"The Changing Face of Infectious Disease"

antibiotic resistance = natural selection at work:

Pneumococcus, staphylococcus, and all the others can and do develop resistance.

Only Group A streptococci have not developed resistance to beta lactams.

M. tuberculosis in Russia etc.. Value of DOT (directly observed therapy)

Our emphasis should be in reducing the selection pressures that antibiotics put on bacteria. We should attempt to shift control over to the body's own defenses where ever practical. Humans are in reality a microbial garden, colonized from our eyebrows with mites to our bowels with more than 600 species of microorganisms. Most are innocent commensals (dining at the same table) with protective benefits. They facilitate food digestion and provide us with nutrients and vitamins. They protect us against a few truly harmful microorganisms that may be frequently encountered. The immune system in the intestinal mucosa would not develop in the absence of these microbes.

Imunizations: H influenzae for kids. MMR, pertussis essential. Polio still needed.

Strep pneumoniae (protein conjugate and polysaccharide), Meningococcus.

Influenza A / B yearly. Avian influenza has potential for catastrophe.

H5N1 in Hong Kong 1997-98. H9N1 in 1999. 1918 pandemic due one of these days… For travel: hepatitis A, tetanus, diphtheria, yellow fever (once)

Hepatitis B very important preventable STD. Vaccinate at a young age.

Hepatitis C no vaccine, but blood transfused before 1991ŕ risk factor. IV drug abuse = risk. Host factors are important in outcome of hepatitis. Most patients do not develop cirrhosis.

Bioterrorism: Anthrax, botulism, hemorrhagic viruses, plague, smallpox, tularemia. Surveillance is essential. Discovery favors the prepared mind 

Pertussis carriers = adults with chronic cough, no whoop.

Food borne illness

Cholera into Peru 1991 from Asia. We live in a truly global village so expect to see food borne illness commonly. E coli 0157:H7 ŕ renal disease. Rarely febrile. Antibiotics make the disease worse.

Healthcare worker infections

HBV (30%) > HCV(3%) > HIV (0.3%) risks from known needle stick + patient.

"Stealth bugs" are organisms that cannot readily be seen on a gram smear or on regular culture. In the respiratory tract they include viruses, chlamydia species, Mycoplasma pneumoniae, Legionella species, Mycobacterial species, Coxiella burnetti (Q fever), and some fungi. Their frequency is often host and locale dependent. The specific diagnosis begins with the clinical history. We need to learn how to anticipate epidemics through improved surveillance, so that we can intervene early. We must recognize the importance of interdependence amongst ecosystems. We cannot abruptly move into an entirely new environment without invoking peril. Malaria, plague, lyme disease, lassa fever, Ebola virus fever, are just a few of the many examples of mankind's ignorance of ecosystem biology.

Peter P. McKellar, MD Phoenix, Arizona peter@samaritan.edu

 

 

 

 

 

 

 

 

Epidemiology of Infectious Diseases / Emerging Pathogens

The control and/or eradication of infectious diseases through vaccines and health care improvements was thought to be within reach by 1970. Infectious disease specialists would only be needed in developing ("third world") countries. Since the 1970's, however, we have seen a panoply of new and reemerging infections and we have recognized that "third worldization" exists in the USA. The bacteria really have not changed. More likely, there are subtle changes in human behavior and technology that have provided organisms new access to humans. For example, aerosolization of water in showers, supermarket produce spraying, air conditioning and evaporative cooling has contributed to the emergence of legionnaires disease and atypical mycobacteria (MAC). Extra absorbant tampons selected for toxic shock syndrome with Staphylococcus aureus. Food poisoning with Campylobacter species, Salmonella species, and E. coli O157 more likely occurred from major changes in the food technology and distribution than from underlying changes in the virulence of these bacteria.

"Pathogenic microbes" are merely trying to survive. Killing the human host is not usually in the best interests of the microbe. Humans are in reality a microbial garden, colonized from our eyebrows with mites to our bowels with more than 600 species of microorganisms. Most are innocent commensals (dining at the same table) with protective benefits that are largely overlooked. They facilitate food digestion and provide us with nutrients and vitamins. They protect us against a few truly harmful microorganisms that may be frequently encountered. The immune system in the intestinal mucosa would not develop in the absence of these microbes.

Commensal transient microbes can become opportunistic pathogens especially in the compromised patient. Clearly, some microbes have become "professional" pathogens especially in the hospital setting.

Some microbes have adapted exclusively to humans (typhoid, gonorrhea, syphilis, and tuberculosis for examples).

"Stealth bugs" are organisms that cannot readily be seen on a gram smear or on regular culture. In the respiratory tract they include viruses, Chlamydia species, Mycoplasma pneumoniae, Legionella species, Mycobacterial species, Coxiella burnetti (Q fever), and some fungi. Their frequency is often host and locale dependent. The specific diagnosis begins with the clinical history which is never complete and always evolving. Compromised hosts like the HIV patient have forced us to broaden our differential diagnoses and to be more aggressive in the documentation of specific pathogens. Future approaches will need to address how best to rapidly identify the specific etiology of pneumonia. In many cases the growth of an organism in sputa does not prove causation. Our therapies for respiratory infections are relatively effective when we target specific pathogens. Antimicrobial resistance is often a result of excessive and inappropriate use combined with poor follow-up and compliance. New diagnostic techniques, new antimicrobial agents, and new vaccines, cannot hide the fact that we are more susceptible than ever to new infectious diseases. Stealth bugs are just one small part of the microecology that shares an evolutionary origin with mankind. A paradox of evolution is that the harder we assail the world of microorganisms, the more varied and aggressive they become.

Mycobacterium tuberculosis is a stealth bug that is easy to miss if the history of risk factors is overlooked. Mycobacterium avium complex (MAC) has been common amongst HIV patients as was Pneumocystis carinii (PCP). Blood cultures specifically for MAC have the highest yield. Sputa for acid fast organisms are less helpful except in the immunocompetent host. PCP is diagnosed from the sputa, but requires a recognition of risk factors. Chlamydia pneumoniae is a stealth bug associated with pneumonia, bronchitis, and sinusitis. Its spectrum of disease extends from asymptomatic to florid pneumonia. Minimal symptoms are the norm, but protracted illness is common. Unlike Mycoplasma pneumoniae, C. pneumoniae produces pneumonia more commonly in older age groups. Upper respiratory symptoms usually predate the pneumonia. Diagnosis is difficult at present because of reliance on serologic tests that are not generally available. Legionella pneumonia is the classic stealth bug. A major clue to its presence is the absence of response to beta lactam antibiotics.

Infectious diseases are the leading cause of death throughout the world.

Only smallpox has been eradicated. How do we explain the emergence of pathogens new and old that now confront us? Population growth, expanding poverty, urban migration, societal behavior changes, international travel, rapidly changing technology all contribute.

Disease surveillance systems have been underfunded and the natural cycles of infections seem poorly understood. As a consequence, our

vulnerability to new infectious diseases has never been greater.

The population of the world may be a major contributing factor:

1 AD = 250 M, 1800 = 1 B, 1900 = 2 B,

1960 = 3 B, 1975 = 4 B, 1987 = 5 B.

2030 estimated 8.4 B

Immigrant/refuge influx into the USA over the past 10 years has made some rare diseases relatively common. For instance, extrapulmonary tuberculosis, malaria, neurocysticercosis, typhoid fever, and schistosomiasis are now seen in many states in the USA.

 

Modern medicine needs to return to evolutionary theory. In the control of disease, we must act in harmony with the natural systems that have evolved to counter disease threats in the first place. We stress our immune systems daily with chemical toxins, UV light, hormones, and a variety of other insults. The destruction of tropical ecosystems, eg: rain forest, has promoted a host of new micro-organisms, eg: HIV. We need to stop thinking that we are immune from biological threats that will potentially limit our survival. Instead, we need to recognize the obvious; we are colonized, penetrated, and dined on by a host of micro-organisms that have evolved with us and may have evolved into us. In essence we have a poor understanding of the interplay of disease, human and microbial evolution, and modern therapeutics.

In 1992 - 1993, there were six major infectious disease outbreaks in the United States. 1) Cryptosporidiosis in Milwaukee water supply,

2) Hanta viral pulmonary syndrome in the Four Corners area,

3) Multiple antibiotic resistant intestinal infections in New York City hospitals, 4) a major flu epidemic, 5) multi-drug resistant infections at Urban day care centers amongst common organisms, 6) a large outbreak of meat-born food poisoning in the West due to E.coli 0157:H7.

Human resistance to disease has been a major factor in our emergence as a successful species long before we had developed medicine. Research into old infectious diseases demonstrates an evolutionary paradox: the more aggressively we assail the world of micro-organisms, the more varied and aggressive bacterial and viral strains become. We fail to recognize that disease is part of life. Diseases do not arise suddenly to strike on suspecting hosts. Indeed, evidence from Egyptian mummies and Chilean Indian remains reveal that tuberculosis and rheumatoid arthritis existed many millennia ago.

We need to understand the evolutionary origins of diseases in order to fully comprehend how to prevent them, and we need to incorporate evolutionary models of disease in order to treat them effectively. All human disease has evolutionary origins. Our blindness to the natural forces that have shaped human disease has contributed to our medical dilemmas today.

Most pathogens do not want to cause illness and death. Most pathogens that enter human populations for the first time produce transient, highly fatal illnesses that may or may not take hold. Rarely does a new pathogen last long enough in a human population to become endemic or to become a chronically recurring disease.

Why have the tropical areas become epicenters for so many diseases?

The density of species found in the tropics is enormous compared to other parts of the world. Human encroachment on such areas has very significant impact. It is now felt likely that man-made environmental disturbances account for most of the newly emergent diseases seen in contemporary human populations. Migration patterns and travel provide new routes for "microbial traffic". The same was true with the plague in the middle ages, which followed caravan trade routes from Asia to Europe. The expansion of agriculture has brought on new diseases. Argentine hemorrhagic fever (Junin virus) has increased dramatically in Northern Argentina with the expansion of corn farming and increasing contact with rodents.

Ebola virus probably first arose in monkeys and then was transmitted to humans who invaded their habitat. Ebola virus was too virulent to establish a focus of further infectivity initially. The initial infection was in northern Zaire in August, 1976. A similar virus was imported in a group of Philippine monkeys brought to Reston, Virginia in 1989. A basic tenant of infectious diseases is that we cannot disrupt natural relationships without impairing our own welfare. Farming, logging, wars, any major migration of humans profoundly impacts the occurrence of diseases.

Lyme disease is another example. Woodlands have been converted to farmlands and housing developments, bringing mankind closer to natural risks. New habitats for rodents species have developed, but the predator species such as wolves, bears, and lions that would ordinarily control deer populations no longer exist. The expansion of certain animal populations (deer mice) unchecked by predators allows for arthropod parasites to likewise expand. Ticks carry an abundance of diseases. A lack of surveillance led to the current epidemic of lyme disease. Lyme disease clearly existed in the 19th century, but not until 1977 was the cause known. It now is the most commonly reported arthropod borne disease in the USA. When a tick-born agent infects humans for the first time it is often highly virulent. Deer are intermediate hosts for the adult ticks that carry the lyme spirochete (Borrelia burgdorfii). Man has become a new intermediate host for this organism. Rather than generating an effective immunity that would limit its spread, the lyme disease organism provokes an immune reaction that contributes to the arthritis and other complications associated with the disease. A human vaccine trial began in 1994.

Plague in 1347 in Europe is another example of extension of farming into woodlands combined with mass migrations to urban centers, unhygienic conditions, and man living close to rats that had fleas. A more modern-time plague outbreak occurred in Vietnam where ecosystem disruption occurred on an enormous scale. In 1964, a major outbreak occurred in Vietnam. Previous to that time there had been virtually no outbreak of the plague in the past century. Deforestation by herbicides coupled with massive migrations and physical deforestation of large regions drove rodent species to urban areas.

Dengue fever is a mosquito-borne viral disease that is rooted in the subtropical areas of the world. Since the 1950's, dengue hemorrhagic fever has undergone a resurgence especially among southeastern Asian populations. In late 1970's dengue spread to South America. Ecological disturbances and poor flood control have produced expanded habitats for mosquitos. In 1985 the Asian tiger mosquito (Aedes albopictus) was imported into Florida in water that was carried in a shipment of used tires from Southeast Asia. This insect vector is now widely distributed through the southern part of the United States. Pesticides spraying of the tiger mosquito has led to emergence of resistance strains. In addition, the CDC has now isolated 16 different strains of newly recognized viruses of the arbovirus group from this tiger mosquito. Eastern equine encephalitis virus, the most fatal of these viruses, is amongst that group.

Other examples of environmental disturbances throughout the world are easy to spot. Malaria has dramatically increased in Rwanda, in large part due to social disruption of war. To understand the impact of new diseases and how humans have attempted to master them, one needs to recognized that the engine of evolutionary change is natural selection.

We hold the mistaken belief that antibiotic resistance can be simply overcome by developing new antibiotics. We need to recognize that microbes are not idle bystanders. They possess remarkable genetic versatility and rapidly turn over their genetic materials.

Our emphasis should be in reducing the selection pressures that antibiotics put on bacteria. We should attempt to shift control over to the body's own defenses where ever practical. Solutions include the following:

1) Strict limitation of antibiotics, especially when they are proposed for prophylaxis.

2) If antibiotics are indicated, appropriate doses should be used to assure complete eradication of the infectious organism.

3) Avoid antibiotics to which resistance has been shown to emerge rapidly.

4) Use susceptibility tests prior to using antibiotics whenever possible.

5) Use antibiotics intermittently to breakup constant selection forces.

6) Increase reliance on vaccines, eg: pneumococcal vaccine.

7) Periodically remove antibiotics from commercial use to permit the re-emergence of sensitive strains.

Cholera as a model: the current pandemic of cholera began in Peru in January, 1991 due to social upheaval, poverty and absence of social services such as safe water supplies. The epidemic has spread throughout all of the Americas. The causative organism for this outbreak was an entirely new strain of vibrio cholerae called O-139. Earlier surveillance would have curtailed it.

AIDS. The lethality of AIDS is not due to toxicity, but rather due to its ability to destroy the host's immune system. It is likely that HIV has spread from a near relative primate species to humans only within the last 4 or 5 decades. Monkey eating habit of some cultures in central Africa may have contributed to the spread. The earliest report of AIDS in humans can reliably be traced to 1959 when a sea captain who returned with a cargo from Africa to England developed a mysterious fatal infection. His serum has in retrospect been demonstrated to have HIV antibodies present. In 1969 a young boy in St. Louis was found to have HIV positive serum after dying of PCP. (His serum was analyzed in 1985 when serological testing for HIV became available.) A variety of social factors have contributed to the explosion of AIDS throughout the world. The destruction of traditional social norms is a major contributor, as are new roads, travel and urbanization.

Malaria. Ecosystem disruption has favored the spread of malaria and concentrations of insect vectors. There are a few areas of the world where humans live "in harmony" with their landscape and have very low rates of malaria, even though they are in high risk areas. Natural selection has applied pressures to prevent malaria in humans. Examples include sickle cell hemoglobin with collapse of the cell and greater ease of phagocytosis when parasites are within the red cell. Carriers of sickle cell trait have intermediate resistance to malaria. Other genetic defenses against malaria include G6PD. People deficient in G6PD have less glutathione inside their red cells. This is a necessary nutrient for malaria parasite metabolism. Another defense is a variant of Duffy blood group antigen. The Duffy antigen appears on the surface of red blood cells and seems to be a receptor for P.vivax. Duffy negative populations have lower risk for malaria.

Natural selection generally protects an individual only up to successful child rearing time.

Homo sapiens have become the most prolific, large species on the planet. They are attractive hosts for parasites and micro-organisms. Human population density contributes to the spread of diseases. Human population control seems imperative. We need to learn how to anticipate epidemics through improved surveillance, so that we can intervene early. We must recognize the importance of interdependence amongst ecosystems.

We cannot abruptly move into an entirely new environment without invoking peril. Malaria, plague, lyme disease, lassa fever, Ebola virus fever, are just a few of the many examples of mankind's ignorance of ecosystem biology. New vaccines are a more appropriate approach for controlling the risk of infection from malaria or HIV then are chemical antibiotics. In 1970, there was a gross misperception that infectious disease was under control and that modern medicine could dominate any pathogen. We now recognize that in order to regain control over emerging infectious disease, we need a dramatic improvement in vaccination and surveillance programs, better control of disease vectors, and special education programs. Man has shaped the diseases that afflict us as much as they have shaped man. Clearly we are responsible for modern diseases such as AIDS, TB and lyme disease.

With considerable hubris, we have attempted to subvert Nature's patterns through scientific means. We face extinction as a a race if we do not recognize the survival advantages that Nature has produced over billions of years. The experience with Ebola virus at Reston, Virginia showed how unprepared we are for a major ID disaster. Paradoxically, improvements in sanitation and vaccination may make us more susceptible since they leave the human herd more innocent of microbial experience.

 

1) The Coming Plague: newly emerging diseases in a world out of balance Laurie Garrett. 1994. Farrar, Straus & Giroux ($25) This is a comprehensive view of many of the serious infective problems that confront us and some of the reasons why they are occurring. If you liked Paul de Kruif's Microbe Hunters (1926) you will enjoy this comprehensive, well documented overview of infectious disease plagues and how we have brought them upon ourselves.

2) Breakout: the evolving threat of drug resistant disease. Marc Lappe 1995. Sierra Club Books ($14) A look at the threatening diseases from an evolutionary medicine viewpoint. He makes a strong case for our present, serious predicament being due to our ignoring evolutionary theory. Emerging infections are not random events, but rather direct effects of environmental changes mostly caused by homo sapiens.

3) A dancing matrix: how science confronts emerging viruses.

Robin M. Henig. 1994 Random House ($12)

4) Emerging infections: microbial threats to health in the United States. How human demographics, behavior, industry, technology, economic development, land use, international travel and commerce contribute to microbial adaptation. Concise recommendations are made to counter the deterioration in public health occurring throughout the USA. Institute of Medicine. Washington, D.C.: 1992. Handouts

National Academy Press