks, mites, roaches and other insects may transmit viral infections. a) In some cases this is passive or mechanical transmission, that is the virus simply has to survive on in the insect and does not replicate. b) Or, it may be by active or biological transmission in which the virus reproduces in the insect's tissues. In passive transmission, there is usually no specificity in the association between the insect and the virus - polio and hepatitis A can be transmitted in this way. In mechanical transmission, from the blood or tissue fluids of a vertebrate host usually during viremia and the virus multiples in the insect - Yellow fever, Dengue, the encephalitis viruses, etc.

Campylobacter jejuni

Most common cause of inflammatory diarrhea in developed countries.

Opportunism

Most disease causing agents are highly opportunistic in nature and can fill an open niche with billions of descendants in very short order. This dreaded circumstance occurs in the course of human disease usually when the immune system is severely suppressed. In fact, opportunistic characteristics of microorganisms often underlie therapeutic failure. a) This is especially true for some viruses that have the capacity for both rapid expansion and high genetic mutability. A good example of this type of organisms is the flu virus which has proven to be one of the most evolutionarily adept organisms. The flu virus has been responsible for recurring epidemics throughout history. a) One of the most impressive modern day examples of this is the Spanish Flu which occurred as a pandemic during and shortly after WWI, killing an estimated 40 million people worldwide. Unlike infections with relatively stable viruses like measles or mumps, exposure to the flu does not always confer virus-specific immunity on its hosts. a) As a result , the highly mutable flu virus does not have to wait for a whole new generation of uninfected children to find a susceptible host.

Nosocomial Infections

Multiple STD's are common in both sexes. a) The changing nature of and the increase in STDs have several causes: use of contraceptive measures other than the condom, changing practices in homosexual and heterosexual activities, the importation of new infections and strains from other parts of the world, and increased public confidence in the effectiveness and availability of antibiotic therapy. Nosocomial Infections a) These are infections acquired after admission to a hospital. b) Over 2 million patients annually develop nosocomial infections in the U.S. - c) one can only imagine what this number might be in hospitals in developing countries. These infections in the U.S. contributed on average to 4 additional days in the hospital and resulted in roughly 80,000 deaths. In order of decreasing significance, the sites of infection were: the urinary tract, pneumonias, surgical wound and bloodstream infections. E. coli, Staph aureus, Enterobacter, Pseudomonas and Enterococcus were the most common pathogens involved and most of these showed some degree of natural resistance to antibiotics, or showed a high potential for developing such resistance.

Innate Immunity

Non-specific aspects of immunity in which the immune response reacts to all foreign antigens with more or less equal vigor. But, innate immunity differs from acquired immunity both quantitatively and qualitatively. The non-specific immune response we call innate immunity consists of a variety of weapons, prominently including: macrophages and some of their cytokines, neutrophils, complement, natural killer cells, eosinophils and others.

Occupation

Occupational risks involve special types of exposures in certain occupations. We gave several examples earlier during the semester in our discussion of the general principles of epidemiology. Examples: Humans who work with animals or animal carcasses are at increased risk of infection with brucellosis, anthrax, tularemia, leptospirosis, rabies, etc. Those who work in hospitals are at increased risk for exposure to HIV, hepatitis, and other diseases. Those working in the day care centers or in institutional settings involving children are at increased risk for infection with a long lost of diseases. Those working in outdoor settings are at increased risk for infection with vector borne diseases.

Flu Variation

Of course as we have mentioned several times during the semester, the most dramatic genetic changes in the flu viruses occur most frequently in China, where avian strains of the flu in domestic ducks infect nearby pigs and then the people in contact with them. a) When such genetic reorganizations occur in the Type A flu, as they did in 1957, 1968, 1977 and 1993, the resulting flu strains cause widespread disease throughout the world. The reasons for the great success of these major genetic changes in the flu viruses pivots on the ability of the variant flu strains to infect previously infected as well as uninfected hosts. The more radically altered flu strains have a selective advantage over previous strains that left behind thousands of immunized and resistant hosts. In this situation, the antiviral forces of the human immune system are pitted against the rate of genetic change of the virus. a) Modern biomedical sciences has tipped the balance in favor of man with annually updated vaccines against the current flu strains and with surveillance for the emergence of any new strains.

Conducting the Study

On the basis of this Preliminary Assessment, the hypothesis was formulated that this was a food borne outbreak due to an agent with an average incubation period of 14 hours that was present in or introduced into one or more of the food items served exclusively in the three dining halls where students became ill. For a more intensive investigation, questionnaires concerning foods eaten, time of onset, and the clinical symptoms were distributed to both well and sick students who ate in the three dining halls in question. These questionnaires were returned by 366 ill students and 740 well students, representing all of the ill and 2/3rds of the well students. The clinical data revealed that the illness lasted less than 24 hours and was characterized mainly by diarrhea and abdominal cramps. Nausea and vomiting were rare. The average incubation period was too long for a staphylococcal enterotoxin, and the clinical features did not fit a Shigella or a Salmonella infection.

Variation in Tissue Target

On the other hand, other diseases, such as: Lyme disease, tuberculosis, syphilis and others may involve different tissues or organs in different persons, resulting in both qualitative and quantitative variation - the appearance of different clinical presentations in different people.

Bacterial Challenge

On the other hand, severe systemic manifestations may accompany the presence of large numbers of bacteria in the blood, a condition which is called septicemia. Bacteria in the blood may succeed in establishing foci of infections wherever the blood flow is slow enough, or they may multiply in sites previously damaged by prior disease or injury. Examples: a) Streptococcus viridins establishing an infection on abnormal heart valves producing acute bacterial endocarditis, or b) The establishment of sites of infection by Staphylococcus in the long bones of children leading to osteomyelitis. Some bacterial infections may spread via the blood to the skin leading to a rash. In many of these cases the organisms are invading endothelial cells lining the fine capillaries which leads to hemorrhaging under the skin. a) A condition commonly seen in some of the rickettsial diseases like Lyme disease (target rash) and RMSF. Some organisms like syphilis (secondary stage of the disease) leaves the blood vessels and multiplies in the extravascular tissues which results in highly infectious lesions that discharge to the exterior.

Characteristics of organisms that produce infection

Once an organism has survived transport through the environment, several bacterial characteristics are important in the initiation and development of infection. One of these characteristics is infectiousness, which can be simply expressed as a ratio: the number of infected ÷ the number of susceptible and exposed. A second characteristic is pathogenicity, which can be expressed as: the number of diseased ÷ the number of infected. The pathogenic process is quite complex and can itself involve a number of key factors. For example: adherence to host surfaces is highly specific and important in development of infection with a variety of organisms. a) Epithelial surfaces provide such sites for many bacteria. b) Hemophilus influenzae attaches to the respiratory epithelium. c) Neisseria gonorrheae attaches to the urethral epithelium. d) Salmonella. Shigella and E. coli attach to the intestinal epithelium.

Infection vs Disease

Once infection has occurred, a number of factors influence whether clinical disease will develop and contribute to its severity. Many of these factors are intrinsic to the host, but several pathogen factors will also contribute to this picture (virulence, portal of entry, antibiotic resistance, etc.). For example, entry points that are close to vital organs or that permit access to the blood stream may result in more severe or complicated infections. a) If we step back and look at all of the host factors that play a role in this process, we can pigeon hole them into three major groupings: 1) those that lead to exposure 2) those that lead to infection among those effectively exposed 3) those that lead to clinical disease among those infected.

More on Immune Response

One key requirement for the evolution of multicellular life forms was the development of methods for assuring the recognition and integrity of "self". In the absence of the ability to recognize and destroy foreign cells, multicellularity could not have succeeded as a strategy. The mammalian immune system is the most sophisticated and effective antimicrobial defense system in nature and represents the culmination of >2 billion years of evolutionary refinement of the methods for discriminating "self" from "non-self". Defense against microorganisms takes place at several levels in mammals. a) In addition to immunity, resistance is the collection of physical (skin and mucous membranes) and chemical barriers (skin pH and lysozyme in saliva and tears) to invasion of the body by pathogens. As stated earlier in the semester, immunity is generally divided into Innate and Acquired immunity

Staphylococcus

One of the genetically flexible organisms turned out to be Staphylococcus. a) Because it is a normal inhabitant of human skin and nasal mucosae it had ample opportunity to rapidly evolve novel mechanisms of antibiotic resistance and quickly did so as fast as the pharmaceutical industry could come up with new drugs. This was fueled by gross overuse and improper use of antibiotics as well as a failure for laboratory support needed to detect antibiotic resistance Methicillin‐ resistant Staphylococcus aureus (MRSA) is a cause of staph infection that is difficult to treat because of resistance to some antibiotics. Staph infections— including those caused by MRSA—can spread in hospitals, other healthcare facilities, and in the community where you live, work, and go to school

Respiratory Route

Organisms infecting via the respiratory route are airborne in droplet nuclei. The source of organisms released into the environment and traveling by air are released from the surfaces of the oropharyngeal and respiratory surfaces of humans; infected lesions of the skin Animals and inanimate objects such as water-cooling towers as in the case of Legionnaires' disease.

Prehistoric Disease Events

Paleolithic crossings of the Bering Strait by immigrants from Asia led to the formation of groups such as the Eskimos and Native Americans, as well as the South American Indian populations, all of whom show many unusual adaptations. The Eskimos for example carry extra insulating fat to sustain them over periods of starvation and to protect them against the cold, thickened eyelids to reduce snow glare and protect against the wind -driven snow, thickly padded cheek bones for insulation and a reduced genetic variability that leads to the development of autoimmune diseases like diabetes. Adaptations that provided an advantage during periods of human prehistory, may confer little or no advantage or even disadvantage in holders of these traits today. Up to this point we have discussed evolution as it proceeds primarily in a direction that favors individuals. a) But negative selection is equally important. Negative selection explains the elimination of antibiotic-sensitive bacteria in the gut during antibiotic treatment.

Invasiveness

Pathogenic microorgansims must immunoevade and, as stated earlier, the array of immunoevasive strategies employed by disease agents would boggle the mind. Toxins and extracellular proteins are important to the ability of some disease agents to establish infection and spread through the host's tissues. A wide variety of proteolytic enzymes are employed by microorganisms to spread through the tissues. These kinds of properties provide strong support to the invasiveness of a disease agent.

More Kid Afflictions

Pneumonia is the 6th most common cause of death in the U.S.. Under 6 months of age about 30% are caused by Chlamydial infections acquired often from the mother during birth. In older adults, most pneumonias are bacterial in origin with Streptococcus pneumoniae causing between 50 and 90% of these illnesses

More Risks

Pregnancy represents a special risk situation in which periods of immunosuppression occur during the late fetal and lactational periods. Differences between the sexes in portal of entry of microorganisms may result in different patterns of infection and disease. For example: There is a much greater risk among male homosexuals who practice passive anal intercourse for infection with HIV. a) Females are on average at greater risk for infection than males from a single act of unprotected intercourse with a male partner infected with a sexually transmitted disease. b) This includes HIV

Risks

Race doesn't usually influence infection as long as exposure is equal. a) Exceptions would include the decreased mortality and morbidity seen in blacks compared to whites with respect to malaria, and the increased severity of tuberculosis in blacks compared to whites. Socioeconomic status of the individual or the community affects the frequency, nature and age at which infectious diseases attack. a) In developing countries and low socioeconomic settings, infectious diseases, particularly respiratory and enteric pathogens are a leading cause of morbidity and mortality. b) Socioeconomic status influences infection and disease through a complex interaction of factors such as personal and environmental hygiene, nutritional status, crowding and exposure to animal reservoirs and insect vectors Travel is an increasingly important risk factor bringing people into dangerous new settings, especially in tropical and developing countries. A wide variety of bacterial, helminth, viral and protozoal enteric infections are common hazards encountered by travelers. a) Enterotoxigenic E. coli is the most common cause of enteric upset and accounted for 42% of all diarrheal episodes in travelers to Latin America, 36% in Africa and 25% in Asia.

Intestinal Infections

Regarding intestinal infections and foodborne poisons: a) While viruses are the major cause of food and waterborne outbreaks world wide, within the U.S., evaluating 3000 outbreaks of known etiology, the CDC found 66% were caused by bacteria, 25% chemicals, and only 5% viruses. The major players among the bacteria were: a) Salmonella (45%), b) Staphylococcus aureus (14%), c) Shigella (12%), d) Clostridium perfringens (10%) and e) Clostridium botulinum (8%). We must keep in mind that foodborne outbreaks are GREATLY underreported. The causes of enteric infections vary with age and geographic region and keep in mind that enteric infections are second, if not equal to, respiratory infections in commonality. In developed countries it has been estimated that the incidence of enteric infections is 1-3 enteric illnesses/year/person, while in developing countries the average is 5-18 enteric illnesses/year/person.

Breaking an Outbreak

Remember, an epidemic is deemed to have taken place if the number of cases of the disease exceeds that which is expected for a given population in a given geographic region. At the start of an infectious disease outbreak, a clinical or epidemiological definition of a case of the disease is usually required until the agent is isolated and identified and accurate/reliable immunodiagnostic or other methods for identifying those who are infected is developed. Examples of this approach were seen with AIDS, Legionnaire's disease, Hanatvirus, West Nile and toxic shock syndrome as well as others. Here is why it is important for diseases to reportable a) If a disease is not reportable, it may be difficult to know whether or not we are dealing with an epidemic!

Respiratory Transmission

Respiratory transmitted bacterial infections are the most difficult to control Particle size is one of the most important considerations, since particles larger than 5 μm in diameter are usually filtered out in the nose, while smaller particles are deposited on the mucosal surfaces of the upper and lower respiratory tract. Again keep in mind that respiratory infections are he most difficult diseases to prevent

Tissue Damage

Results from the direct action of the bacteria, their toxins, indirect injury, inflammation or immunological process of some kind.

Transmission by Insect Vectors

Rocky Mountain Spotted fever (RMSF) is transmitted by the bite of a tick, which may remain infective for long periods of time. Moreover, the infection is maintained in nature by transovarian transmission from mother to offspring. The transmission of bubonic plague in the sylvatic cycle is through the rat flea (Xenosylla cheopis) between infected wild rodents. Borrelia burgdorferi, the causative agent of Lyme disease and Ehrlichia chaffiensis , the causative agent of Ehrlichiosis, both of which are transmitted by ticks, are serious causes of human disease. RMSF has been replaced by Borrelia burgdorferi as the most common cause of tick-borne illness in the U.S

Scientists Warned Us

Scientists have been warning us for decades about the consequences of uncontrolled human reproduction. Unlike other species of animals on the planet, man DOES foul his own nest and has a devastating impact on this planet. We have mentioned earlier some of the reasons we have chosen to ignore these warnings, and now we are facing the consequences -DISEASES, DISEASES AND MORE DISEASES. As was stated earlier, Mother Nature always controls animal populations by KILLING OFF THE EXCESS WITH DISEASE. We are not immune to that process!!!

Pepto-Bismol

Similar studies were conducted in Madagascar with strains of Shigella and showed a similar situation to that seen in Venezuela, with a vast majority of the Shigella strains multiply resistant to antibiotics and showing increased morbidity and mortality. All too often, the solution for diarrheal diseases, especially when they occurred in developed countries, is the administration of more antibiotics. In places like Mexico, Brazil and other developing countries, citizens can purchase any antibiotic over the counter and often totally screw up the dosage or duration which promotes antibiotic resistance. a) To add to the problem, physicians in developed countries give travelers to developing countries, antibiotics as a preventive for control of diarrheal diseases. Of course routine prophylactic use of antibiotics can reduce the attack rate for diarrheal disease in travelers, BUT AT WHAT PRICE! One very serious negative impact is on the local inhabitants. a) While travelers may be protected from infection, they put native populations at serious risk of acquiring infections with organisms that have acquired multi-antibiotic resistant genes from organisms in antibiotic using tourists. A simpler and less dangerous solution is to take Pepto Bismol as a prophylactic which has been shown to provide 65% protection to traveler's diarrhea without inducing drug resistance.

Secondary Spread

Sometimes the epidemic curve of a common source outbreak will be altered because of secondary spread (person-to-person - E. coli, Shigella, Cyrptosporidium in day care settings, etc.).

Vietnam War and Plague

The Vietnam war provides a more modern example of the relationship between ecosystem disruption and the spread of disease. Wars in general cause massive ecosystem disruption. The Vietnam war was associated with the spread of many infectious diseases, including cholera and dysentery. Ecosystem disruption during the Vietnam war was on a massive scale, creating the exact conditions that it has been hypothesized would lead to the emergence of new diseases and the spread of old ones. Plague had been present in Vietnam at low levels in a sylvatic reservoir for hundreds of years. The large scale destruction caused by the war forced a variety of rodent species into contact with the plague bacillus, many of which had previously been free of this disease. One of the first signs that plague had been integrated into the ecosystem was the discovery of scout and tracker dogs of the military. New human outbreaks of the plague were being reported in Vietnam as early as 1962. a) Major outbreaks began to occur in isolated areas that had historically been plague-free. b) The disease continued to spread in 1965 and 1966, but it was not until 1968 that the U.S. medical community was alerted to the problem.

Direct Contact Transmission

The agent is transmitted directly from an infected human or animal to a susceptible host. Examples: Sexually transmitted diseases or those such as Tularemia acquired from direct contact with an infected animal.

Indirect Contact Transmission

The agent moves from the source to the susceptible host by means of an inanimate object. Droplet transmitted agents are enclosed in large droplets that travel about three feet through the air before they contaminate the mucous membranes of a susceptible host or fall to a horizontal surface. Bacterial infections of the skin are usually transmitted person to person from an infected lesion. a) They are commonly due to staph or strep or a combination of the two. They are manifested as boils, ulcers and other types of skin lesions, and are most common in warm tropical climates and in settings of poor personal hygiene. b) Yaws (Treponema pertenue) is an example of a bacterial pathogen that uses this strategy for transmission

Environment

The environment contains all of the necessary components for transmission such as air, water, food, reservoirs, vectors and hosts. Through climatic elements the environment influences exposure of the host to infection. Warm weather and tropical conditions in the developing regions of the world promote occupational and recreational exposures to water, sewage, swimming pools, wild animals and insects; they promote skin infections in unclothed persons. Many organisms grow and survive better in warmer climates , especially many of the enteric organisms. So, coupled with much poorer environmental, food, water and personal hygiene, it is not surprising that we see high numbers of intestinal infections in tropical regions.

Patterns of Host Response

The epidemiologist must study not only the clinically ill, but the full range of possible host responses that follow infection. These can range through a gradient from inapparent infection to severe illness to death. a) You will recall from an earlier discussion that this is called the Biological Gradient. b) The biological gradient can be compared to an iceberg, with the largest share of biological responses submerged beneath the surface of the water in the form of subclinical infections. Many of the host and agent factors that we discussed earlier in relation to determination of infection and disease will help determine a host's status in the biological gradient. It is important to keep in mind that the host can show quantitative and qualitative differences in response to the same bacterial infection and these qualitative responses are manifested by different clinical syndromes. Many bacterial diseases such as anthrax, cholera, diphtheria leprosy and others present with fairly characteristic clinical features that vary quantitatively but not qualitatively

The Culprit

The evidence incriminating a food is usually based on the greatest difference in percentage ill between those who ate and those who did not eat a particular food. In this outbreak, 70% of those who ate beef with gravy became ill, compared to 5% who did not eat this item who became ill. Furthermore, no one who ate beef without gravy became ill, thus incriminating the gravy as the likely source. Unfortunately, all of the gravy, except that which had remained refrigerated, had been discarded. Moreover, nothing grew in bacteriological culture of the gravy that had remained refrigerated. However, stool samples from over 90% of the ill students tested positive for heat-resistant Clostridium perfringens. a) One out of 24 of the food handlers was also positive for this bacterium. No stools from healthy students who had not eaten beef with gravy were positive. It was learned that 27 gallons of bone beef stock had been kept overnight in the refrigerator in 9 gallon plastic bags, mixed with 7 gallons of fish beef stock the next day, heated to a rolling boil, and served separately from the roast beef. Apparently heating items in this large a volume prevented homogeneous high temperature and the allowed the organisms to grow.

Viral Adaptability

The evolutionary reality of rapid viral evolution such as that seen among the RNA viruses, is bleak for our side. For some viruses, the rate of evolution seems to almost always defeat the immune system. Populations of RNA viruses like HIV and flu, actually have a maximally tolerable rate of mutation! a) That is, their rates of genetic change from generation to generation are so great that it is right on the edge of virus survival. Another example of viral adaptability is the Hepatitis B or C virus which cause a highly variable inflammation of the liver against which the patient develops antibodies. a) As the disease progresses, so does the virus. b) A typical patient experiences swings in symptoms from extreme debilitation to partial recovery, while the virus undergoes a parallel set of changes. As many as three different forms of the virus can be produced in a single patient, each evolving at a different rate. a) As a patients symptoms move from severe to grave, the more virulent form of the virus is isolated. The Hep virus hits the host with a mixture of viruses that keep ahead of host defenses and the best adapted one is selected for in the chronic stage of the disease.

Evolution of Disease Agents

The fact is that major epidemics have been documented following every major human migration, war or revolution. a) When you couple these events with new waves of commerce and exploration, local epidemics can quickly become major pandemics, like HIV. Evolutionary theory states that organisms that have evolved together exist in a state of dynamic equilibrium. a) When this equilibrium is disturbed, one or more of these species may undergo a shift in population and changes in their relationships with other species in the ecosystem. Much of the farmland of New England, once forests, has remained uncultivated for many decades, and has gradually returned to the previous wooded state. a) In fact, more of New England is now forested than has been the case since Colonial times. These "new" forests lack their original checks and balances among forest species, and many humans live in close proximity to these forests. In the transitional stage between farmland and forest, a number of species have expanded or contracted as their habitats changed. a) For example - new areas of weedy grasses and shrubs provided superb habitat for rodents. One of the key factors missing in this situation is the large predatory species that used to keep rodent populations in check, have been wiped out by man.

The Family

The family unit also provides an important setting for exposure and spread of infectious diseases - the genetic background as well as nutritional habits play a key role here. Cultural and behavioral patterns as well as the level of hygiene within families create fertile ground for exposure. The number and age of family members and the degree of crowding within the home will affect the transmissibility of infection.

Fecal-Oral Transmission

The fecal-oral route of infection is a close rival in frequency to respiratory spread and there are many sources of infection. Bacteria from diseased persons or carriers exit via the gastrointestinal tract into the macroenvironment and are transmitted from there to humans via water, food or direct contact. a) These organisms constitute a major group of bacterial infections. The mouth is the most common portal of entry. Some enteric infections involve only a human to human cycle such as typhoid fever and cholera. Others, such as salmonellosis, campylobacteriosis and yersiniosis involve animal reservoirs. a) This group of organisms cause what are referred to as the enteric fevers

Routes

The site of deposition of a virus-containing aerosol particle within the respiratory tree may not be the site with the highest concentration of susceptible cells, but in general, the number of virus particles needed to establish an infection is less than that required of any other type of organism. For example: with adenoviruses, as few as 7 viruses is sufficient to establish infection in the respiratory tree - adenoviruses invade primarily cells of the respiratory, gastrointestinal tract and the conjunctiva. The very low doses also required for infection by the nasal route for rhinoviruses (most important cause of the common cold) and coxsackieviruses (belongs to the large group of viruses called the enteroviruses that cause common colds, meningitis, myocarditis, rashes, pneumonia, etc.) indicates that the nose may be the primary route for infection of man with these two virus groups in their causation of the cold. With many of these viruses, hands are one of the most important modes of transmission to the nose, eyes or mouth. In one study of respiratory - transmitted viruses, the average sneeze contained around 2 million viruses while the average cough contained 100,000 viruses.

Skin

The skin is the third most important site of entry and escape of viral infections. Penetration of intact skin is unlikely, but may be accomplished by animal bites (rabies) or by needle stick or blood transfusion (Hep viruses, CMV, EBV, HTLV-I & II and HIV 1 & 2). Abraded skin can serve as a entry point for some viruses, such as those that cause warts. The skin serves as a portal of exit for those viruses that cause skin vesicles or pox lesions from which the viruses are shed - herpes, smallpox. Chickenpox, HPV, etc.

Acquired Immunity (Antigen-Specific Immunity)

The third component of vertebrate immunity is antigen-specific immunity (tailored to respond specifically to the antigens of the pathogen mounting the attack) also known as, acquired immunity. This component of immune response is unique to vertebrates. Orchestrated by the lymphocytes, acquired immunity recognizes antigen in a highly specific fashion. Only the subset of lymphocytes which recognizes and engages the specific antigen (and no other) will expand and organize a complex sequence of immunological reactions to destroy the antigen and the organism that expresses it. Such reactions include antigen specific antibody production in several forms.

Animal Reservoirs

The truth be known, many of the most important diseases that have afflicted humans have probably arisen in small ecosystems where they had little impact on the morbidity and mortality of the animals they infected within that small ecosystem. a) A classic example is the Tick Borne Bitterroot Fever, which was confined to ticks and their rodent hosts in a tiny valley in Wyoming. b) It became an important tick borne disease of humans with the first migration of human settlers, after which it spread around the Western U.S. with human migration. The tropics provide many more examples: Argentine hemorrhagic fever (20% mortality in man) was originally confined to wild mouse populations in Argentina. a) When man began to store massive amounts of corn in the 1930s and 1940s, man came in contact with these and other rodents and with the disease agents they carried. b) AHF appeared suddenly in the human population and now infects 1000's of people each year in association with rodent population explosions. African Hemorrhagic Fever (EBOLA - 50 to >90% mortality) was associated with wild mammals and made the jump to man after human contacts increased through human encroachment on virgin ecosystems. a) Because the virus killed humans so fast and in such great numbers it burned itself out each time it arose, but it is still waiting in the wings

Rats Rule

There are many examples of how great an impact major human migration can have on disease success. a) Look for example at the huge bubonic plague outbreaks of the past, or the dissemination of measles and smallpox among the native inhabitants of the South Pacific, Greenland and the Americas. Whenever an ecological disturbance occurs, the species that are best at surviving are those that are most flexible. a) This includes those that live off of others for food and shelter, or those that show great adaptability to diverse habitats and food sources. b) The organisms that are best in this regard are rodents, birds and insects. While populations of larger organisms like primates and ungulates may crash, this leaves man living with rodents, birds and arthropods. a) Rodents have their own collection of diseases with potential for infecting man, and arthropods that can transmit new diseases to and among humans. b) Moreover, this situation places man in the position of being the next best large host for the arthropods and disease agents that have evolved within this ecosystem. c) Probably both HIV and malaria were exposed to and adapted to humans in this manner.

Our Drugs Are Failing

There is ample evidence of the emergence of drug resistance among some of our most formidable microbial adversaries. Infectious diseases have been the major killers of human kind over the last several thousand years. On a global basis, they are still the number one cause of human mortality. Many infectious diseases, particularly those that kill humans before they reach reproductive age, have had a strong impact on human evolution. a) But recently, mankind has had an enormous impact on the evolution of microorganisms via the use of chemical controls.

Pathogen Selection

These cases show that many old and some new disease agents have acquired a very broad resistance to antimicrobials. A lion's share of this type of evolution among disease agents is occurring among patients whose immune systems are compromised by old age, alcoholism and drug abuse or diseases such as AIDS. It is quite clear that the main cause for emergence of drug resistance in disease agents is ignorance of evolutionary mechanisms and potential. REMEMBER: When drug resistance is present in a disease agent that infects a human and you give the drug or drugs to which this agent is resistant, you will kill off all of the normal flora of the gut which are not resistant to this drug and effectively remove one of the most important forces designed to keep disease agents in check - the competing natural flora of the gut. Because of this, one often encounters a worsening of a disease when one applies antibiotics to kill a resistant pathogen. An additional danger here is that if the agent is allowed to reach its full pathologic potential, we run the risk of selecting for more pathogenic members of the population and often we will see an increase in its infectiousness and pathogenicity as it passes to others

Perinatal Transmission

These infections occur at the time of childbirth. In congenital infections the organism is transmitted vertically from an infected mother via the placenta to the fetus. a) Congenital syphilis, measles and toxoplasmosis are examples. Infections may occur horizontally from an infected cervix or uterus as the child passes through the birth canal. a) Examples would be gonococcal ophthalmia, herpes and chlamydial infections. Infections may be acquired immediately after birth, as in tetanus neonatorum due to contamination of the cut umbilical cord by soil or a contaminated substance applied to the umbilical stump.

Exotic Organisms

These numbers make it clear how a massive revolution can take place in microorganisms that occupy the body under a protracted series of antibiotic treatments. When a patient is prescribed a broad-spectrum antibiotic to treat an infection, the natural flora and fauna of the body are killed off wholesale, followed by rapid recolonization by new bacterial and fungal survivors. a) This leads to overgrowth of yeasts, fungi and harmful bacteria. In these cases, the exotic organisms may have been held in check by natural competition with the native organism occupying the body. a) A very common example of this are the vaginal yeast infections experienced by most women when they take antibiotics, go on birth control pills, experience an emotional upset, etc. - Candidia albicans . In fact, antibiotic usage is so prevalent, and such a common cause of vaginal yeast infections that it has produced a large secondary market for douches, over-the-counter antifungals and other female products for use in response to these disruptions of the vaginal ecosystem.

Typhoid Fever

Typhoid fever is a life ‐threatening illness caused by the bacterium Salmonella Typhi. Not common in the United States, Canada, Western Europe, Australia, or Japan, but it is common in many other countries. An estimated 22 million people worldwide each year. In the United States, about 350 people are diagnosed with typhoid fever each year, most often after traveling outside of the United States to countries such as India, Bangladesh, and Pakistan.

Deadly Carrier

They first administered two powerful antibiotics with no clinical improvement. a) They then hit her with two different antibiotics to which she appeared to respond and the Serratia was cleared from her blood. Six days later, up came the Serratia in her blood again, but this time in a mutated form. This time the organism was resistant to all but one of the antibiotics tested. Try as they might, they could not defeat the organism even with this antibiotic because the patient was experiencing severe renal failure and they had to keep backing off on the drug. a) The patient died 4 days later. In 1983, dozens of previously healthy youngsters in a community of native Americans on a reservation in the Four Corners area of the Southwest became ill with a bloody diarrheal disease which was remarkably resistant to antibiotics. The source of the outbreak was traced to an adult patient who had been chronically treated with antibiotics in the hope of reducing the risk of recurrent urinary tract infection. Her intestinal bacteria slowly adapted to the persistent presence of the antibiotics with which she was treated and became resistant to these and related drugs. At some point, probably as a result of poor sanitation, her normal E. coli met with a Salmonella species and transferred the genetic information for antibiotic resistance to the Salmonella. a) This resulted in a large epidemic on the reservation that proved untreatable with standard antibiotics.

Rapid Expansion

This has been the basis for deaths in a number of outbreaks with E. coli 0157:H7, in which administration of antibiotics to which the E. coli 0157 was resistant led to a dramatic increase in the pathogenicity of the organism. When you put all of these ingredients together in a setting where human population density is high, sanitation poor, and where pre-existing antibiotic resistance abounds because of misuse and overuse of antibiotics, we see creation of an evolutionary nightmare. The misuse of antibiotics in poultry and cattle creates a similar situation that can pose great threat for epidemics among humans. Another feature of antibiotic resistant organisms is that they can expand rapidly. This was clearly demonstrated in a study in Venezuela where it was shown that in 1989 that the virulent form of toxigenic E. coli, the cause of 70% of "Traveler's diarrhea", had acquired multiple resistance to most standard antibiotics. a) This was found to be true of 84% of the Venezuelan strains of E. coli. b) The greatest concern that emerged from this study was that antibiotic resistance was contained in genetic material that carried both virulence and antibiotic resistance!

Acute Otitis Media - Inner Ear Infection

This is a very common infection in children with a peak at about 6 to 18 months. Initiation of infection is highest in the fall and winter. Family aggregation is very common. Accurate diagnosis requires aspiration of fluid from the middle ear. a) In one study bacterial antigen was isolated 66% from these aspirates with the most common bacterium isolated being Streptococcus pneumoniae while Hemophilus influenzae was second.

What Were the Circumstances?

This question is asked in two phases: 1) a preliminary assessment based on available data; and 2) a more intensive investigation when the situation is better defined.

Preliminary Assessment 2

To help in lab identification of infected and diseased persons, appropriate materials should be collected from patients (fecal, sputum, urine, whole blood for culture, diagnostic tests and chemical profiles, etc. a) For example: A higher level of antibodies to the disease agent in diseased versus unexposed persons implicates that agent in the epidemic. In addition, appropriate samples form the environment (water, food) and from vectors should be collected for immediate and later use in isolating the agent. These preliminary data obtained form the above actions will allow formulation of a hypothesis of transmission and will support recommendations for immediate control and isolation techniques needed

Risky Behavior

Travel or residence in endemic countries, exposes people to a wide variety of pathogens specific to the tropics, such as malaria, schistosomiasis, cholera, leishmaniasis, Chagas disease, etc. Even gardening in the back yard or walking in the woods at home can expose a person to Ehrlichiosis, Lyme, toxoplasmosis, cryptosporidiosis, and many others.

Sexually-Transmitted Diseases

Unlike urinary tract infections in younger women, which tends to be related to frequency of sexual intercourse and tends to be uncomplicated, in the elderly it is more difficult to treat and its pathogenesis is related to abnormal bladder function, bladder outlet obstruction, vaginal and urethral atrophy, use of long-term, indwelling catheters and puddling related to bed confinement. The spectrum of organisms causing infections relates to the ecology of the patient's environment: those residing in nursing homes, especially those with permanent catheters, tend to have a greater variety of pathogenic organisms, many of which may be antibiotic resistant. Sexually-transmitted Diseases- a) Chlamydia trachomatic infections are among the most commonly encoutered sexually-transmitted diseases. The infection rates have risen in 1984 from 3.2/100,000 to 183/100,000 in 1992 in the U.S. a) However, in our larger cities the infection rate has risen to 300/100,000 with an estimated 4 million new infections annually. b) Many of these cases are associated with pelvic inflammatory disease with serious consequences, such as ectopic pregnancy and infertility. Many of the sexually transmitted diseases operate in synergy with HIV infection and transmission of both are promoted by the presence of the other agent

Urinary Transmission

Urinary spread of infection is not common, but may occur with typhoid fever from an infected human and with leptospirosis from different animals. Urine contamination of water is a common mode of transmission among this group of organisms.

Dermal Transmission

Viruses transmitted fecal-orally rely on fecal contamination of hands, food, water, milk, flies, etc. This route of transmission is much easier to block than is the aerogenic route by employing frequent hand -washing; good personal hygiene; proper cleanliness, storage and preparation of food; pasteurization of milk; good waste disposal and purification of drinking water.

More on Incubation Period

We are quite familiar with the incubation periods for many bacterial diseases. Signs and symptoms due to preformed toxins usually occur within 36 hr after ingestion, sometimes as soon as 2-4 hr, as in diarrhea due to Staphylococcus toxin contamination of food. Travelers' diarrhea due to toxigenic E. coli has an incubation period of 12-72 hr. Pontiac fever, the term used to describe an acute fever disease due to Legionella pneumophila without the pulmonary phase (first identified in Pontiac, MI) has a peak incubation period of 36 hr compared with a peak incubation period for full blown Legionnaires disease of 5 days. In general, diseases due to direct involvement of epithelial surfaces have incubation periods under one week (Strep sore throat, bacterial pneumonias, shigellosis, cholera, gonorrhea, etc.).

Samples

Whether or not a causative agent can be identified, the key directive is to break the chain of transmission, and these data (even if they don't allow identification of the agent responsible), can usually be used to break the chain of transmission. It is also important to freeze up some of the serum and other samples from victims of the outbreak so that, even if you don't identify the agent now, these data can be used in the future to tie this outbreak to the agent when it is discovered in any future or when new lab techniques become available. These kinds of samples proved very helpful in identifying outbreaks caused by Legionnaires and hantavirus.

More STDs

While the overall trends in recent years have been downward for gonorrhea and syphilis, Adolescent women between the ages of 15 and 19 years, show a gonorrhea and syphilis rate three times that of the general population. a) This is a reflection of the greater amount of sexual activity within this group now compared to the past. In 1970, only 29% of women in this age group had experienced sexual intercourse, while by 1988, 52% had experienced sexual intercourse. The risk for STDs in general is greater for blacks than for whites, for example the rates of primary and secondary syphilis in blacks is 60-times that seen in whites and 40 times greater for gonorrhea. a) For Hispanics these rates are 5 and 3-fold higher respectively STDs in general are most common in the 18 to 30 age group because of greater sexual activity and more partners. a) They are more commonly diagnosed in men, both because men have more sexual partners and greater sexual activity

Intensive Study

With this kind of information gleaned from the preliminary study. a) One can now embark on an Intensive Study . b) The intensive study is designed to confirm or refute the hypotheses you have formulated in the preliminary study. The questionnaires for this phase should include all possible circumstances under which the epidemic occurred and be administered to those that are ill, to those exposed but not ill and to a comparable group neither exposed nor ill. Serum should be collected from all of these groups for antigen and antibody tests and the data from the completed questionnaires should be statistically analyzed for comparison of attack rates for these three groups and for any relationship between risk factors and the occurrence of disease.

Main Circumstances Under Which Epidemics Usually Occur

introduction into a new group of susceptibles into a setting where a disease is endemic; when a new source of infection is introduced into an area from which the agent has been absent for a long period of time (many susceptibles are now present); when effective contact is made between a preexisting disease agent of low endemicity and susceptible persons as a result of changes in social, sexual, behavioral or cultural practices; increased susceptibility of a population due to immunosuppression or other factors that impact on host response (viral infection, nutritional changes, presence of chronic disease, treatment with immunosuppressive drugs, etc.) increased virulence or dosage of microbial agent (massive outbreak of waterborne Cryptospordium infection in the north central U.S.