Chapter 7
Infectious Diseases

Pursue him to his house, and pluck him thence; Lest his infection, being of a catching nature, Spread further.

—William Shakespeare, Coriolanus, 1608

Infectious (contagious) diseases are caused by microorganisms—viruses, bacteria, parasites, or fungi—transmitted from one person to another through casual contact, such as influenza; through bodily fluids, such as HIV (human immunodeficiency virus); or via contaminated food, air, or water supplies. Infectious diseases also may spread by vectors of disease such as insects or arthropods that carry the infectious agent.

Infectious diseases are a leading cause of death worldwide, according to the World Health Organization (WHO). Not long ago, the U.S. government and medical experts believed that widespread use of vaccines, antibiotics, and public health measures had effectively eliminated the public health threat of infectious diseases. Throughout the world, however, new and rare diseases are emerging, and old diseases are resurfacing. Some of these infections reflect changes associated with increasing population, growing poverty, urban migration, drug-resistant microbes, and expanding international travel.

The mistaken belief that infectious diseases were problems of the past prompted the governments of many countries, including the United States, to neglect public health programs aimed at preventing and treating infectious disease. By 1994, however, enough troubling new diseases had arisen and old ones recurred that a federal commission recommended that the United States spend $125 million to implement a plan to respond to and contain infections.

The Centers for Disease Control and Prevention (CDC) tracks certain infectious diseases ("notifiable diseases") for the U.S. Public Health Service (PHS). The CDC defines a notifiable disease: "A notifiable disease is one for which regular, frequent, and timely information regarding individual cases is considered necessary for the prevention and control of the disease." The list of nationally notifiable diseases is revised periodically. For example, a disease might be added to the list as a new pathogen (an organism that causes disease) emerges, or a disease might be deleted as its incidence declines. Physicians, clinics, and hospitals must report any occurrences of these diseases to the CDC each week. Table 7.1 shows the nationally notifiable infectious diseases tracked in 2006.

MOST FREQUENTLY REPORTED DISEASES

Among the CDC's notifiable diseases the three most frequently reported infectious diseases in the United States in 2003 were chlamydia (877,478 cases—the highest it has been since voluntary reporting began in the mid-1980s), gonorrhea (335,104 cases), and acquired immune deficiency syndrome (AIDS; 44,232 cases), all sexually transmitted diseases. The remaining notifiable infectious diseases in the top ten were as follows:

• Salmonellosis—a foodborne disease causing fever and intestinal disorders (43,657 cases)
• Syphilis, all stages—a sexually transmitted disease that occurs in three stages; it can be congenital (an infant can be born with the disease) (34,270 cases)
• Shigellosis—foodborne and waterborne dysentery (23,581 cases)
• Lyme disease—a disease spread by ticks (21,273 cases)
• Varicella (chicken pox)—a disease (usually of childhood) marked by a vesicular rash on the face and body caused by the herpes varicella zoster virus (20,948 cases)
• Giardiasis—a common protozoal infection of the small intestine, spread via contaminated food and water and direct person-to-person contact (19,709 cases)

• Tuberculosis—an airborne disease that usually affects the lungs but also can affect the bones and other organs (14,874 cases)

Table 7.2 shows the number of cases of these and other notifiable diseases reported to the CDC each month in 2003.

RESISTANT STRAINS OF BACTERIA

Antibiotics generally have been considered "miracle drugs" that control or cure many bacterial infectious diseases. However, during the last decade nearly all major bacterial infections in the world have become increasingly resistant to the most commonly prescribed antibiotic treatments, primarily because of repeated and improper uses of antibiotics. Decreasing inappropriate antibiotic use is the best way to control this resistance.

Bacteria such as pneumococcus, which causes pneumonia and children's ear infections—diseases long considered common and treatable—are evolving into strains that are proving to be untreatable with commonly used antibiotics. Pneumococcal bacteria cause many hundreds of thousands of cases of pneumonia, bacterial meningitis (inflammation of the tissue covering the brain and spinal cord), and almost half of the more than twenty-five million annual visits to American pediatricians for otitis media (middle ear infections). Since the 1980s, national rates of penicillin resistance have soared from less than 5% of patients treated to more than 30% of patients treated in 1996 (Jay C. Butler et al, "The Continued Emergence of Drug-Resistant Streptococcus Pneumoniae in the United States: An Update from the Centers for Disease Control and Prevention's Pneumococcal Sentinel Surveillance System," Journal of Infectious Diseases, vol. 174, no. 5, November 1996).

Investigators from the Department of Microbiology—a collaborative operation between Toronto Medical Laboratories and the Mount Sinai Hospital at the University of Toronto, Canada—made an even more alarming projection of pneumococcal resistance to penicillin in the United States from 2000 to 2004. The investigators developed a mathematical model that predicted that doubly resistant strains would increase from 8.6% in 1996 to an estimated 40.6% in 2004 (Allison McGeer and Donald E. Low, "Is Resistance Futile?" Nature Medicine, vol. 9, no. 4, April 2003, http://www.nature.com/nm/journal/v9/n4/full/nm0403-390.html).

To treat patients with penicillin-resistant pneumococcus infections, physicians use a combination of other antibiotics, such as vancomycin, imipenem, and rifampin for resistant pneumonia and clindamycin or cefuroxime for ear infections. One of the national health goals for 2010 is to achieve 90% coverage of noninstitutionalized adults age sixty-five and older for both influenza and pneumococcal vaccinations. In 2000 the U.S. Advisory Committee on Immunization Practices added adults age fifty to sixty-four to the universal recommendations for influenza vaccination. Many public health professionals are advocating widespread use of the pneumococcal vaccine in the hope that it will produce "herd immunity"—when a large proportion of the population is immune, the

likelihood of person-to-person spread is so small that the disease does not proliferate and even nonimmune individuals are protected from disease.

Increase in Escherichia Coli Infection Caused by Antibiotics

On July 25, 2002, a study funded by the National Institutes of Health (NIH) reported increasing rates of Escherichia coli (E. coli) infection attributable to antibiotic use among premature infants. The study, published in the New England Journal of Medicine (vol. 347, no. 4), examined the medical records of more than five thousand babies born throughout the United States and found that E. coli infection rates had more than doubled from three per one thousand births to seven per one thousand births. E. coli and group B streptococci are bacteria that frequently exist in the gastrointestinal tract and cause no medical problems. If, however, they are passed at birth from a pregnant mother to her unborn child, then the infant's immune system may be unable to effectively combat the infection.

The study found that rates of group B strep infection among infants decreased by almost 75% during the 1990s, probably in response to increasing use of antibiotics during labor and delivery (the birthing process) to prevent mother-to-infant spread of the infection. The antibiotic most often used was amoxicillin, an antibiotic that combats strep but does not harm E. coli. As a direct result of the effort to reduce strep infections, E. coli infections increased. The researchers observed that E. coli had surpassed group B strep as the most commonly occurring infection among premature infants. This finding is considered troubling because E. coli infection is potentially more dangerous than strep infection.

Addressing the prevalence of infection attributable to antibiotic use, an April 2006 report from the National Institute of Allergy and Infectious Diseases (NIAID is one of the National Institutes of Health) asserted that antimicrobial resistance is driving up health care costs, increasing the severity of disease, and increasing mortality rates from selected infections. The institute found that more than 70% of the bacteria that cause hospital-acquired infections were resistant to at least one of the antibiotics most frequently used to treat them. Patients infected with antibiotic-resistant organisms were more likely to have longer hospital lengths of stay and require treatment with medications that were less effective, more toxic, and more costly ("The Problem of Antimicrobial Resistance," National Institute of Allergy and Infectious Diseases, http://www.niaid.nih.gov/factsheets/antimicro.htm).

Educating Physicians and Patients about Appropriate Use of Antibiotics

According to the CDC, antibiotic resistance is among the most urgent public health problems in the world. In 1995 the CDC Division of Bacterial and Mycotic Diseases began a national campaign to reduce antimicrobial resistance by encouraging appropriate use of antibiotics. In 1999 the CDC worked with several medical professional societies to develop educational programs for medical students, physicians, and patients. In a published statement, Dr. Richard Besser, medical director of the CDC's National Campaign for Appropriate Antibiotic Use, called for physician and public support to tackle the problem. Dr. Besser asserted:

The biggest problem is inappropriate prescribing of antibiotics. Up to 40% of antibiotics prescribed in physicians' offices are for viral infections, which are not treatable with antibiotics. There are many reasons for this, including demand from patients, time pressures on physicians, and diagnostic uncertainty. Patients want to get back to work or get their children back to school, and physicians want their patients to feel satisfied with treatment. The result is over-prescribing of antibiotics, resulting in the development of resistant bacteria. The best way to combat this practice is to educate physicians and the public to decrease both demand and over-prescribing. In addition, providing clinicians with better means of diagnosing respiratory infections may remove some of the uncertainty that promotes over-prescribing.

In February 2004 the CDC reported that pressure from parents makes a difference in the pediatrician's prescribing method. One study funded by a grant from the Robert Wood Johnson Foundation showed that doctors prescribe antibiotics 65% of the time if they feel that parents expect them, but only 12% of the time if they feel parents do not expect them (Rita Mangione-Smith et al., Presentation of UCLA Study at the May 6, 2002, Pediatric Academic Societies, Baltimore, MD). A study published in the October 2005 issue of the Journal of the American Academy of Nurse Practitioners found that nurse practitioners and physicians continue to prescribe inappropriate antibiotics to patients with viral upper-respiratory tract infections, a practice that may lead to increased rates of antimicrobial resistance. The researchers also found that highly marketed broad-spectrum antibiotics are being prescribed excessively to patients with diagnoses of viral illnesses despite the fact that it is well accepted that antibiotics offer no benefit in the treatment of these illnesses.

Reducing antibiotic use lowers rates of drug-resistant bacteria. Investigators in France tested two methods intended to reduce the rate of penicillin-resistant pneumococci present in kindergarten students (Didier Guillemot, Emmanuelle Varon, Claire Bernède, Philippe Weber, Laurence Henriet, Sylvie Simon, Cécile Laurent, Hervé Lecoeur, and Claude Carbon, "Reduction of Antibiotic Use in the Community Reduces the Rate of Colonization with Penicillin GNonsusceptible Streptococcus pneumo-niae," Clinical Infectious Diseases, vol. 41, no. 7, October 1, 2005). The first prescription-reduction method involved not prescribing antibiotics for respiratory tract infections that were thought to be viral, since antibiotics work against bacteria, not viruses. The second approach, a dose/duration method, entailed using only recommended doses of antibiotics for no longer than five days. The researchers also targeted physicians, pharmacists, parents, and children in the groups receiving both types of treatment with an information campaign about antibiotic resistance and appropriate antibiotic use. A control group of children and their doctors received no specific information about antibiotic use.

At the conclusion of the study, antibiotic use had declined by more than 15% in both treatment groups, compared with less than 4% in the control group. While colonization by regular pneumococci was higher in the treatment groups than in the control group, colonization by penicillin-resistant pneumococci was lower in the treatment groups than in the control group. The prescription-reduction group saw the greatest decline in penicillin-resistant colonization—from 53% to 35%—and the dose/duration group dropped from 55% to 44%. The control group remained virtually unchanged. This indicates that reduced antibiotic use permits drug-susceptible bacteria to re-establish themselves as dominant colonizers of the respiratory tract. The investigators concluded that reducing the number of prescriptions and the dose and duration of needed antibiotics has the potential to generate significant and rapid reductions of penicillin-resistant pneumococcal colonization in areas that have high rates of drug-resistant bacteria.

These findings highlight the need for professional and public awareness and understanding of the need to assume active roles in preventing antibiotic resistance. Consequences of failure of antibiotics to treat formerly treatable illnesses could be dire: longer-lasting illnesses, more physician office visits or longer hospital stays, the need for more expensive and toxic medications, and even death.

PREVENTION THROUGH IMMUNIZATION

Many infectious diseases can be prevented by immunizations. According to the National Immunization Program of the CDC, there are fifteen diseases that can be prevented by vaccination and for which vaccinations are recommended. Some other diseases are preventable by vaccination, but vaccination is not recommended for everyone because the risk of contracting these diseases is not great enough to warrant widespread immunization. They include anthrax, meningococcal infection, rotavirus, and smallpox. (See Table 2.1 in Chapter 2 for the 2006 schedule of childhood and adolescent immunizations. Table 7.3 lists the 2005–06 adult immunization recommendations.) The fifteen vaccine-preventable diseases are as follows:

• Diphtheria—This bacterial infection causes potentially fatal respiratory infections that are treated with antibiotics. People diagnosed with diphtheria are isolated until cultures are negative to prevent the spread of the disease.

• Haemophilus influenza type b (Hib)—This bacterial infections causes respiratory infections and other diseases, such as meningitis.
• Hepatitis A—The virus is spread through fecal (stool) or oral routes, though it may also be transmitted via blood or sexual contact. Outbreaks usually occur from contaminated food and water; military workers, children in day care centers, and their care providers are considered at high risk.
• Hepatitis B—It is transmitted by blood, sexual contact, or from mother to unborn child; intravenous drug users, gay men, and health care workers are at high risk.

• Influenza (flu)—This viral infection produces sudden fever, muscle aches, and respiratory infection symptoms.
• Lyme disease—This bacterial disease is spread by infected ticks and produces fever, headache, joint and muscle pain, swollen lymph nodes, and a distinctive circular skin rash. It may be treated with antibiotics or prevented by vaccine.
• Measles—This highly contagious viral disease produces red circular spots on the skin.
• Meningitis—Meningococcal vaccine was added to the 2005–06 schedule for select populations such as college students living in dormitories to prevent bacterial meningitis caused by infection with Neisseria meningitides. Meningitis means inflammation of the meninges—the covering of the brain and the spinal cord, and it is characterized by fever, vomiting, intense headache, and stiff neck.
• Mumps—This highly contagious viral disease produces swelling of the parotid glands.
• Pertussis (whooping cough)—This bacterial infection causes illness marked by spasms of coughing.
• Pneumococcal—This bacteria causes pneumonia, an inflammation of the lungs.
• Poliomyelitis (polio)—A viral disease, polio causes fever, atrophy (wasting) of skeletal muscles, and paralysis.
• Rubella (German measles)—This viral infection is usually mild in children but can seriously harm an unborn child when contracted by a woman early in her pregnancy.
• Tetanus—Bacteria produce a toxin that causes victims to have painful muscle spasms.
• Varicella (chickenpox)—This is a highly contagious viral disease marked by skin eruptions of fluid-filled lesions that itch.

Until the 1960s, for example, poliomyelitis (polio) was a serious threat to children, adolescents, and even adults. After the discovery of vaccines to prevent this disease, massive worldwide immunization programs were carried out, and by 1994 an international health commission declared that indigenous (in-country) transmission of wild (not developed in laboratories or contained in vaccines) poliovirus had been stopped in the Western hemisphere. The last reported case of polio documented in the United States was 1979. A global polio eradication initiative is spearheaded by the WHO, Rotary International, the CDC, and the United Nations Children's Fund (UNICEF), with the goal of global eradication by 2008.

INFLUENZA

Influenza (the flu) is a contagious respiratory disease caused by a virus. When a person infected with the flu sneezes, coughs, or even talks, the virus is expelled in droplets into the air and may be inhaled by anyone nearby. It also can be transmitted by direct hand contact. The flu primarily affects the lungs, but the whole body experiences symptoms. The infected person usually becomes acutely ill, with fever, chills, weakness, loss of appetite, and aching muscles in the head, back, arms, and legs. The person with influenza infection also may have a sore throat, a dry cough, nausea, and burning eyes. The accompanying fever increases quickly—sometimes reaching 104 degrees Fahrenheit—but usually subsides after two or three days. Influenza leaves the patient exhausted.

For healthy individuals, the flu is typically a moderately severe illness, with most adults and children back to work or school within a week. For the very young, the very old, and people who are not in good general health, however, the flu can be very severe and even fatal. Complications such as secondary bacterial infections may develop, taking advantage of the body's weakened condition and lowered resistance. The most common bacterial complication is pneumonia, but sinuses, bronchi (lung tubes), or inner ears also can become secondarily infected with bacteria. Less common but very serious complications include viral pneumonia, encephalitis (inflammation of the brain), acute renal (kidney) failure, and nervous system disorders. These complications can be fatal.

Who Gets the Flu?

Anyone can get the flu, especially if there is an epidemic in the community. (An epidemic is a period when the number of cases of a disease exceeds the number expected based on past experience.) During an epidemic year, 20-30% of the population may contract influenza. Not surprisingly, people who are not healthy are considered at high risk for most strains of influenza and their complications. The high-risk population includes those who have chronic lung conditions, such as asthma, emphysema, chronic bronchitis, tuberculosis, or cystic fibrosis; those with heart disease, chronic kidney disease, diabetes, or severe anemia; people residing in nursing homes; those older than age sixty-five years; and some health care workers.

Vaccines

Influenza can be prevented by inoculation with a current influenza vaccine, which is formulated annually so that it contains the influenza viruses expected to cause the flu the next year. The viruses are killed or inactivated to prevent those who are vaccinated from getting influenza from the vaccine. After being immunized, the person develops antibodies to the influenza viruses. The antibodies are most effective after one or two months. High-risk people should be vaccinated early in the fall because peak flu activity usually occurs around the beginning of the new calendar year. The flu season usually runs from October to May and peaks in December and January.

Each year's flu vaccine protects against only the viruses that were included in its formulation. If another strain of flu appears, people still can catch the new strain although they were vaccinated for the primary expected strains. The 2003–04 flu season was one of the worst in recent memories, with a nationwide shortage of vaccine early in the season, a time when the virus was peaking, and children were dying from the illness (at least 142 individuals under eighteen years old).

Most people have little or no noticeable reaction to the vaccine; 25% may have a swollen, red, tender area where the vaccination was injected. Children may suffer a slight fever for twenty-four hours or have chills or a headache. Those who already suffer from a respiratory disease may experience worsened symptoms. Usually, these reactions are temporary. Because the egg in which the virus is grown cannot be completely extracted, people with egg protein allergies should consult their physicians before receiving the vaccine and, if vaccinated, should be closely observed for any indications of an allergic reaction.

Pandemic Influenza

In "Pandemic Flu: Key Facts" the CDC defines pandemic flu as "a global outbreak of disease that occurs when a new influenza A virus 'emerges' in the human population, causes serious illness, and then spreads easily from person to person worldwide" (http://www.cdc.gov/flu/pandemic/pdf/pandemicflufacts.pdf). Pandemics are different from seasonal outbreaks or even epidemics of influenza. Seasonal outbreaks are caused by influenza viruses that already move from person to person, while pandemics are caused by new viruses, subtypes of viruses that have never passed between people, or subtypes that have not circulated among people for a very long time.

In the past, influenza pandemics have produced high levels of illness, death, social disruption, and economic loss. The twentieth century saw three pandemics. The CDC reports that the 1918–19 "Spanish flu" claimed one half million lives in the United States and as many as fifty million people throughout the world. Nearly half of the deaths were young, healthy adults. In 1957–58, "Asian flu" was responsible for seventy thousand deaths in the United States. The 1968–69 "Hong Kong flu" proved fatal for thirty-four thousand people in the United States. All three pandemics involved avian influenza, or bird flu. The 1957–58 and 1968–69 pandemics were caused by viruses containing a combination of genes from a human influenza virus and an avian influenza virus; the 1918–19 pandemic virus also appears to have been an avian flu.

Many scientists feel that it is inevitable that there will be another pandemic and that it is only a matter of time until the next influenza pandemic occurs. Although the severity of a future pandemic cannot be predicted, the CDC hypothesizes in "Pandemic Flu: Key Facts" that without effective vaccination against the flu or treatment for it, a "medium-level" pandemic in the United States could produce 89,000-207,000 deaths, 314,000-734,000 hospitalizations, 18-42 million outpatient visits, and another 20-47 million people being sick. Between 15% and 35% of the U.S. population could be affected, and the economic impact could be staggering—ranging from $71.3-$166.5 billion.

AVIAN INFLUENZA

Avian influenza is an infectious disease of birds caused by type A strains of the influenza virus. The disease, which was first identified in Italy more than one hundred years ago, occurs worldwide. Because these viruses usually do not infect humans, there is little or no immune protection against them. If an avian influenza virus infected people and gained the ability to spread easily from person to person, an influenza pandemic could begin. The first cases in humans probably resulted from contact with infected birds or surfaces contaminated with excretions from infected birds. The disease usually only affects birds and pigs; the first documented infection of humans occurred in Hong Kong in 1997. An outbreak of avian flu has affected bird populations in countries throughout Asia and Europe. It has affected humans as well—as of 2006 human cases of influenza A (H5N1) infection had been reported in Cambodia, China, Indonesia, Thailand, Vietnam, and Turkey.

The spread of H5N1 virus from person to person has been rare and as of June 2006 had not continued beyond one family living in close quarters in Indonesia. There is still, however, considerable cause for concern and vigilance, because the recent avian flu outbreaks in Asia and Europe have killed more than half of those infected. Even more frightening, most cases have occurred in previously healthy children and young adults as opposed to the old and infirm who generally succumb to influenza. However, it is possible that the only cases currently being reported are those in the most severely ill people and that the full range of illness caused by the H5N1 virus has not yet been defined.

PREPARING FOR A PANDEMIC

A vaccine is rarely available in the early stages of a pandemic. When a new vaccine against an influenza virus is being developed, scientists around the world work together to select the virus strain that will offer the best protection against that virus. Manufacturers then use the selected strain to develop a vaccine. Once a potential pandemic strain of influenza virus is identified, it takes several months before a vaccine will be widely available. For example, research to test a vaccine to protect humans against H5N1 virus began in April 2005, and clinical trials were underway in 2006.

Four different influenza antiviral medications (amantadine, rimantadine, oseltamivir, and zanamivir) are approved by the U.S. Food and Drug Administration (FDA) for the treatment and/or prevention of influenza. All four usually work against influenza A viruses. But the drugs are not always effective because influenza virus strains can become resistant to one or more of these medications. For example, the influenza A (H5N1) viruses identified in humans in Asia in 2004 and 2005 have proven resistant to amantadine and rimantadine, as has the seasonal flu strain that circulated in the 2005–06 U.S. influenza season ("CDC Health Alert: CDC Recommends against the Use of Amantadine and Rimandatine for the Treatment or Prophylaxis of Influenza in the United States during the 2005–06 Influenza Season," January 14, 2006, http://www.cdc.gov/flu/han011406.htm).

The U.S. Department of Health and Human Services (HHS) supports pandemic influenza activities in the areas of surveillance, vaccine development and production, strategic stockpiling of antiviral medications, research, and risk communications. In May 2005 U.S. Secretary of HHS Mike Leavitt created a multiagency National Influenza Pandemic Preparedness and Response Task Group. This initiative involves the CDC and public and private agencies at every level (international, national, state, local, and private) in planning for a potential pandemic. By early 2006 pandemic flu planning was underway—national, state, and local municipality programs, plans for businesses and schools, and advice for families and individuals. Prepared by the CDC, Table 7.4 outlines steps individuals and families can take to prepare for a pandemic flu, such as stockpiling nonperishable food and regular prescription medication.

On January 12, 2006, Leavitt announced $100 million in funding for state and local pandemic flu preparedness. This funding is part of $350 million included in the recent emergency appropriation for combating pandemic influenza passed by Congress in December 2005. Each state will receive a minimum of $500,000, with additional allocation of funds by population. States and municipalities will use these funds to accelerate and intensify current planning efforts for pandemic influenza. Current planning emphasizes practical, community-based procedures that could prevent or delay the spread of pandemic flu and help to reduce the burden of illness communities would have to manage during an outbreak ("HHS Announces $100 Million to Accelerate State and Local Pandemic Influenza Preparedness Efforts," HHS Press Office, January 12, 2006, http://www.hhs.gov/news/press/2006pres/20060112.html).

TUBERCULOSIS

Tuberculosis (TB), a communicable disease caused by the bacterium Mycobacterium tuberculosis, is spread from person to person through the inhalation of airborne particles containing M. tuberculosis. The particles, called droplet nuclei, are produced when a person with infectious TB of the lungs or larynx forcefully exhales, such as when coughing, sneezing, speaking, or singing. These infectious particles can remain suspended in the air and may be inhaled by someone sharing the same air.

Most TB (approximately 85%) occurs in the lungs (pulmonary TB). Risk of transmission is increased where ventilation is poor and when susceptible people share air for prolonged periods with a person who has untreated pulmonary TB. The disease, however, may occur at any site of the body, such as the larynx, the lymph nodes, the brain, the kidneys, or the bones. This type of TB infection, which occurs outside the lungs, is referred to as extrapulmonary. With the exception of laryngeal TB, people with extrapulmonary TB are usually not considered infectious to others.

TB does not develop in everyone infected with the bacteria. In the United States about 90% of infected people never show symptoms of TB. Nevertheless, 5% of people infected develop the disease in the first or second year after infection. Another 5% show symptoms later in life. For people with compromised immune systems, the risk of developing TB is much higher. For example, more than 10% of those infected with both TB and HIV (the virus that causes AIDS) develop full-blown TB symptoms within a year, according to Elizabeth L. Corbett et al in "The Growing Burden of Tuberculosis: Global Trends and Interactions with the HIV Epidemic" (Archives of Internal Medicine, vol. 163, no. 9, May 12, 2003).

Ancient Enemy and Continuing Threat

Each year, two million people worldwide die from TB, according to the WHO, and more than eight million people become sick with TB annually (http://www.who.int/mediacentre/factsheets/who104/en/print.html). Overall, one-third of the world's population is infected with the TB bacillus. This has increased dramatically since the HIV/AIDS epidemic swept through many countries. In 2000 the WHO estimated that at least five million adults worldwide—primarily in sub-Saharan Africa, Latin America, and Asia—had been infected with both AIDS and M. tuberculosis. Corbett et al report that TB accounts for 11% of deaths from AIDS worldwide.

After several decades of decline, TB made a comeback in the United States in the late 1980s and early 1990s. From 1985 to 1993 more than 64,000 new TB cases were reported. In 1992 the CDC reported 26,673 cases of TB, up from 22,201 in 1985. Since 1992 the number of cases has declined steadily, and by 2004 it had decreased to 14,517. (See Table 7.5.)

The decline in the total number of TB cases reported to the CDC is attributable to new public health programs that monitor the complicated drug-treatment protocols for patients with TB. The success of prevention and treatment programs varies depending on the location and population. Despite these overall national declines in TB incidence, substantial disparities exist between rates in the majority of U.S. residents and rates in two U.S. populations—foreign-born people and U.S.-born non-Hispanic African-Americans, both of which experience higher rates of TB. (See Table 7.6 and Figure 7.1.)

Treatment has become increasingly difficult because new strains of multidrug-resistant (MDR) TB have developed. If the disease is not properly treated or if treatment is not completed, some TB can become resistant to drugs, making it much harder to cure. According to the CDC, in 2003, the most recent year for which drug-susceptibility data were available, there were 114 cases of MDR TB, and it was more common in foreign-born people (1.2%) than in U.S.-born residents (0.6%; http://www.cdc.gov/od/oc/media/pressrel/fs050317.htm). The CDC also reports that in 2000, 80.8% of patients with TB completed therapy in one year or less, and 92.2% completed therapy overall.

The CDC reports in Emerging Infectious Diseases (Anthony S. Fauci, Nancy A. Touchette, Gregory K. Folkers, "Emerging Infectious Diseases: A 10-Year Perspective from the National Institute of Allergy and Infectious Diseases," vol. 11, no. 4, April 2005, http://www.cdc.gov/ncidod/eid/vol11no04/pdfs/04-1167.pdf) that researchers are using genomic (science that studies the structure and function of genes) techniques to identify key molecular pathways that could be used to develop improved TB treatments and vaccines. In 2004, for the first time in sixty years, clinical trials of two new vaccines designed to prevent TB began. Many promising new anti-TB drug candidates also are now entering the drug pipeline. Derivatives of known anti-TB drugs, such as thiolactomycin and ethambutol, are currently being screened for activity against Mycobacterium tuberculosis, and another new anti-TB drug, SQ109, is under development.

March 24 of each year has been designated "World TB Day" by the NIAID to recognize the global threat to health posed by the disease. If the disease is not controlled and treatment is not improved, it is estimated that between 2002 and 2020 approximately one billion people will be newly infected with TB, more than 150 million people will get sick from TB, and thirty-six million will die of TB, according to the WHO.

HIV/AIDS

AIDS is the late stage of an infection caused by HIV, a retrovirus that attacks and destroys certain white blood cells, which weakens the body's immune system and makes it susceptible to infections and diseases that ordinarily would not be life threatening. AIDS is considered a bloodborne, sexually transmitted disease because HIV is spread through contact with blood, semen, or vaginal fluids from an infected person.

Around the World

AIDS and HIV were virtually unknown before 1981, when testing and reporting of the disease became mandatory, but awareness grew as the annual number of diagnosed cases and deaths steadily increased. By 2006 more than forty million people worldwide were estimated to be living with HIV/AIDS, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the WHO. Of those infected, thirty-eight million were adults and about 2.3 million were children younger than age fifteen. Nearly five million people were newly infected with the virus in 2005. Two-thirds of all people infected with HIV lived in sub-Saharan Africa. In 2005 an estimated 25.8 million people in this region were living with HIV, and AIDS killed approximately 2.4 million people in the region the same year. Unlike women in other regions in the world, African women are much more likely (about twice as much) than men to be infected with HIV—more than three-quarters (77%) of all women infected with HIV are in sub-Saharan Africa ("AIDS Epidemic Update," UNAIDS, WHO, December 2005, http://www.unaids.org/epi/2005/doc/report_pdf.asp).

Since the epidemic began, more than twenty-five million people have died of AIDS; more than three million died in 2005 alone. Of those, more than half a million were children.

In the United States

The CDC reports in HIV/AIDS Surveillance Report, 2004 (http://www.cdc.gov/hiv/stats/2004Surveillance Report.pdf) that by December 2004 there were an estimated 462,792 persons in the United States living with HIV/AIDS, in the thirty-five areas with confidential name-based HIV infection reporting since 2000. Of all HIV infections diagnosed in 2003, 39% progressed to AIDS within twelve months after HIV infection was diagnosed. In 2003 an estimated 43,171 diagnoses of AIDS in the United States were made. Adult and adolescent AIDS cases totaled 43,112, with 31,614 cases in males and 11,498 cases in females, and an estimated fifty-nine AIDS cases were diagnosed in children under age thirteen.

The HIV/AIDS Surveillance Report, 2004 also notes that from 2000 through 2004 the estimated number of AIDS cases increased about 7% among males and 10% among females. In 2004 males accounted for nearly three-quarters (73%) of all HIV/AIDS cases among adults and adolescents. Rates of AIDS cases in 2004 were 25.6 per one hundred thousand among males and nine per one hundred thousand among females. (See Table 7.7.) Since its recognition in 1981, the disease has killed more than half a million people in the United States.

How Is AIDS Spread?

HIV/AIDS is not transmitted through casual contact with an infected person. The CDC has identified several behavioral risk factors that greatly increase the likelihood of a person's chances of being infected. Table 7.8 shows the estimated numbers of those diagnosed with AIDS by year of diagnosis and selected characteristics of patients, including the ways in which they contracted the disease.

More than twenty-five years of research and observation have definitively concluded that the HIV infection can only be transmitted by the following methods:

• By oral, anal, or vaginal sex with an infected person; worldwide, heterosexual sex is the most common mode of transmission
• By sharing drug needles or syringes with an infected person
• From an infected mother to her baby at the time of birth and possibly through breast milk
• By receiving a transplanted organ or bodily fluids, such as blood transfusions or blood products, from an infected person

Because avoiding these methods of transmission virtually eliminates the possibility of becoming infected with HIV, unlike some other infectious diseases, AIDS is considered almost entirely preventable.

High concentrations of HIV have been found in blood, semen, and cerebrospinal fluid. Concentrations one thousand times less have been found in saliva, tears, vaginal secretions, breast milk, and feces. There have been no reports, however, of HIV transmission from saliva, tears, or human bites. In fact, in 1995 the National Institute of Dental Research in Bethesda, Maryland, reported that a small protein found in human saliva actually blocks the virus from entering the system.

Opportunistic Infections

Once HIV has destroyed the immune system, the body can no longer protect itself against bacterial, fungal, parasitic, or viral agents that take advantage of the compromised condition, causing opportunistic infections (OIs). OIs are illnesses caused by organisms that would not normally harm a healthy person. Because the patient is considered to have AIDS if at least one OI appears, OIs are considered "AIDSdefining events." OIs are not the only AIDS-defining events; the diagnosis of malignancies such as Kaposi's sarcoma, Burkitt's lymphoma, invasive cervical cancer, and primary brain lymphoma also are considered AIDS-defining events.

One of the most common opportunistic infections is Pneumocystis carinii pneumonia, a lung infection caused by a fungus. Other infections to which patients with AIDS are susceptible are toxoplasmosis (a contagious disease caused by a one-cell parasite); oral candidiasis (thrush); esophageal or bronchial candidiasis; extrapulmonary cryptococcosis; pulmonary TB; extrapulmonary TB; Mycobacterium avium complex (MAC), a serious bacterial infection that can occur in one part of the body, such as the liver, bone marrow, and spleen, or can spread throughout the body; and cytomegalovirus disease (CMV), a member of the herpes virus group.

Treatment of AIDS

The first drug thought to delay symptoms was zidovudine (earlier known as AZT, later as ZDV), but its effects have been found to be temporary at best. Several other drugs work on the same principle as ZDV, but until the advent of protease inhibitors (PIs), a class of drugs that became available in the mid-1990s, it seemed that there was no way of stopping HIV. Protease inhibitors appear to keep HIV from reproducing, unlike ZDV and similar drugs, which help keep HIV out of the cell's chromosomes. Even if the PIs are not entirely effective long term in reducing patients' viral "loads," they have improved patients' prospects simply by creating more roadblocks for HIV. Unfortunately, HIV mutates so rapidly that it eventually becomes resistant to most drugs when they are used alone.

Treatment recommendations change rapidly in response to the development of new drugs and clinical trials indicating the effectiveness of different combinations of antiretroviral drugs. Researchers are acting quickly to develop new mixtures of the recently approved and older drugs. Because HIV mutates to resist any drug it faces, including all PIs, researchers have found that varying the combination of drugs prescribed can "fool" the virus before it has time to mutate.

Still, there are reasons for optimism in the battle against HIV/AIDS. The CDC reports in Emerging Infectious Diseases that since the use of combinations of drugs that target different proteins involved in HIV pathogenesis (a treatment strategy known as highly active antiretroviral therapy or HAART), rates of death and illness in the United States and other industrialized countries have been dramatically reduced—the death rate due to HIV/AIDS in Europe and North America has fallen by 80%. As of 2006 more than twenty antiretroviral medications were approved by the FDA that target HIV, and researchers were pursuing novel strategies for prevention and vaccine development. Although the first large-scale trial of an HIV vaccine reported in 2003 was disappointing, as of 2006 there were fifteen clinical trials of different vaccine strategies underway, including viral and bacterial vectors, DNA vaccines, virus-like particle vaccines, and peptide vaccines. Even if a cure for the disease is not imminent, new and better drugs used in various combinations have made HIV infection a chronic but manageable disease, much like diabetes.

COMPLICATIONS, COSTS, AND SIDE EFFECTS OF TREATMENT

Patients undergoing therapy with these anti-retroviral drugs or drug combinations must be highly disciplined. For instance, Crixivan must be taken on an empty stomach, every eight hours, not less than two hours before or after a meal, and with large amounts of water to prevent development of kidney stones. Patients also must be careful never to skip doses of Crixivan; otherwise, HIV will quickly grow immune to its effect. (Crixivan has been found to generate cross-resistance, meaning it made patients resistant to other PIs.) Invirase must be taken in large doses. Norvir must be carefully prescribed and administered because it interacts negatively with some antifungals and antibiotics used by patients with AIDS. Because there are a variety of minor and serious risks associated with use of these drugs, patients must be closely monitored by health care practitioners.

The drug regimens are complicated, produce severe side effects in a substantial number of patients, and are costly. The cost of protease inhibitors, such as Viracept and Crixivan, ranges from $4,800 to $8,000 for a year's supply. When combined with ZDV or any of the other commonly used antiretroviral drugs—such as lamivudine (3TC), zalcitabine (ddC), didanosine (ddI), or stavudine (d4T)—the cost is approximately $18,000 per year. Lifetime treatment costs for HIV/AIDS are estimated to be in excess of $155,000. According to Benjamin Young, MD, PhD, of the University of Colorado School of Medicine, the cost of HAART varies from $1,000 to $2,000 per month. Dr. Young observed that many variables are involved in calculating the actual cost to the

individual—insurance coverage, governmental assistance programs, and pharmaceutical company patient-assistance programs. For some patients, drug clinical trials offer access to these costly medications ("The Cost of HAART," in "Ask the Experts about Choosing Your Meds," The Body.com, http://www.thebody.com/Forums/AIDS/Starting/Current/Q140963.html). Government programs and private insurers alike are looking for ways to pay for, and in some cases, avoid paying for, these new therapies.

NEW, MORE EFFICIENT HIV TREATMENT

In January 2006, an international team of AIDS researchers determined that a once-daily combination of three antiretroviral drugs is more effective as initial treatment for HIV infection than the previous and widely used three-drug combination. The researchers found that after one year of treatment, a regimen of antiretroviral pills, called tenofovir DF (Viread) and emtricitabine (Emtriva), plus efavirenz (Sustiva), improved patients' ability to suppress the virus by 14%. Even more promising, the new regimen produced fewer side effects and researchers were optimistic that the simpler, more convenient regimen would encourage more people to seek treatment and increase adherence to prescribed treatment (Joel E. Gallant et al, "Tenofovir DF, Emtricitabine, and Efavirenz vs. Zidovudine, Lamivudine, and Efavirenz for HIV," New England Journal of Medicine, vol. 354, no. 3, January 19, 2006, http://content.nejm.org/cgi/content/abstract/354/3/251).

HIV and Tuberculosis

TB occurs with increasing frequency among people infected with HIV. In fact, HIV infection has become one of the strongest known risk factors for the progression of TB from infection to disease. A 1996 report from the Conference on Retroviruses and Opportunistic Infections concluded that the decline in CD4+ T-cells is greater in patients with HIV who develop TB than in those who remain free of the disease. In some geographic areas as many as 58% of people with TB were HIV-positive. Figure 7.2 shows the estimated percent of persons ages twenty-five to forty-four with TB that also are infected with HIV from 1993 to 2003.

Of the many diseases associated with HIV infection, TB is one of the few that is transmissible, treatable, and preventable. It is important to note that HIV is a blood-borne infection and cannot be spread through air. A person with HIV who has TB can spread TB nuclei through the air, but they cannot spread HIV this way.

LYME DISEASE

Spread by the bites of infected deer ticks, Lyme disease is the most commonly reported vector-borne disease in the United States. (Vector-borne means the indirect transmission of an infectious agent that occurs when any animal that transmits human disease touches or bites an individual.) Lyme disease is caused by the Borrelia burgdorferi organism and produces early symptoms such as skin rashes, headache, fever, and general illness; if untreated, the disease can cause arthritis and heart damage.

The CDC began to track Lyme disease in 1982, and the disease was added to the list of nationally notifiable diseases in 1990. Figure 7.3 shows the dramatic increase in the number of reported cases since the early 1990s. In 2004 the CDC received reports of 19,804 cases of Lyme disease, with the majority of cases occurring in twelve northeastern and north central states—Connecticut, Rhode Island, New Jersey, New York, Pennsylvania, Delaware, Massachusetts, Wisconsin, Minnesota, Maine, New Hampshire, and Maryland. In these twelve states the average was 27.4 cases for every one hundred thousand persons.

In December 1998 the FDA announced approval for the world's first vaccine against Lyme disease. Doctors warned, however, that although the vaccine, LYMErix, developed by SmithKline Beecham, would help prevent Lyme disease, it would not eliminate the threat entirely. To achieve the best immunity, a person must receive a series of three shots over the course of a full year.

Because LYMErix is not 100% protective, the FDA warned that people still must take precautions against ticks. Wearing long-sleeved shirts and long pants, tucking pants legs into socks, and spraying the skin and/or clothing with tick repellents can keep ticks away from the skin. If a tick is found on the body, it should be removed promptly, and the affected individual should be alert for early symptoms of the disease. Immediate medical treatment is imperative to prevent long-term health damage from Lyme disease.

WEST NILE VIRUS

West Nile virus (WNV) is common in Africa, West Asia, and the Middle East, and it can infect birds, mosquitoes, horses, humans, and other mammals. It is spread by bites from infected mosquitoes, and although most people who become infected have few or no symptoms, some develop serious and even fatal illnesses. The virus first was reported in the United States in 1999, and the CDC has tracked its westward spread across the United States. During 2003 and 2004 WNV caused approximately 12,400 cases of human illness, including more than 360 deaths in the United States (http://www.cdc.gov/ncidod/dvbid/westnile/qa/cases.htm).

According to the CDC, the presence of West Nile virus in either humans or infected mosquitoes is permanently established in the United States. Although human illness from the virus is relatively rare, the disease, which is more likely to be fatal in elderly people and young children, was responsible for the death of 119 people in 2005 (http://www.cdc.gov/ncidod/dvbid/westnile/surv& controlCaseCount05_detailed.htm). Figure 7.4 shows the distribution of human WNV cases by state as well as infection of birds, animals, or mosquitoes.

The CDC advises taking precautions against mosquito bites, such as using insect repellent; wearing long pants and long-sleeved shirts treated with insect repellents; remaining indoors during dawn, dusk, and early evening, the hours when mosquitoes are most likely to bite; and removing standing water to prevent mosquitoes from laying eggs and breeding near homes and other populated buildings.

In 2006 there were at least two promising vaccine candidates against WNV. One, based on a yellow fever vaccine virus that contains two WNV genes, was being evaluated in human clinical trials. A second vaccine developed at NIH uses a virus into which WNV genes have been inserted. This vaccine protects monkeys and horses against WNV infection, and a clinical trial was underway. Several novel therapies also were being tested to treat persons already infected with WNV. The protective effect of an immunoglobulin product was being tested in hospitalized patients who have WNV encephalitis (viral infection of the brain). Investigators also were evaluating many naturally occurring and laboratory-made compounds to find out if they can combat WNV. The CDC reports in Emerging Infectious Diseases that as of February 2005 fifteen hundred compounds had been screened for antiviral action against WNV, and 2-3% were shown to have antiviral activity against WNV. Other research is focusing on the roles of mosquitoes and animals in virus transmission and testing new mosquito control methods.

SEVERE ACUTE RESPIRATORY SYNDROME

Severe acute respiratory syndrome (SARS) is a viral respiratory illness caused by a coronavirus that first was reported in Asia in late 2002. The illness spread to more than two-dozen countries in North America, South America, Europe, and Asia before the global outbreak was contained in July 2003. SARS seems to be transmitted primarily by person-to-person contact, through respiratory droplets, which travel via coughs or sneezes to the mucous membranes of other people or to surfaces that others touch. Symptoms of the disease may include high fever (more than 104 degrees Fahrenheit), body aches, malaise (overall discomfort), diarrhea, and mild respiratory symptoms; after two to seven days the infected person may develop a dry cough. The disease then progresses to pneumonia in most people.

According to the WHO, 8,098 people worldwide became sick with SARS during the outbreak, and 774 died. In the United States eight people—all of whom had traveled to parts of the world where the virus was present—contracted the disease.

In 2005 the NIAID applied its resources to developing diagnostics, vaccines, and identifying antiviral compounds to combat SARS-associated coronavirus (SARS-CoV). Among the many projects that have received NIAID support are the development of a "SARS chip," a DNA microarray to rapidly identify SARS sequence variants, and a SARS diagnostic test based on polymerase chain reaction (PCR) technology. (PCR is a technique for amplifying DNA sequences by as many as one billion times, and it is important in biotechnology, medicine, and genetic research.)

The CDC reports in Emerging Infectious Diseases that researchers have developed two candidate vaccines that protect mice against SARS. Another promising vaccine protects against infection in monkeys when delivered as a nasal spray. Passive immunization (immunity acquired by the transfer of antibodies from another individual) is also being assessed as a treatment for SARS. In 2004 screening of more than twenty thousand chemicals identified about fifteen hundred compounds with activity against SARS-CoV, and at least one has been deemed a candidate for further clinical development.

RESPONDING TO BIOLOGIC TERRORISM: INTENTIONAL EPIDEMICS

In September and October 2001, in an unprecedented event, twenty-two letters containing Bacillus anthracis spores sent through the U.S. Postal Service caused anthrax outbreaks in seven states: Connecticut, one case; Florida, two cases; Maryland, three cases; New Jersey, five cases; New York City, eight cases (includes a case of a New Jersey resident exposed in New York City); Pennsylvania, one case; and Virginia, two cases. Five of the letters resulted in fatal cases of anthrax.

These anthrax attacks "starkly exposed the vulnerability of the United States and the rest of the world to bioterrorism," according to the NIAID. Accordingly, the organization has devoted one third of its research portfolio to accelerated programs to prevent, diagnose, and treat possible intentional epidemics. Efforts focus on "Category A" agents considered to be the worst bioterror threats (smallpox, anthrax, botulinum toxin, plague, tularemia, and hemorrhagic fever viruses such as Ebola) and on Category B and C priority agents that also pose significant threats to human health.

More than sixty NIAID biodefense initiatives were funded in fiscal years 2002–05, the CDC reported in Emerging Infectious Diseases. Among them were funding for eight regional centers of excellence for biodefense and emerging infectious diseases research and construction of two national biocontainment laboratories and nine regional biocontainment laboratories. These facilities provide the secure space needed to carry out the nation's expanded biodefense research program. Researchers have sequenced the genomes of all biological agents considered to pose the most severe threats, and the NIAID has awarded contracts to screen new chemical compounds as possible treatments for bioterror attacks.

NIAID also has been active in vaccine development as a biodefense countermeasure. The institute has supported the development of a next-generation anthrax vaccine, known as recombinant protective antigen (rPA), which as of 2006 was undergoing clinical trials. Several new smallpox vaccines also were being tested for safety and efficacy. A clinical trial of a new DNA vaccine against Ebola virus and human testing of an adeno-virus-vectored Ebola vaccine began in 2005.