CHAPTER 172

Biology of Infectious Disease

Microorganisms are tiny living creatures, such as bacteria and viruses. Microorganisms are present everywhere. Despite their overwhelming abundance, relatively few of the thousands of species of microorganisms invade, multiply, and cause disease in people.

Many microorganisms live on the skin and in the mouth, upper airways, intestine, and genitals (particularly the vagina) without causing disease. Whether a microorganism lives as a harmless companion to a person or invades and causes disease depends on the nature of the microorganism and on the state of the person’s natural defenses.

Resident Flora

Healthy people live in harmony with most microorganisms that establish themselves on (colonize) the body. The microorganisms that usually occupy a particular body site are called the resident flora. Microorganisms that colonize people for hours to weeks but do not establish themselves permanently are called transient flora.

The resident flora at each site includes several different types of microorganisms. Some sites are normally colonized by several hundred different types of microorganisms. Environmental factors—such as diet, sanitary conditions, air pollution, and hygienic habits—influence what species make up a person’s resident flora. If disturbed, for example by washing or use of antibiotics, the resident flora usually promptly reestablishes itself.

Rather than causing disease, the resident flora often protects the body against disease-causing organisms. However, under certain conditions, microorganisms that are part of a person’s resident flora may cause disease. Such conditions include the use of antibiotics and a weakened immune system (as occurs in people with AIDS or cancer, people taking corticosteroids, and those receiving chemotherapy). When antibiotics used to treat an infection kill a large proportion of certain types of bacteria of the resident flora, other resident bacteria or fungi can grow unchecked. For example, a vaginal yeast infection may occur in women taking antibiotics for a bladder infection.

Development of Infection

Infectious diseases are usually caused by microorganisms that invade the body and multiply. Invasion by most microorganisms begins when they adhere to cells in a person’s body. Adherence is a very specific process, involving “lock-and-key” connections between the microorganism and cells in the body. Whether the microorganism remains near the invasion site or spreads to other sites depends on such factors as whether it produces toxins, enzymes, or other substances.

Some microorganisms that invade the body produce toxins. For example, Clostridium tetani in an infected wound produces a toxin that causes tetanus. Some diseases are caused by toxins produced by microorganisms outside the body. Food poisoning caused by staphylococci is one example. Most toxins contain components that bind specifically with molecules on certain cells (target cells). Toxins play a central role in such diseases as tetanus, toxic shock syndrome, botulism, anthrax, and cholera.

TYPES OF INFECTIOUS ORGANISMS

After invading the body, microorganisms must multiply to cause infection. After multiplication begins, one of three things can happen:

Microorganisms continue to multiply and overwhelm the body’s defenses.

A state of balance is achieved, causing chronic infection.

The body—with or without medical treatment—destroys and eliminates the invading microorganism.

Many disease-causing microorganisms have properties that increase the severity of the diseases they cause (virulence) and help them resist the body’s defense mechanisms. For example, some bacteria produce enzymes that break down tissue, allowing the infection to spread faster.

Some microorganisms have ways of blocking the body’s defense mechanisms, such as the following:

Interfering with the body’s production of antibodies or T cells (a type of white blood cell), which are specifically armed to attack the microorganisms

Being enclosed in protective outer coats (capsules) that prevent white blood cells from ingesting the microorganisms. (The fungus Cryptococcus actually develops a thicker capsule after it enters the lungs for the specific purpose of resisting the body’s defenses.)

Resisting being split open (lysed) by substances circulating in the bloodstream

Producing substances that counter the effects of antibiotics

Microorganisms that do not at first have ways of blocking the body’s defenses sometimes develop them over time. For example, some microorganisms exposed to penicillin become resistant to that drug.

Defenses Against Infection

Physical barriers and the immune system defend the body against organisms that can cause infection. Physical barriers include the skin, mucous membranes, tears, earwax, mucus, and stomach acid. Also, the normal flow of urine washes out microorganisms that enter the urinary tract. The immune system uses white blood cells and antibodies to identify and eliminate organisms that get through the body’s physical barriers (see page 1096).

Physical Barriers

Usually, the skin prevents invasion by microorganisms unless it is damaged—for example, by an injury, insect bite, or burn. Other effective physical barriers are the mucous membranes, such as the linings of the mouth, nose, and eyelids. Typically, mucous membranes are coated with secretions that fight microorganisms. For example, the mucous membranes of the eyes are bathed in tears, which contain an enzyme called lysozyme that attacks bacteria and helps protect the eyes from infection.

Identifying an Infectious Organism

Usually, doctors need to know which specific microorganism is causing a disease. Many different microorganisms can cause a given disease (for example, pneumonia can be caused by viruses, bacteria, or fungi), and the treatment is different for each organism.

There are many ways to identify microorganisms.

Examination under a microscope: Despite the development of rapid identification systems, direct microscopic examination of samples taken from the site of infection is often the most rapid method of identifying microorganisms that cause disease. Chemical stains are usually applied to make the microorganisms easier to see. The size and shape of the microorganisms and their stained color can help distinguish between different types. However, the microorganisms must be of sufficient size and number to be seen with a regular microscope. For example, viruses are too small to be seen with a regular microscope.

Culture: Usually, microorganisms are too few or too small to see, so they may be grown in the laboratory until there are enough to be identified with chemical tests. The process of growing the organism is called a culture. Many microorganisms, such as the bacteria that cause gonorrhea or strep throat, can be grown this way.

Cultures can also be used to test the sensitivity of microorganisms to various antibiotics. This testing can help a doctor determine which drug to use in treating an infected person. This strategy is particularly important because microorganisms are constantly developing resistance to antibiotics that were previously effective.

Tests that detect antibodies: Some microorganisms, such as the bacteria that cause syphilis and the human immunodeficiency virus (HIV), are very difficult to culture. These infections, and many others, can be identified by finding antibodies to the microorganisms in the infected person’s blood or body fluids (for example, cerebrospinal fluid).

Antibody-based tests are used to identify many infections, but they are not always reliable. These tests may not become positive for several days or weeks after people become ill. Also, these tests may indicate infection when none is present because they detect antibodies from a previous infection. Antibodies often stay in the body for many years after an infection has gone away.

Nucleic acid amplification tests: These tests, such as the polymerase chain reaction (PCR), identify pieces of the microorganism’s genetic material (DNA), which are present only when the organism is present.

These tests are done only when a doctor already suspects a particular disease. Therefore, a doctor’s understanding of all the features of a disease, including symptoms, physical examination results, and risk factors, is essential for diagnosing an infection.

The airways filter out particles that are present in the air that is breathed in. The walls of the passages in the nose and airways are coated with mucus. Microorganisms in the air become stuck to the mucus, which is coughed up or blown out of the nose. Mucus removal is aided by the coordinated beating of tiny hairlike projections (cilia) that line the airways. The cilia sweep the mucus up the airways, away from the lungs.

The digestive tract has a series of effective barriers, including stomach acid, pancreatic enzymes, bile, and intestinal secretions. The contractions of the intestine (peristalsis) and the normal shedding of cells lining the intestine help remove harmful microorganisms.

The bladder is protected by the urethra, the tube that drains urine from the body. In males older than 6 months, the urethra is long enough that bacteria are seldom able to pass through it to reach the bladder, unless the bacteria are unintentionally placed there by catheters or surgical instruments. In females, the urethra is shorter, occasionally allowing external bacteria to pass into the bladder. The flushing effect as the bladder empties is another defense mechanism in both sexes. The vagina is protected by its normal acidic environment.

The Blood

One way the body defends against infection is by increasing the number of certain types of white blood cells (neutrophils and monocytes), which engulf and destroy invading microorganisms. The increase can occur within several hours, largely because white blood cells are released from the bone marrow, where they are made. The number of neutrophils increases first. If an infection persists, the number of monocytes increases. The blood carries white blood cells to sites of infection. The number of eosinophils, another type of white blood cell, increases in allergic reactions and many parasitic infections, but usually not in bacterial infections.

Certain infections, such as typhoid fever, actually lead to a decrease in the white blood cell count. How these infections cause the decrease is not known.

Inflammation

Any injury, including an invasion by microorganisms, causes inflammation in the affected area. Inflammation, a complex reaction, results from many different conditions. Through release of different substances from the damaged tissue, inflammation directs the body’s defenses to do the following:

Biological Warfare and Terrorism

Biological warfare is the use of microbiological agents for hostile purposes. Such use is contrary to international law and has rarely occurred during formal warfare in modern history, despite the extensive preparations and stockpiling of biological agents by most major powers during the 20th century. It is uncertain whether other countries or dissident groups have biologic warfare capability. For a variety of reasons (including uncertain military efficacy and the threat of massive retaliation), experts consider the use of biological agents in formal warfare unlikely. However, biological agents are thought by some people to be an ideal weapon for terrorists. These agents may be delivered clandestinely, and they have delayed effects, allowing the user to remain undetected.

Potential biological agents include anthrax, botulinum toxin, brucellosis, encephalitis viruses, hemorrhagic fever viruses (Ebola and Marburg), plague, tularemia, and smallpox. Each of these is potentially fatal and, except for anthrax and botulinum toxin, can be passed from person to person.

Anthrax spores are relatively easy to prepare and, unlike most other agents, can be spread through the air, creating the potential for distribution by airplane. Theoretically, 1 kilogram of anthrax could kill 10,000 people, although technical difficulties with preparing the spores in a sufficiently fine powder would probably limit actual deaths to a fraction of this number.

Despite these theoretical concerns, the only successful terrorist use of anthrax—multiple pieces of contaminated mail delivered to a variety of locations in the United States in 2001—resulted in only a handful of deaths and a small number of serious infections (22 total cases). More people were contaminated with anthrax spores without developing illness, possibly because of extensive use of the antibiotic ciprofloxacin. However, there was extreme public anxiety related to these incidents.

The number of false threats of anthrax reported was very large. In 1999, the FBI received an average of one false report of anthrax use per day. Even more false reports, both hoaxes and reports by alarmed citizens mistaking harmless material for anthrax, were reported after the 2001 anthrax attack.

The only other successful use of a biological agent by a terror group in the United States occurred in 1984. In this event, 751 people developed diarrhea resulting from the intentional contamination of a salad bar with Salmonella in Oregon. The bacteria were introduced by a religious cult trying to influence the results of a local election. No one died, and the election was not affected.

Defense against bioterrorism involves several factors:

Intelligence information to disrupt the terrorists before they can use the weapons

Early detection

Availability of protective antibiotics

Immunization of selected populations (such as the military)

Wall off the area

Attack and kill any invaders

Dispose of dead and damaged tissue

Begin the process of repair

However, inflammation may not be able to overcome large numbers of microorganisms.

During inflammation, the blood supply increases. An infected area near the surface of the body becomes red and warm. The walls of blood vessels become more porous, allowing fluid and white blood cells to pass into the affected tissue. The increase in fluid causes the inflamed tissue to swell. The white blood cells attack the invading microorganisms and release substances that continue the process of inflammation. Other substances trigger clotting in the tiny vessels (capillaries) in the inflamed area, which delays the spread of the infecting microorganisms and their toxins. Many of the substances produced during inflammation stimulate the nerves, causing pain. Reactions to the substances released during inflammation include the chills, fever, and muscle aches that commonly accompany infection.

Infection From Medical Devices

Usually, people think of infection as occurring when microorganisms invade the body and adhere to specific cells. But microorganisms can also adhere to medical devices (such as catheters, artificial joints, and artificial heart valves) that are placed in the body.

Microorganisms may be present on the device when it is inserted if the device was accidentally contaminated. Or infecting organisms from another site may spread through the bloodstream and lodge on an already implanted device. Because implanted material has no natural defenses, the microorganisms can easily grow and spread, causing disease.

Some Causes of Fever

Infection

Cancer

An allergic reaction

Hormone disorders, such as pheochromocytoma or hyperthyroidism

Connective tissue disorders, such as rheumatoid arthritis, systemic lupus erythematosus (lupus), and giant cell arteritis

Excessive exercise, especially in hot weather

Excessive exposure to the sun, especially in hot weather

Certain drugs, including anesthetics, antipsychotics, tumor necrosis factor inhibitors (used to treat rheumatoid arthritis), drugs with anticholinergic effects, and overdoses of aspirin

Damage to the hypothalamus (the part of the brain that controls temperature), as may result from a head injury or a tumor

Immune Response

When an infection develops, the immune system responds by producing several substances and agents that are designed to attack the specific invading microorganisms (see page 1099). For example, the immune system may create killer T cells (a type of white blood cell) that can recognize and kill the invading microorganism. Also, the immune system produces antibodies that are specific to the invading microorganism. Antibodies attach to and immobilize microorganisms—killing them outright or helping the neutrophils target and kill them.

Fever

Body temperature increases as a protective response to infection and injury. The elevated body temperature (fever) enhances the body’s defense mechanisms, although it can cause discomfort. However, certain people (such as alcoholics, the very old, and the very young) may experience a drop in temperature in response to severe infection.

Temperature is considered elevated when it is higher than 100° F (37.8° C) as measured by an oral thermometer. Although 98.6° F (37° C) is considered normal temperature, body temperature varies throughout the day. It is lowest in the early morning and highest in the late afternoon—sometimes reaching 99.9° F (37.7° C).

A part of the brain called the hypothalamus controls body temperature. Fever results from an actual resetting of the hypothalamus’s thermostat. The body raises its temperature to a higher level by moving (shunting) blood from the skin surface to the interior of the body, thus reducing heat loss. Shivering (chills) may occur to increase heat production through muscle contraction. The body’s efforts to conserve and produce heat continue until blood reaches the hypothalamus at the new, higher temperature. The new, higher temperature is then maintained. Later, when the thermostat is reset to its normal level, the body eliminates excess heat through sweating and shunting of blood to the skin.

Fever does not stay at a constant temperature. Sometimes temperature peaks every day and then returns to normal. Alternatively, temperature varies but does not return to normal—called remittent fever. Doctors no longer think that the pattern of rise and fall of fever is very important in diagnosis.

Substances that cause fever are called pyrogens. Pyrogens can come from inside or outside the body. Microorganisms and the substances they produce (such as toxins) are examples of pyrogens formed outside the body. Pyrogens formed inside the body are usually produced by monocytes and macrophages (types of white blood cells). Pyrogens from outside the body cause fever by stimulating the body to release its own pyrogens. However, infection is not the sole cause of fever. Fever may also result from inflammation, cancer, or an allergic reaction.

Usually, fever has an obvious cause, which is often—but not always—an infection (such as influenza, pneumonia, or a urinary tract infection). Usually, a doctor can easily diagnose the infection with a brief history, physical examination, and occasionally a few simple tests, such as a chest x-ray and urine tests. However, sometimes the cause is not readily discernible.

If fever continues for several days and has no obvious cause, a more detailed investigation is required. There are many potential causes of such a fever. Common causes in adults include infections, diseases caused by antibodies produced by the body against its own tissues (autoimmune disorders), and undetected cancer (especially leukemia or lymphoma).

To determine the cause of a fever, a doctor begins by asking a person about present and previous symptoms and disorders, drugs currently being taken, exposure to infections, and recent travel. The pattern of the fever usually does not help with the diagnosis. However, there are some exceptions: A fever that recurs every other day or every third day is typical of malaria.

Recent travel (especially overseas) may give clues to the cause of a fever because some infections occur only in certain areas. For example, coccidioidomycosis (a fungal infection) occurs almost exclusively in the southwestern United States. A history of exposure to certain materials or animals is also important. For example, people who work in a meatpacking plant are more likely to develop brucellosis.

After asking questions, the doctor does a thorough physical examination to find a source of infection or evidence of disease. Blood and other body fluids may be sent to the laboratory to try to grow the microorganism in a culture. Other blood tests can be used to detect antibodies against specific microorganisms. An increase in the white blood cell count usually indicates infection. The differential count (the proportion of different types of white blood cells) gives further clues. For example, an increase in neutrophils suggests a relatively new bacterial infection. An increase in eosinophils suggests the presence of parasites, such as tapeworms or roundworms.

A fever of unknown origin may be diagnosed when people have a fever of at least 101° F (38.3° C) for several weeks and extensive investigation does not reveal a cause. In such cases, the cause may be an unusual chronic infection or something other than infection, such as a connective tissue disorder, cancer, or another disorder. Ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI) may help a doctor diagnose the cause. Injection of white blood cells labeled with a radioactive marker can be used to identify areas of infection or inflammation. If these test results are negative, the doctor may need to obtain a biopsy specimen from the liver, bone marrow, or another site of suspected infection. The specimen is then examined under a microscope and cultured.

Because fever helps the body defend against infection and because fever itself is not dangerous (unless it is higher than about 106° F [41.1° C]), there is some debate as to whether fever should be routinely treated. However, people with a high fever generally feel much better when the fever is treated.

Drugs used to lower body temperature are called antipyretics. The most effective and widely used antipyretics are acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen. However, aspirin should not be given to children and teenagers to treat a fever because it increases the risk of Reye’s syndrome (see box on page 1769), which can be fatal.

Prevention of Infection

Several measures help protect people against infection. Hand washing is an effective way of preventing the spread of infectious microorganisms from one person to another. Hand washing is particularly important for people who handle food or who have frequent physical contact with other people. People visiting hospital patients who are seriously ill may be asked to wash their hands and put on a gown, mask, and gloves before entering the patient’s room.

SPOTLIGHT ON AGING

Infections are more likely and usually more severe in older people than in younger people for several reasons:

Aging reduces the immune system’s effectiveness (see page 1103).

Many long-term (chronic) disorders that are common among older people—such as chronic obstructive pulmonary disease, cancer, and diabetes mellitus—also increase the risk of infection.

Older people are more likely to be in a hospital or a nursing home, where the risk of acquiring a serious infection is greater. In hospitals, the widespread use of antibiotics allows antibiotic-resistant organisms to thrive, and infections with these microorganisms are often more difficult to treat than infections acquired at home.

Sometimes, to prevent an infection, antibiotics are given to people who do not yet have an infection. This preventive measure is called prophylaxis. Many healthy people who undergo certain types of surgery—particularly abdominal surgery and organ transplantation—require prophylactic antibiotics.

Vaccination can also prevent infections (see page 1144). People who are at increased risk of developing infections (especially infants, children, older people, and people with AIDS) should receive all the vaccinations necessary to reduce this risk.

Infections in People With Impaired Defenses

Many disorders, drugs, and other treatments can cause a breakdown in the body’s natural defenses. Such a breakdown can lead to infections, which can even be caused by microorganisms that normally live harmlessly on or in the body. A breakdown can result from the following:

Extensive burns: Risk of infection is increased because damaged skin cannot prevent invasion by harmful microorganisms.

Medical procedures: During a procedure, foreign material may be introduced into the body, increasing the risk of infection. Such procedures include insertion of a catheter into the urinary tract or a blood vessel and insertion of a tube into the windpipe.

Drugs that suppress the immune system: These drugs include cancer chemotherapy drugs, drugs used to prevent rejection after an organ transplant (such as azathioprine, methotrexate, and cyclosporine), and corticosteroids (such as prednisone).

Radiation treatments: Such treatments may suppress the immune system, particularly when bone marrow is exposed to radiation.

AIDS: The ability to fight certain infections decreases dramatically in people with AIDS, especially late in the disease (see page 1254). People with AIDS are at particular risk of opportunistic infections (infections by microorganisms that generally do not cause infection in people with a healthy immune system). People with AIDS also become more severely ill from many common infections.