Exam 3

Less Pathogenic / Virulent

A comparison of HIV-1 and HIV-2 provides one test of this hypothesis. The most virulent form of HIV has evolved predominantly in East and Central Africa where social conditions foster rapid exchange of sexual partners and frequent sexual contacts. In contrast, on the West coast of Africa, where social conditions historically tend to be more stable and sexual standards more rigorous and adhered to, the more benign HIV-2 prevails. Moreover, within this HIV-2 belt we see an example of this same principle.

Crucibles

A long list of fecal-oral transmitted organisms have caused outbreaks in day care centers - e.g. E. coli, salmonella, crytosporidosis, giardiasis, amebiasis, Enterobius, HAV, Streptococcus, enteroviruses. Shigella, etc.- as well as many aerogenically transmitted and contact transmitted organisms - Haemophilus, head lice, etc. As stated earlier, these child-care centers are crucibles for development of epidemics of a variety of infectious diseases.

Tuberculosis

A look at tuberculosis provides insights into the forces that shape virulence in person-to-person transmission. Discovered more than 125 years ago, Mycobacterium tuberculosis, causative agent of tuberculosis, was considered the scourge of its time. By the turn of the century, TB has killed almost 1/4th of all Englishman and comparable numbers of people on the continent. Significant control was not exerted over this disease until the 1960s when streptomycin was discovered. a) The first of 11 antibiotics with anti-tubercular activity

Clean Water Hurts Cholera

A person suffering from cholera need only contaminate bedding or clothing that will be washed in a nearby stream to spread the disease. This same water will be used for cooking and washing foods. Thus, even after cholera patients are weak and bedridden, they can still infect others. Substitution of purified water selects for less virulent forms of the disease. A WHO study showed that heroic efforts to provide purified drinking water between the 1950s and 1960s in Africa supported the emergence of the less virulent form of the disease in Africa, the El Tor form which replaced a more virulent form that had been previously circulating in that region of the world (Classic Vibrio cholerae). But by the 1980s and 1990s water purity was again compromised and witnessed the emergence of the much more virulent 0139 form of cholera.

Opportunistic Infections

AIDS patients are generally overwhelmed by the unbridled growth of opportunistic infections. The organisms causing these infections also undergo rapid evolutionary changes during their explosive expansion in an immunologically compromised host. This produces strains of opportunistic organisms that are able to colonize immunologically compromised patients with greater efficiency. With these events continually occurring in AIS patients world wide, it is a no- brainer that opportunistic organisms will emerge eventually that will have the capacity to infect patients whose immune systems are impaired to a lesser degree. For example, Pneumocystis infections showing up in renal transplant patients who simply shared the same waiting room as AIDS patients.

S.E. Asia

After WWI, with the urbanization of S.E. Asia, Aedes aegypti thrived and dengue became hyperendemic in most of S.E. Asia. It was under these conditions that epidemic Dengue Hemorrhagic Fever (DHF -defined later) emerged in S.E. Asia. Dengue enjoyed great success in S.E. Asia during this period showing 3 times as many DHF cases in the most recent 9 years as were seen in the previous 30 years. Epidemic Dengue was seen in the Caribbean during WWII but then no Dengue outbreaks were seen in this region between 1946 and 1963.

Long Latency and Low Virulence

Among the disease agents that rely on person to person transmission and show limited viability outside their host, natural selection exerts pressure on them to have a long latency period and not cause life-threatening illness for a long time if ever. Organisms like leprosy with a long latent period preceding the appearance of full-blown disease, was among the most successful and prevalent human diseases. In theory, long latency and low virulence insures that a disease agent that cannot escape to the environment, has a chance to be transmitted before killing the host.

The Macrophage is Home Too

An example is a variant of HIV that has a predilection for replicating inside macrophages rather than CD4+ T helper cells. a) This has profound implications, it means that persons harboring this macrophage-infecting strain are high risk transmitters because macrophages are migratory and can show up in many places in the body in large numbers. Other features that HIV acquires via mutation can have equally devastating results. a) For example, patients whose HIV strains suddenly begin producing colonies of fused cells (syncytia) face a drastic acceleration of their downward clinical course and require much more aggressive therapy than do those infected with non-syncytial forming strains. In these hosts new opportunistic infections become much more common and resistance to such infections fades rapidly

It's Bad!

An ominous report form CDC should have warned us of this disastrous threat to public health. In 1982 and 1983, an outbreak of antibiotic-resistant TB swept through nurseries and schools in four western states. Other reports appeared in 1985 that showed that TB could not only mount resistance to Isoniazid (the standard drug of choice for treating TB) but also the drug Rifampin, a drug used prophylactically to protect children and adults. By 1993, at least half of all TB reported in New York showed single or multiple drug resistance.

Viral Variation

Another aspect of viral evolution is the genetic differences in the HIV strains seen between one individual and the partner whom they infected. For example in one study, a mother's HIV strain differed by almost 10% from that of her daughter who had been infected in her mother's uterus. This amount of variation carries significant immunological implications. If HIV can undergo evolutionary divergence from one person to their sex partner and from mother to child, it greatly reduces the likelihood of finding an immunological common denominator that will thwart transmission and subsequent infection. This of course impacts most greatly on the development of a vaccine, which is the Holy Grail of our anti-viral approach.

Multidrug Resistant TB

Antibiotic resistance is one of the biggest public health challenges of our time. 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). 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.

Arboviruses

Arboviruses cause a lot of encephalitis around the globe and are transmitted by specific species of mosquitoes and ticks. Moreover, these systems rely on specific ecological systems. Of course, as with any arthropod borne disease, transmission of these viruses is dependent on ambient temperature and therefore are limited to certain seasons in the temperate regions of the world. In tropical climes they can be transmitted throughout the year, although transmission in some regions may be elevated during the rainy season.

Cholera Pandemic

Areas in which poor hygiene prevails are especially promotive of this disease agent strategy, because as patients become sicker they constantly contaminate the water supply. Support for this idea comes from data that show a correlation between ease of water-borne transmission and lethality. Where pathogens that cause diarrheal diseases required person to person transmission, they were less virulent than those able to infect large numbers of people simultaneously via a common water system. We are in the midst of the most recent of many global pandemics caused by cholera, a rapidly debilitating and dehydrating diarrheal disease. Cholera, caused by a water-borne vibrio, occurs in four stages beginning with invasion.

Indiscriminate Sex

Around 1978, the bath houses of San Francisco and other major urban center in the U.S. served as epicenters for the establishment of the AIDS epidemic in America. The book and movie entitled "As the Band Played On" documents these events quite well. During the period from 1970 to 1983, the gay community in San Francisco was enjoying an unprecedented degree of sexual freedom. In the late 1970s it was not uncommon for a single, sexually active gay male to have unprotected sex with 10-30 partners a week, and as noted by the CDC reports on the subject, as many as 1000 partners a year!!!

Extreme Natural Selection

As the frequency of sexual contacts increased, yet to be discovered HIV was probably undergoing an extreme form of natural selection. Many scientists believe that had the bathhouses been closed, safe sex guidelines followed and contact-tracing programs pursued religiously at the first sign of the epidemic, many lives could have been saved and the epidemic in America would not have been nearly as bad. However, in the early years of the epidemic in America, resistance was strong to contact tracing on the grounds that the disease was not exclusively sexually transmitted and to protect civil rights. Leaving the bath houses open was part of the political agenda of a group that did not want to be singled out as the focus of a fatal disease

A New Agent is a Mean Agent

As we have seen back in Africa, similar primate viruses have been devastating routinely when man is caught up in their cycle. Such viruses are simply demonstrating one of the axioms of disease evolution - that many of the most virulent and lethal viral and bacterial illnesses are the newest ones to cross over to the human species. Most disease agents start out their association with a new host in a more or less highly virulent state. Often, but not always, as the host and pathogen adapt to each other the evolve toward diminished virulence and lowered pathogenicity. In some cases, one time disease agents may become commensals of tomorrow. This is not to suggest that commensals do not take a toll from the host. In fact, it can be readily demonstrated in germ-free chickens and mice that wiping out the normal intestinal flora yields significant weight gains and increased vitality compared to normal animals housing the usual complement of intestinal flora and fauna.

Ease of Transmission Leads to Virulence

As we stated earlier, if a virulent organism can proliferate and be transmitted before the host dies, there is no pressure for it to become less virulent. If selection favors the rapid movement of an organism from one host to another, it is also likely to encourage the genes for rapid growth and virulence (these two characteristics are often genetically connected). It appears that virulent pathogens solve their transmission problems by achieving such high concentrations in an infected host and have such high proliferative ability once inside a new host, that even minor contact or contamination is sufficient to transmit. This is particularly true when an insect vector or environmental vehicle such as water are the main routes of transmission. With these rules in mind we can now examine hospital infections. Most noscomial infections are characterized by high concentrations of microorganisms in the infected host, who now serve as reservoirs of disease. Coupled with a wide variety of transmission hosts, such as nurses, orderlies, janitors and physicians, a germ that establishes itself in the crowded conditions of an urban hospital can count on lots of help for its dissemination.

Spread Like Wildfire

As you can see from the map on the previous slide, prior to 1981, before the introduction of multiple serotypes of the virus into this hemisphere, there was no DHF in the Americas. a) After the introduction of other serotypes we see the rise of DHF throughout the tropics in this hemisphere. The large Cuban outbreak in 1981 included a substantial number of cases of DHF. a) That is because the epidemic was caused by DEN-2 which infected a population partially immune to DEN-1

Dengue Fever

At some point in the past with the clearing of the tropical forests of Asia and development of human settlements, dengue viruses moved out of the jungle and into rural environments. Here Dengue was transmitted to humans by peridomestic mosquitoes (Aedes aegypti and Aedes albopictus). Human migration and commerce moved the virus into villages, towns and cities of tropical Asia. On another front, the slave trade caused widespread distribution of the African mosquito (Aedes aegypti) into the New World during the 17th, 18th and 19th centuries. Today we see improved aviation and cargo ships brining new threats as well.

Uphill Battle

But again the treatment is likely to ineffectual without the immune system to "mop" up after the antibiotics, exerting a further selective force for survival of resistant tubercle bacilli. And so it continues, until the patient is a walking factory of highly infectious, highly resistant TB organisms. The next patient to get this infection, occasionally one of the medical personnel treating the patient, begins an uphill battle with great disadvantage.

Sweeping Across the Globe

By 1992, the cholera epidemic had reached 14 Latin American countries, affecting almost 400,000 people and causing 4,000 deaths. After the outbreak swept through S. America, it spread back to Africa where it had appeared in force 20 years earlier. In Africa, social upheavals created circumstances for the reemergence of cholera in the many refugee camps in which millions of people resided. As of Mid-1993, cholera was reported in 30 of the 46 African countries and had created hotspots in Mozambique, Malawi, Zimbabwe and Zambia. Another outbreak of cholera which began in Bangladesh in December of 1992, was sweeping Southeast Asia, and by March 1993 had infected 107,000 people with 1,500 deaths.

Tuberculosis Comes Back

By the end of the 1960s TB was considered a diminishing threat in the US has the number of cases fell to record lows. Within the last decade, TB has undergone a global resurgence. In 1990, more cases of TB were reported in the world than at any time in recorded history. WHO reported 8 million active cases and 2.9 million deaths worldwide, making TB the leading cause of death among all infectious diseases. Since 1985, TB has been growing at an exponential rate in the U.S., with 39,000 more cases between 1984 and 1990 than were predicted by CDC. By 1995, 27,000 people had active TB in the U.S., up 20% since 1985.

Caribbean Crisis

By the end of the decade many countries had been re-infested by the mosquito, a process that continued during the 80s and 90s until in 1995 it was reported that A. aegypti enjoyed a distribution similar to that seen in the 1940s before eradication began. While a type of Dengue called DEN-2 was already present in this area of the world, a new serotype (DEN-1) was introduced into the Caribbean in 1977 and over the next 4 years it caused major and minor epidemics in Cuba, Mexico, Jamaica, Venezuela, Central America and northern S. America. What had happened in S.E. Asia was also happening in this hemisphere, deforestation and increased movement of people.

50 STDs

Changing sexual behavior has increased dramatically the rate of infection with Chlamydia, which accounts for about 33% of all sexually transmitted diseases in the U.S. and is a major cause of PID. Chlamydia and AIDS are only 2 of the nearly 50 different STDs known, Clearly, prevention of transmission is the most important means of reducing the rate of infection and of reducing the virulence of these diseases

Climatic Changes

Climatic changes, such as the ones we are facing with global warming, will undoubtedly alter the distribution of vectors for a range of diseases, making perhaps malaria, dengue and other diseases able to survive and achieve endemicity in areas from which they are currently excluded. We all now know about West Nile virus and the fact that it made its debut into the Western hemisphere back in 1999 in new York City. a) This was indeed a new virus to the U.S.. b) This first outbreak appeared in August 1999 in the form of two patients with encephalitis who were seen by a physician who alerted the New York City Department of Health

DHF

Dengue hemorrhagic fever occurs when the patient contracts a different dengue virus after previous infection(s) by another type. a) Prior immunity to a different dengue virus type is important in the production of this severe disease and while recovery from infection by one provides lifelong immunity against that serotype, it confers only partial and transient protection against subsequent infection by the other three. DHF is a possible sequel to Dengue fever. a) This event occurs about the time that fever declines in the patient. b) DHF is associated with increased vascular permeability, hypovolemia (decrease in blood volume), elevated hematocrit (increase in packed RBCs upon spin down of the blood due to decreased blood volume) and hemorrhaging.

Aedes

Dengue viruses are transmitted form viremic patients (viruses in the blood) by most commonly Aedes aegypti and Aedes albopictus. Aedes aegypti bite during the day time and live and breed around human habitations. The movement of infected persons explains such important epidemiologic features such as spread along major highways and by ships and airplanes. a) Viruses spread where people travel during daytime hours - to neighbors houses, to the houses of relatives and to markets and schools.

Dengue in the US

Dengue wasn't always absent from the U.S. Short epidemics occurred in the U.S. over the past 200 years. During the 1700s we saw outbreaks in Philadelphia and in the 1800s epidemics were reported in Florida, Texas, Hawaii, Georgia and S. Carolina. a) Hardest hit were Houston, Galveston, New Orleans, Mobile, Vicksberg and Charleston. b) And in the 1900s, we saw outbreaks in Hawaii, Brownsville, Galveston, Houston, and in several parts of Florida and Georgia. The current Pandemic of Dengue began in the Asian and Pacific Theaters after WWII with war-related ecological disruption and demographic changes that resulted in increased transmission.

The Peru Runs

During the incubation period following invasion the patient typically has diarrhea, fever and headache. Without treatment the patient typically enters stage 2 and typically develops severe purging, vomiting and cramping. a) In the third and most severe stage, the patient may collapse systemically and die. One of the major outbreaks in the recent past began in Peru in 1991, largely as a result of social upheaval, poverty and the absence of a safe water supply

Emerging

Earlier we discussed a few of the group of diseases that are referred to as "Emerging Diseases". That list included: a) Dengue, of which there are currently an estimated 100,000,000 cases annually worldwide; b) Lyme disease, which has become the most important tick-borne disease in North America with around 35,000 cases per year; c) HIV which infects around 60,000,000 people worldwide with about 70% of which are located in sub-Saharan Africa and is associated with a long list of opportunistic infections such as those shown on the table on the next slide; and d) human monocytic Ehrlichiosis caused by Ehrlichia chaffiensis and human granuloytic Ehrlichiosis caused by Ehrlichia ewingii.

Bleeding and Shock

Early symptoms of dengue hemorrhagic fever are similar to those of dengue fever, but after several days the patient becomes irritable, restless, and sweaty. a) These symptoms are followed by a shock-like state. Bleeding may appear as pinpoint spots of blood on the skin and larger patches of blood under the skin. a) Bleeding may occur from minor injuries. Shock may cause death. a) If the patient survives, recovery begins after a one-day crisis period. b) DHF carries about a 10% mortality without treatment and a 1% mortality with supportive treatment.

More Consequences of Viral Change

Emerging infectious diseases are infections that have recently appeared within a population or those whose incidence or geographic range is rapidly increasing or threatens to increase in the near future. Emerging infections can be caused by: a) Previously undetected or unknown infectious agents b) Known agents that have spread to new geographic locations or new populations c) Previously known agents whose role in specific diseases has previously gone unrecognized. d) Re-emergence of agents whose incidence of disease had significantly declined in the past, but whose incidence of disease has reappeared. This class of diseases is known as re-emerging infectious disease

Control Mosquitos Outside Your Home

Empty and scrub, turn over, cover, or throw out any items that hold water like tires, buckets, planters, toys, pools, birdbaths, flowerpot saucers, or trash containers. a) Mosquitoes lay eggs near water. Cover water storage containers (buckets, cisterns, rain barrels) so that mosquitoes cannot get inside to lay eggs. Use larvicides to treat large containers of water that will not be used for drinking and cannot be covered or dumped out. If you have a septic tank, repair cracks or gaps. a) Cover open vent or plumbing pipes. b) Use wire mesh with holes smaller than an adult mosquito.

Dengue Outbreaks

Epidemic Dengue is often seen in settings in which much or all of the population is non-immune. Outbreaks are often explosive with a majority of patients being older children and adults. Attack rates may be as high as 80 to 90% in such a population (most often 40 to 50% attack rates seen). Outbreaks usually occur in urban areas during rainy seasons

Tuberculosis Comes Back With a Vengence

Events that were unimaginable just a decade ago now were recurring with disturbing regularity. During 1989-1990, at a New York State correctional institution, a swift and fatal TB epidemic killed 13 inmates. Between 1990 and 1992, a half-dozen New York metropolitan hospitals reported outbreaks with many deaths. These events were being caused by a previously "defeated", preventable and curable disease. WHY???? While many factors contributed to this alarming situation, one in particular - failure to control this organism when it infects AIDS patients-stands out as the most serious and avoidable screw-up

Educate

For ANY of the STDs it is imperative that a community encourage behaviors that limit unprotected sex since such limitations also slow any evolutionary changes in microorganisms, in particular the development of virulence. That is also why sex education of our young people is so important - it must not be viewed that we are providing them with the information to engage in sex (they will do that on their own with or without help, stupid) but that we provide them with the necessary knowledge to protect themselves and their sexual partners, and ultimately the community, against disease. With less sexual contact, forces that reduce virulence and promote longer latency are brought into play.

Global Warming

Global climate change also underwrites the potential for major changes in the distribution of vectors and their accompanying diseases, as well as some vector-independent disease agents. Increasing global temperatures can lead to changes in rainfall patterns and other climatic elements. This can cause the spread of water-dependent vector species which can lead to expansion of the range for a number of vector borne diseases. But global temperature changes will also be associated with droughts in other areas of the globe. a) This can lead to famine, contamination of concentrated water supplies and a variety of other undesirable changes all of which can promote transmission of food and water-borne diseases.

Mismanagement Galore

Global trade in food and the rapid transport of humans for pleasure, immigration and business around the globe has allowed the transport of contaminated food or infected persons from a rural tropical location to Washington, D.C., New York City, London or Paris within the incubation period for most infectious diseases. This has created a whole new set of problems which favor the spread of disease agents globally. The mismanagement of global surface waters in the name of generating hydroelectric power or providing drinking and irrigation water for humans has expanded the range of many species of insect vectors, dramatically increasing the range of vector transmitted diseases. a) For this and other reasons, dams have proven to be damn stupid

HIV/AIDS

HIV is the single greatest threat to the survival of our species today. One of the reasons this is true is because of its ability to be transmitted to young people and their offspring both sexually and through body fluids, but above all because of its lethality. It is the most deadly disease facing young people between the ages of 22 and 45 in most of the developed countries of the world.

Incredible Pandemic

HIV is threatening our planet with an incredible pandemic - one in which just about every sexually active person is at risk. a) The increases shown in the success of HIV are quite impressive. For example, in Thailand, between 1990 and 1992, the number of HIV infected persons jumped from 50, 000 to 450,000. Today it is estimated that about 5 million of the 60 million inhabitants of Thailand are infected with HIV. At its present rates of infection and lethality, the virus is inexorably selecting out the most vulnerable human subpopulations and leaving behind a residuum of resistant people who by virtue of their behavior (monogamy or asexuality) or perhaps their immunological capability, manage to avoid infection.

HIV-2

HIV-2 had arisen as a human pathogen about the same time as HIV-1 but shows a milder disease course and lower mortality. HIV-2 has appeared to have adapted to a slow rate of spread. Why the differences in two such closely related disease agents? It appears that in West Africa, where HIV-2 exist in man, sexual contacts tend to be much fewer because of stronger tribal and religious taboos. Thus, a virus that has reduced virulence and longer latency, like HIV-2, is better adapted to this situation. This lends additional support to the hypothesis that reducing rates of transmission will select against virulence and also supports the idea that HIV virulence is related to the frequency of sexual contact in a population

Virus and Insects

Humidity and temperature have a profound effect on Dengue transmission. Due to high humidity during the rainy season, mosquito survival is longer. The time required viruses ingested by the mosquito to reach the insects salivary glands for injection into man (extrinsic incubation period) is an important variable in epidemic transmission. The higher the external temperature, the shorter the extrinsic incubation period.

Emergence of New Zoonoses

In 1967, animal traders sent a shipment of African Green monkeys from Uganda to the U.S. Several of the technicians who were culturing the African green cells became extremely ill. They experienced facial swelling, bleeding and shock and were only rescued by extreme methods at a local hospital. In a few days other techs in the lab below the first one suddenly became ill and only immediate supportive therapy saved their lives. The cause of the illness was Marburg virus that had infected the first batch of workers directly, and had then passed through cracks in the concrete floor and via the air ducts to the people in the floor below. Twenty -two years later, in Reston, Virginia, a primate Ebola reared its ugly head in a shipment of primates from Asia to the U.S. a) Again, three lab techs were infected but their symptoms were much less severe than with the Marburg outbreak. b) CDC quickly found at least two other primate centers contaminated with this virus, one in Pennsylvania and one in Texas. All monkey shipments were halted. Most of us are familiar with the primate Herpes B virus that has proven to be almost 100% fatal in humans.

New York City

In New York City in 1991, 1/3rd of the tested TB strains were already resistant to Isoniazid, and 15% were resistant to both Isoniazid and Rifampin. To make matters worse, a study of the records for TB treatment during 1989 and 1990 revealed that antibiotic usage and treatment protocols were defective for 28 out of 30 patients (80%!!!) with an average of almost 4 errors per patient.

Cloud Babies

In pediatric units, certain infants carry and disperse so many Staphylococcus and Hemophilus that they are referred to as "Cloud Babies". Once such a reservoir of infection exists, the movement of deadly pathogens is no problem. For example, a nurse might touch each infant in a nursery up to 20 times a day. Only a strict regiment of hygienic controls in a neonatal intensive care unit helps prevent interbaby transfer of germs. Environmental selection for the survival of potentially virulent organisms is also encouraged in hospital settings because fecal contamination of surfaces is common, especially wherever diarrheal diseases occur. Aerosols containing infectious droplets can be produced simply by flushing a toilet or taking a shower. In hospitals microorganisms are often subjected to intense selective pressures by the institutions sanitation and disinfection services. Repeated exposure to the same disinfectants over months and years can select for resistant bacterial strains. Common hospital germs may be able to survive in wash pails and disinfectant solutions. For these reasons it is considered wise wise to change disinfectants quarterly during the year.

Slower Development

In the West African country of Senegal, where HIV-2 is the most common cause of AIDS, infection leads to AIDS at an extremely slow rate which indicates a very long latency and lower virulence. In contrast, in the City of Abidjan in the Ivory Coast, which has experienced significant social upheaval and a loosening of sexual mores with greater utilization of prostitutes as a means of sexual release, the HIV-2 in this region is more virulent

Breakbone Fever

In the public health community, limited human and financial resources had created a "crisis mentality" that placed emphasis on implementing emergency control methods rather than developing programs for preventing epidemic transmission. Dengue is also known by the nickname "breakbone fever" because it is so painful that it feels like your bones are breaking. The signs and symptoms of Dengue include: retro-orbital headache (behind the eyes), fever, rash, severe muscle pain, loss of appetite, nausea, vomiting, abdominal pain, metallic taste to food, change bin psychological state, severe prostration (knocked off your feet), slowed heart rate, and a decrease in neutrophils and lymphocytes in the peripheral circulation

New Human Virus

It is an evolutionary enigma how HIV could produce a uniformly fatal disease, but part of the answer lies in the newness of HIV as a human pathogen. In this regard, the virus follows the pattern of an infectious agent that only recently has taken up residence in a new host. This has also been the pattern for other HIV-related viruses that have moved among non-human primate species. For example, the introduction of an HIV-related virus from the Sooty Mangabey monkeys to pig-tailed monkeys was coupled with the dramatic appearance of virulent types of the virus with greater amounts of genetic diversity and higher mutability than seen in the original strain..

Day Care

It is estimated that today fully 2/3rds of women with children under 18 years old are in the workforce. a) That translates into an incredible increase in the number of children in day-care centers. We have talked before about the child as a vector for a variety of diseases and we said that their relative unhygienic habits and lack of immunological experience with a large number of diseases makes children a very dangerous group for transmission of diseases into the family setting and into the general population

Partnership Between AIDS and TB

It is in the immunological wasteland of AIDS, that powerful new evolutionary forces are influencing this disease. The current resurgence of TB in Africa, the urban centers of the U.S. and in S. America and Asia, is being fueled by the AIDS epidemic. The weakened immune systems of AIDS patients allows the adaptable TB bacillus to have its way with the host and provides greater opportunity for microevolution. AIDS creates and evolutionary vacuum in which almost any and all new variants of TB can survive.

Stop the Mosquitos

It was to be 15 more years before epidemic Dengue reemerged as a major public health problem in the Americas. What was behind this hiatus? a) A.aegypti eradication programs were initiated and sustained by Pan American Health Organization in the late 1940s to prevent urban yellow fever (a disease native to the area that was also transmitted by A. aegypti). Unfortunately this program was discontinued in the early 1970s, and failure to eradicate the insect from the entire region resulted in repeated invasions into those countries in which eradication had been achieved.

Arboviruses

Lets give some examples of emerging arthropod-borne viral infections (arboviruses). a) But first, we should mention that transmission of the so called arboviruses is related to the nature of the virus, the distribution and biology of the vector arthropod, and the presence of reservoir hosts. These kinds of epidemics can be extremely difficult to control because of the complex relationships between the vector, man and reservoirs. There are a few constants in the emergence of epidemics of arboviruses. a) For example, when you mess with surface waters (building dams, reservoirs, irrigation projects, etc.), when you mess with natural environments (deforestation, establishment of new human communities, etc.) or when new vectors or hosts serve to amplify the disease agent.

Survival of the Species

Lets say you have a population of people, 2% of whom are infected with HIV. a) Now, if the infected people have a short latent period and are quickly incapacitated by the disease, the likelihood they will transmit it to others in the population is greatly reduced. If, on the other hand, viral replication is reduced and the period of asymptomatic infection is extended, there would exist a dramatically greater opportunity for transmission to others in the population. a) Increased transmission with reduced symptoms is especially likely in view of the sexual mores and personal habits of the high risk populations targeted by HIV. As we have stated several times during the semester, what is in the best interests of individual patient survival, is not always in the best interests of survival of the species.

No Reason to be Nice

Loose sexual mores and iv drug abuse created a loose virus in an evolutionary sense and with the huge rates of body fluid exchange taking place, viral evolution toward virulence was strongly favored. Remember, Easy Transmission = No Reason to be Nice. As the frequency of sexual exchange increases, those viruses with the greatest speed of replication and the highest virulence will be selected. Moreover, as long as the virus that caused the most serious disease was being transmitted before the carriers became sexually unattractive, no decrease in the destructive capacity of the virus can be expected

Dengue Galore

Most countries in this hemisphere went from non-endemicity (no - viruses present) to hypoendemicity (one virus present) to hyperendemicity (multiple virus serotypes co-circulation). This resulted in increased epidemic activity and the emergence of DHF as a major public health problem. In the 80s and 90s there were also major epidemicis in Africa involving primarily DEN-2 and DEN-3. Today, worldwide, more than 100 million cases of dengue fever occur every year. a) A small percent of these develop into dengue hemorrhagic fever

West Nile Strikes U.S.

NYCDH quickly identified a cluster of 6 additional cases in the same neighborhood! a) Initially, the diagnosis was St. Louis Encephalitis virus which was native to N. America but had not appeared in NYC previously. By September 28 of that year a total of 37 cases had been identified in NYC and surrounding areas. a) In early September some exotic birds and crows started dying in the Bronx Zoo and autopsy and more sophisticated diagnostic tests revealed the culprit was a "West Nile-like" virus. This was a new virus to the Western Hemisphere that was first isolated in the West Nile province of Uganda in 1937.

Serotypes are the Key

Nearly all infected adults experience overt illness. The 4 different serotypes of the Dengue virus show variation in clinical severity (DEN-1. -2, -3 and -4). Herd immunity can also govern the severity of outbreaks. When a single Dengue serotype has been endemic for a generation of more even at low to moderate annual transmission rates (10% of the population/annum or higher), most adults will be solidly immune resulting in few if any outbreaks. This is the situation which was seen in early colonial times. a) Since then, dramatic population in creases and movement of people has changed this situation to one in which the virus is quickly provided with non-immune victims.

Virulence and Toxins

Of course these types of disease have evolved with man for a very long period of time. a) Wart viruses, syphilis, herpes and cold viruses are just a few examples. Another aspect of virulence is the microorganism's ability to produce a toxin that poisons the host. Organisms that produce toxins are usually not highly infectious. Thus organisms that produce toxins are generally at a disadvantage in terms of ease of transmission compared to non-toxin producers. The exceptions are primarily among water-borne diseases.

Ebola Outbreak

On March 23, 2014, the World Health Organization (WHO) reported the first cases of EVD in West Africa in what would become the largest Ebola virus epidemic in history. Over two years, a total of 28,616 cases of EVD and 11,310 deaths were reported in Guinea, Liberia, and Sierra Leone. An additional 36 cases and 15 deaths occurred when the outbreak spread outside these three countries. A current outbreak is ongoing in Democratic Republic of Congo

Zika Virus

Prior to 2014, very few travel-associated cases of Zika virus disease were identified in the United States. In 2015 and 2016, large outbreaks of Zika virus occurred in the Americas, resulting in an increase in travel-associated cases in US states, widespread transmission in Puerto Rico and the US Virgin Islands, and limited local transmission in Florida and Texas. In 2017, the number of reported Zika virus disease cases in the United States started to decline. In 2018 and 2019, there have been no reports of Zika virus transmission by mosquitoes in the continental United States

The Condom and Evolution

Recent studies in insects have shown that the availability of hosts is directly proportional to the virulence of the parasite - that is to say that if transmission is easy, then the parasite tends to be more virulent. Theoretically then it should be possible to reduce the lethality of a disease by reducing the number of available hosts. Thus, if this is applicable to human diseases, if we can identify factors that delay transmission they should also be factors that reduce virulence. In practical terms, this means that the CONDOM can be an agent of evolutionary change!

Extrinsic Incubation

Remember, the extrinsic incubation period is the time from ingestion by the mosquito of virus-containing blood to the presence of viruses back in the salivary glands of the mosquito and ready to be injected into the next host. The EIP is shorter at higher temperatures. Infection in the mosquito with some of these viruses can lead to enhanced host-finding capacity thus promoting transmission of the disease agent

Traveling the Globe

Reports have surfaced from various points around the world of people who harbor the virus but show no disease, and of subpopulations that show a greater resistance to HIV than others. AIDS is still traveling the globe easily and widely, riding the waves of social disruption in societies of Sub-Saharan Africa, Southeast Asia and India. Immigrants from rural areas of these regions have settled in urban centers and experienced wholesale disruption of traditional tribal customs, particularly with regard to monogamy and the use of prostitutes, all of which have fueled an incredible rise in the number of people infected with HIV. In many urban center of Africa, and now Asia, prostitutes show rates of infection that approach 100% and carry many other STDs that themselves promote contraction of HIV. The widespread reuse of what are supposed to be disposable injection needles in self-administration of antibiotics, and to a lesser degree, iv drug use, have contributed strongly to this trend.

International Disease Transport

Since that time outbreaks of West Nile had been reported in Israel, S. Africa, France and Romania. To this date we still don't know for certain how that virus got here, but it has been hypothesized that it might have entered in a viremic patient from an endemic area, or it may have entered in an infected bird. Great example of the role international transport can play in invasion of a non-endemic area by an infectious disease

Population

Since the middle of the 19th century, urbanization and industrialization have led to dramatic increases in human population. Much of this increase has been concentrated in huge urban centers around the globe where sanitation has been inadequate and led to increased exposure to human sewage, a decline in the quality and purity of water and food, and very high human density areas that create playgrounds for pathogens. It has been estimated that by the mid 21st Century there will be a doubling of human population from current levels. a) As stated earlier, these levels of human population will dramatically reduce our ability to control infectious diseases and a wide variety of other human health issues.

Reduce Selective Pressure

Some of the basic principles for limiting the emergence of antibiotic resistant organisms are derived from evolutionary theory and are as simple as they are reasonable - It is a matter of reducing the selective pressure exerted by routine use of antibiotics and shifting control over to the body's own defenses where practical: 1) Strictly limit the use of antibiotics , especially when they are proposed for prophylaxis - except in surgeries involving a joint, the heart or intestine. 2) If antibiotics are used, only give appropriate doses that assure complete elimination of the target organism. 3) Avoid prescribing drugs to which resistance has been shown to emerge rapidly in a particular clinical setting. 4) ESTABLISH the drug susceptibility of the disease agent BEFORE employing antibiotics. 5) Use antibiotics intermittently to break up constant selection forces. 6) Increase reliance on vaccines. 7) Remove some antibiotics from use entirely to allow the emergence of vulnerable strains

Avian Influenza

Sporadic human cases of avian influenza continued to be reported in China in 2018. In 2018 China witnessed the first ever human case caused by the H7N4 influenza subtype and additional cases of H7N9, H9N2, H5N6 and H5N1. (WHO, 2019)

Bites

Temperature may also impact on the rate of maturation of mosquitoes: higher temperatures bias toward production of smaller females who are required to take more blood meals to satisfy the energy needs to support egg production. More bites mean greater transmission. a) This situation increases the number of persons infected by a single mosquito and thus increases the "vector capacity" of the mosquito. The most impressive modulator of the severity of Dengue fever is host age. a) Pre-adolescent children have a Dengue fever-line illness but are not as severely incapacitated as older children and adults. Rarely, dengue can be spread through blood transfusion, organ transplant, or through a needle stick injury

Speedy Disease

The AIDS pandemic has demonstrated unprecedented speed in its diffusion compared to any other modern-day disease. While the great cholera pandemics took nearly 20 years to sweep around the globe, HIV accomplished the same feat in 7 years. Because of its newness in the human population and its high mutation rate, it is likely that HIV is undergoing evolutionary changes as I stand here talking with you about it. As the number of infected persons increases, so does the number and genetic variety of viruses carried by them

LaCrosse

The La Crosse encephalitis virus was discovered back in 1960 in a child that died of encephalitis in Wisconsin. It has spread to the Midwestern and Eastern United States since that time. The natural cycle for La Crosse virus involves transmission between Aedes triseriatus mosquitoes and small mammals such as flying squirrels and chipmunks. This is a disease of the suburbs were the mosquitoes breed in tree holes. La Crosse is one of the encephalitis viruses that can be maintained by transovarial transmission

New Cholera Strain

The causative agent in this pandemic was an entirely new strain of cholera called 0139. Concern was great since people who had been vaccinated against cholera or who had contracted and survived cholera in the past had no protective immunity against this new strain of the disease. Cholera owes its lethality to a number of factors. a) typically high densities of bacteria in contaminated water and b) its high infectiousness, c) cholera doesn't require the survival of its victims for transmission.

Rifampin and Isoniazid Doomed

The emergence of multiply resistant TB proved especially catastrophic for AIDS patients. When an AIDS patient is mistakenly given a prophylactic dose of Isoniazid when he already has a silent case of TB (a common occurrence), the level of antibiotic in his blood is insufficient to kill all of the organisms. Instead, the suboptimal dose kills off some of the most susceptible substrains, leaving behind a more robust TB organisms to proliferate. As the patient sickens, he may be given Rifampin and isoniazid in the hopes of gaining a therapeutic foothold against the disease.

Immunoevasion

The hypermutability of HIV also greatly compounds the task facing the immune system. a) The up-front probability is that if the immune system does not quickly destroy the invading HIV completely, the virus will incapacitate the immune system so that it is not only unable to defeat HIV, but it will ultimately lose most of its capacity for dealing with a wide variety of other disease agents which under normal circumstances it would consider " small potatoes." Mathematical models of what transpires during HIV infection have indicated that high mutation rate of HIV could generate strains of the virus which would perpetually evade the host's immune response.

Saint Louis Encephalitis Virus (SLEV)

The most commonly encountered arbovirus infection in North America is St. Louis Encephalitis which is transmitted primarily by Culex tarsalis and the natural cycle is between mosquitoes and wild birds. The SLE virus can multiply in mosquitoes at lower temperatures than most other arboviruses so is well-suited to colder areas. There are no vaccines to prevent nor medications to treat SLE. Care is based on symptoms. SLEV infection is thought to confer life-long immunity against re-infection with SLEV

Japanese Encephalitis Virus (JEV)

The most widespread arboviral encephalitis in humans is Japanese encephalitis. a) There are epidemics and varying degrees of endemicity in countries in Southeast Asia. However, recent evidence indicates this diseases is spreading to nearby countries. a) The virus circulates between water birds and Culex tritaeniorhynchus that breed in rice fields. The agent is amplified in pigs. In endemic areas most adults are immune from past infection with the organism so most disease occurs in children. An age dependent variation is seen in the inapparent infection to apparent infection ratio, which can range from 50:1 to 1000:1. Among those experiencing clinical infection, 20 to 30% are fatal.

Danger!!

The present evolutionary situation with regard to HIV is a disaster waiting to happen for our species. As the HIV-positive population continues to grow, the opportunity for evolutionary drift in the virus and related opportunistic organisms is frightening. Even as we speak, a vast reservoir of human hosts provides a living evolutionary laboratory for a virus and associated disease agents that know no bounds. We can only speculate on what is in store for humans in this dangerous situation.

Dengue / DHF

The reasons for the dramatic emergence of Dengue fever/DHF in the late 1900s as a major public health problem stem from several important factors: 1) The reinfestaion of the American tropics by Aedes aegypti provided a pool of about 300,000,000 people in urban areas , all susceptible to Dengue; 2) Effective mosquito control was non-existent for most of the areas invaded by the mosquito; 3) widespread uncontrolled population growth and unplanned urbanization has occurred during this period of time (changes which resulted in substandard housing and inadequate water, sewer and waste management systems for millions of people living in the tropics); 4) flooding of the market place with consumer goods packaged in non-biodegradable plastic and cellophane that provides ideal larval habitats for mosquitoes; 5) Increased travel of humans by airplane which leads to the transport of Dengue virus between population centers in the tropics; and 6) the public health infrastructure required to deal effectively with infectious diseases has deteriorated in recent years.

A Changing Virus

The same pattern of change in the virulence of HIV is being seen in the U.S. During the late 90s, the latent period for full-blown AIDS had increased to 10 years from 5 years in the 1980s. a) This was due to the encouragement and practice of protected sex. Unfortunately, with the entrance of young people who have not yet experienced the devastating and deadly effects of HIV around them, unprotected sex is coming back in vogue and the rate of infection among gay males in particular is picking up again. The only thing that is holding down the latency period and the high mortality of AIDS this time around is the multitude of drugs capable of delaying the disease. Nevertheless, the virus is changing here and elsewhere in the world. a) This should not be surprising in view of the incredibly high rate at which HIV mutates.

T-Cells are the Trick

The success of HIV appears to be related to the success of other infectious diseases in man. For example, where malaria is endemic, AIDS appears to be particularly virulent. a) While resting T cells provide a poor host cell for HIV, those that have been activated or subverted by other infectious agents serve as excellent crucibles for HOV, and malaria, as well as many other diseases, activate resting T cells in large numbers.

All Are Endangered

The trend appears to be one in which diseases that have adapted to life in AIDS patients have begun to show up in patients who are immunosuppressed but not fully immunocompromised to the same degree as AIDS patients. a) For example, cancer patients. The big question ---- how far will these opportunistic organisms carry their ability to infect non-AIDS patients? WILL THEY START SHOWING UP AT THE MARGINS OF IMMUNOCOMPETENCE?? WILL THE VERY YOUNG AND THE VERY OLD BE THE NEXT VICTIMS OF THESE DISEASES? AIDS patients may be serving as the crucible for adaptation of these disease agents to routine life in humans.

Non-Compliance

The two most common errors were those exact miscalculations that would most likely lead to resistant forms of TB. 1) A treatment protocol began with suboptimal doses or schedules for drugs. 2) A single new drug was added to a treatment program instead of starting a crash program with multiple drugs. 3) Little or no follow-up to make sure patients complied with the doctors recommendations. 4) Inappropriate use of Isoniazid for TB prevention. These errors, multiplied from patient to patient, ensured that multiply - resistant TB would emerge. Moreover, each treatment failure increased the risk of contagion and further evolution toward virulence.

More Consequences of Viral Change

The viral change we talked about last time has other more dire consequences as well. Given the capacity for genetic variability, it is important to keep an eye on what HIV is doing in the individual host as well. New variants of HIV can be found within months of infection within a single individual. This is not surprising in view of the fact that as many as 10 billion viruses are produced each day, including as many as 100,000 different mutant viruses every day! Moreover, during such an intensive evolutionary incubation period, it is probable that some variants will arise that are more likely to be transmitted than is the original HIV found in this host.

Other Encephalitis Viruses

There are several other encephalitis viruses that are endemic in the U.S.: Western (rural areas) and Eastern Equine Encephalitis (Eastern half of the U.S.), California and Venezuelan (South Florida) encephalitis viruses. EE is especially problematic since it appears to be readily transmitted by the recently imported Tiger mosquito, and because this disease carries a high rate of clinical disease and a high mortality. The incubation period for Eastern equine encephalitis virus (EEEV) disease (the time from infected mosquito bite to onset of illness) ranges from 4 to 10 days. a) EEEV infection can result in one of two types of illness, systemic or encephalitic (involving swelling of the brain, referred to below as EEE). Systemic infection has an abrupt onset and is characterized by chills, fever, malaise, arthralgia, and myalgia. Signs and symptoms in encephalitic patients are fever, headache, irritability, restlessness, drowsiness, anorexia, vomiting, diarrhea, cyanosis, convulsions, and coma

Emerging Infections

There are two major categories of emerging infections—newly emerging and reemerging infectious diseases—can be defined, respectively, 1). as diseases that are recognized in the human host for the first time; and 2) diseases that historically have infected humans, but continue to appear in new locations or in drug-resistant forms, or that reappear after apparent control or elimination Since the 1970s, about 40 infectious diseases have been discovered, including : a) SARS, b) MERS, c) Ebola, d) Chikungunya, e) Avian flu, f) Swine flu and, most recently, g) Zika..

Ethical Dilemma

These findings raise a major ethical dilemma. What constraints if any should be placed on AIDS patients to reduce the likelihood of their spreading their secondary infections? If AIDS patients are indeed the breeding ground for new and dangerous human pathogens, should steps be taken to limit their social contacts? a) These were some old ideas circulated by some, but have really no merit Hospitalization and compassionate care are of course the only proper response, but attention must be given to avoiding endangering others who are immunological less fit

TB Goes Nuts in AIDS Patients

This growth pattern is unstoppable in AIDS patients. An AIDS patient carries a 10% a year risk of infection with TB, a rate that is 100s of times normal. When a TB infection disseminates in an AIDS patient, antibiotic levels that would have stopped the TB in an immunocompetent host (in which crucial immunological backup to antibiotics is provided), fail. Because they lack the critical T-cell mediated immune responses of AIDS-free humans, AIDS patients are extremely vulnerable. While TB normally has a maximum case fatality rate of 1 to 10% in immunocompetent patients, the case fatality rate in AIDS patients is between 60 and 100%!!

TB Goes Nuts in AIDS Patients

This growth pattern is unstoppable in AIDS patients. An AIDS patient carries a 10% a year risk of infection with TB, a rate that is 100s of times normal. When a TB infection disseminates in an AIDS patient, antibiotic levels that would have stopped the TB in an immunocompetent host (in which crucial immunological backup to antibiotics is provided), fail. Because they lack the critical T-cell mediated immune responses of AIDS-free humans, AIDS patients are extremely vulnerable. While TB normally has a maximum case fatality rate of 1 to 10% in immunocompetent patients, the case fatality rate in AIDS patients is between 60 and 100%!!!

Dengue Pandemics

This mosquito was spread by sailing ships throughout the area and adapted to humans and urban environments. The mosquito first infested port cities and then moved inland as urbanization expanded. When Dengue viruses were introduced into port cities infested with Aedes aegypti, epidemics occurred. It was in this setting that major pandemics of Dengue occurred during the 18th, 19th and 20th centuries

Africa Targeted

Throughout the developing world it rivals the parasitic diseases as the greatest debilitator of man. Presently, it is making its greatest inroads in Africa, where it is thought to infect over 45 million people. It is estimated that 250 Africans become HIV-infected each hour of each day!!!! There are at present between 55 and 60 million HIV-infected people worldwide.

High Virulence

Unfortunately, perpetuity is not a luxury that the human immune system can afford because the virus is destroying at the same time the precise cells and molecules needed to respond to all infections. a) Interestingly, the same model showed what could be expected to happen in the host with regard to viral change. As an AIDS patient's immune system begins to collapse, several viral strains can be found in the bloodstream of the host. a) As the model predicted, an increase in viral diversity is observed only as long as the immune system is strong enough to exert selective pressure on a viral population. Therefore, as soon as the immune system collapses, dying AIDS patients would be found to have only one or a just a few HIV strains - which should be the one with the highest replication rate and the highest virulence.

Think Before You Prescribe

Unfortunately, these principles, while simple and based on common sense, fly in the face of traditional medical practice. Physician autonomy is a highly guarded privilege in this country, but without some control over the use of antibiotics it will be the rule that antibiotics will be frequently employed under questionable circumstances. While some in the medical community believe that the solution to antibiotic resistance is simple to develop more and better antibiotics, this is unrealistic in the face of spiraling R&D costs and FDA regulations which dramatically lengthen the time for new drug development. One of the most critical issues facing public health today is the need to shift emphasis from treatment of diseases after they are acquired, to prevention of disease. One must remember that the right and privilege to prescribe what is deemed in the best interests of one's own patient is a lofty ideal, but it may compromise the overall effectiveness of antibiotics for the rest of the entire world!!!

There are Alternatives

We have a modern day example of the role that can and has been played by vaccination in dealing with infectious diseases. The emergence of a significant number of vaccine preventable diseases in Russia that has accompanied the decline in vaccination programs there teaches us a powerful lesson. In addition to vaccines, improvements in personal, community and special setting hygiene, and avoidance in our food and water of immune compromising substances, as well as immune suppressing drugs. We should also use scientifically sound findings regarding nutritional supplements to boost our immune systems as part of a broad program of prevention (selenium, Vit. A, E and C, zinc, pycnogenol, grape seed extract, lycopene, etc.). There are many lethal germs awaiting us in non -human primates and rodents.

Causes

We have seen and heard about the emergence of new diseases and the re-emergence of known diseases that we thought we had left behind us. What are the causes of these events? a) While we have touched briefly at different points in this course on factors that contribute to increases in infectious disease, let's focus on the topic for a moment and review some of these causes. We have hammered away at the role of human population growth on the future outlook for infectious disease, but there is ample evidence that it has already begun to have a telling effect on the spread of infectious diseases.

Deforestation and International Trade

We have talked about a long list of diseases that have emerged due to encroachment of humans into previously uninhabited areas. Along with this movement goes the deforestation of vast areas of the planet for mining, agricultural and other human-related activities. a) All of these activities lead to exposure of man to the life cycles of what were non-human diseases and the inclusion of man into the life cycles of some of these diseases. The global transport and international trade in domestic and exotic animal and plant species has set the stage for the emergence of new diseases in many parts of the world, particularly the industrialized parts of the world which often are the recipients of these animals.

War and Disease

We talked earlier about the disease -promoting effects of war and social disruption. Every war has been accompanied by disease outbreaks not seen during peace interludes and the effects of social disruption are seen on the evening news in the form of refugee camps and the accompanying outbreaks of cholera, shigellosis and other diseases associated with unhygienic conditions, fecal contamination of food and water, famine and vector-borne disease transmission within a concentrated and immunocompromised population without adequate medical care. "Katie bar the door", it's a disease playground

Speed-of-Light Resistance

What is equally impressive, and understandable in the face of such a firestorm of viral mutation, is the fact that none of the nucleoside analogs approved by FDA for use in HIV-infected patients, reduces HIV replication for much longer than 6 months on its own, in combination they did not hold the line much longer. This means that the virus becomes resistant to the effects of any or all of these types of drugs very rapidly and with seeming ease. a) Since the advent of protease inhibitors, clinicians have been able to extend the asymptomatic period considerably longer in AIDS patients. From the patients standpoint this is a very desirable thing. a) However, from an epidemiological/public health standpoint a different perspective may emerge.

Genetic Changes in TB is the Danger

When TB infects an immunocompromised host, its survival pattern is different than in an immunocompetent host. In an immunologically intact host the TB bacillus owes its survival to a highly protective waxy envelope and its ability to hide inside macrophages. In an immunologically depressed host the organism doesn't have to hide and can immediately assume the more active and dangerous form of infection, where the bacillus occupies the lungs, liver and muscles. Growth in these locations is unrelenting, and with this greatly expanded growth the TB organism is likely to undergo genetic changes that include new, more virulent subtypes.

Multiple Serotypes = Bad News

When simultaneous or sequential introduction of two or more serotypes occurs in the same area, there may be an increased number of cases with worse clinical presentation (dengue hemorrhagic fever). The term 'hemorrhagic' is imprecise, because what characterizes this form of the disease is not the presence of hemorrhagic manifestations, but the abrupt increase of capillary permeability, with diffuse capillary leakage of plasma, hemoconcentration and, in some cases, with non-hemorrhagic hypovolemic shock (dengue shock syndrome)

Community Spread

With the ability to incubate for long periods of time and reproduce in HIV-infected hosts, TB evolved at a very high rate Infection with HIV has promoted the development of multi -drug resistant strains which cause outbreaks among AIDS patients. These outbreaks are a very serious public health threat because they create great opportunity for the spread of the most resistant, infectious and virulent strains of the TB organism among themselves and THE COMMUNITY AT-LARGE