Infection versus colonization

Infection results when living microorganisms (viruses, bacteria, fungi, or parasites) establish an active and growing presence within the human host. This situation creates characteristic pictures of illness. Some disease elements are created by the damage caused directly by the invading pathogens. Others result from the host’s response to the organisms. The detection of disease requires knowledge of the microbiology of the attacking microorganism and an understanding of the human body’s reactions.

Although bacteria are the most commonly isolated source of infectious illness, only some interactions between mammalian organisms and bacteria produce disease. Infection, an event with important medical consequences, must be distinguished from colonization, a term used for the harmless or adventitious presence of the microorganism in contact with human tissue.

The human host provides many microenvironments that act as sites for a complex microbiological ecology inhabited by diverse strains of bacteria. For example, the colon augments the breakdown of food wastes with innumerable bacterial species, termed coliforms. Coliforms represent harmless symbiotes as long as they remain in their usual habitat. However, these same bacteria can be the source of critical illness when opportunities place them at other biological locations, including the spaces outside the intestinal wall, within the urinary system, or within the bloodstream.

Bacteriologic evaluation of patient specimens can be extremely useful in distinguishing between infection and colonization. Awareness of the source of the specimen is important for the selection of the appropriate test and interpretation of the results. Samples from many sites are commonly contaminated, including saliva, stool, vaginal secretions, and skin swabs. In these sites, the presence of bacteria (and often fungi) need not be interpreted as evidence of disease unless the organism is not part of the usual biology at that location. Clinicians must recognize the species of normal flora specific to each body site and to distinguish them from the harmful organisms recognized as pathogens.

Systemic infection versus localized infection

When illness results from the presence of microorganisms within the host’s tissues, infection is most easily diagnosed by the evaluation of the affected area. Some infections are localized and superficial, such as those involving the skin (e.g., cellulitis) or a mucous surface (e.g., streptococcal pharyngitis or strep throat). For other infections, illness is diffuse, resulting either from a total body invasion by the organism (e.g., the spread of rickettsial organisms in Rocky Mountain spotted fever) or from the body’s global reaction to infection.

Clinical manifestations of infections are based on both local and systemic mechanisms, mediated by the immune system and result from activated defensive cells. As the body recognizes the assault of foreign organisms, immediate reactions at the site are involved in a complex process known as inflammation. Redness and warmth arise from the stimulated local circulation, causing increased blood arrival through dilated capillaries. Swelling results from increased blood vessel permeability, permitting the escape of antibacterial proteins and plasma into the surrounding area. Tenderness and limited local function are due to the presence of the offending pathogen and to the effect of local mediators released from the host’s activated protector cells.

In addition to the local effects of low molecular weight chemical signals, mediators circulate throughout the body and produce systemic signs of illness. Fever is mediated by the brain’s hypothalamus and shows that infection and inflammation have triggered a systemic response. Although it is unclear what advantage is gained by raising the body temperature, fever is one of the earliest and most common responses of infected mammals. When stimulated by the arrival of infectious debris or cellular activating proteins, regional lymph nodes (collection and production sites for immune cells) activate and enlarge. Another manifestation of infection is a more dynamic circulation, resulting in increased heart rate, reduced vascular resistance to blood flow, and lowered blood pressure. Generalized muscular aches and stiffness occur in many areas not directly involved by the infection.

The next elements in the local infection process are much more common for bacterial organisms than for viruses or fungi. When the body’s immune response fails to eradicate a local invasion, the process can result in a closed-space infection. Within this abscess are active and dead defensive cells and countless foreign organisms that are “walled off” from nearby tissue. An abscess may either open spontaneously or require surgical drainage. When infections are especially severe, widespread bodily invasion via the circulatory system, or sepsis, can occur. This process, which allows seeding of distant tissues, is one of the most dangerous late stages of bacterial illness.

Sometimes, the cumulative volume of circulating infectious material and the massive release of immune mediators combine to produce the syndrome of septic shock. This dangerous situation of thready, weak pulse, and poor circulatory perfusion results in deteriorating vital organs’ function, including the heart, brain, and kidneys. Septic shock requires prompt diagnosis followed by aggressive and intensive treatment and may often be fatal.

Upper respiratory infections

Although the most common of infections is often called a “cold” and is usually viral in origin, respiratory infections are not much different when caused by other invading organisms. Patients develop irritation of all respiratory surfaces, including the nose, throat, middle ear, and facial sinuses. These lining tissues become swollen and moist and may obstruct the passage of air. When lymphoid structures (tonsils, adenoids, and lymph nodes) are stimulated to respond protectively to the infection, they enlarge and cause additional symptoms of obstruction and pain. When a corridor for mucus drainage becomes persistently obstructed, immune mechanisms are rendered less effective, and bacteria that are not ordinarily pathogenic can become successful sources of infection and can cause complications. This results in secondary infections in areas where drainage is blocked, including facial sinuses and the middle ear.

Many of the symptoms of the respiratory infection are nonspecific and result from circulating immune activators and foreign proteins. Fever, muscular aches, stiffness, chills, and headaches are common symptoms for any infection. They are especially linked with respiratory infection in most patients’ minds only because colds and flu are such common forms of infection.

Bronchitis and pneumonia

Bronchitis and pneumonia are diagnoses that represent infection of lower respiratory structures. The clinical picture characteristically involves a productive cough, chest pain, shortness of breath, and fever. Bronchitis is associated with excess mucus (usually containing infected material) arising from within the chest. Wheezing (or asthma) represents an inappropriate muscular reflex of the contractile elements surrounding the air passage, which narrows these passages and obstructs air exchange. Pneumonia represents infection of the surface of the lung where oxygen transfers to the passing circulation. Many pneumonias involve “consolidation” or filling of the usually empty spongy lung tissue with the combined debris of the attacking organisms, reactive immune cells, and fluids. Pneumonia patients, with illness in one or more of the lungs’ lobes, suffer obliteration of the respiratory surface in addition to the consequences of reduced airflow into the lungs, causing respiratory insufficiency. This causes poor oxygenation (manifested by the desaturated blue color of circulating blood), weakness, shortness of breath, and risk of death.

Hepatitis

Direct infection of the liver is often subtle, only occasionally manifested by local tenderness over the liver itself (in the upper right corner of the abdomen). More universal among patients with liver disease is prominent and disabling fatigue, with loss of appetite, and the onset of jaundice. This last sign represents the escape of bilirubin (a breakdown product of normal red blood cell turnover) from the liver’s usual metabolic machinery. This displaced pigment accounts for the yellow skin and dark urine of hepatitis patients, and its absence from feces may be reported as “clay-colored” stools.

Fibrous scarring from repeated and widespread liver infection leads to cirrhosis. This situation can occur even when cellular damage has quieted but causes dangerous disruption in blood reaching the liver and pressure alterations in the abdominal cavity.

Liver failure is a rare but potentially fatal consequence of infection in this organ. Reduction in the metabolic and synthetic functions of the liver can lead to the development of clotting disorders, abdominal distension with extracellular fluid, deteriorating mental function, and unregulated blood sugar.

Dermatitis

Since skin is the outermost layer of the host, infectious rashes are the most easily noted of the body’s reactions to invading organisms. Unfortunately, for many common patterns of illness, the skin’s pattern of reaction is nonspecific, and noninfectious immune responses can confuse the patient and clinician regarding their origin. Furthermore, some rashes may be associated with infectious disease affecting body elements elsewhere, including systemic illnesses like measles, Lyme disease, and meningococcal meningitis.

Cellulitis is a primary infection of the skin appearing as a spreading area of redness. It usually originates with local mechanical injury. Other obvious and direct skin infections may involve specific skin structures, such as hair follicles, sweat glands, and nail beds. Again, primary injury often triggers local infection at these sites. The organisms responsible are usually those already present at the skin’s surface. Infection may also be caused by organisms introduced by the agent of mechanical injury (e.g., an animal tooth in a bite wound). Remote and systemic disease is also possible from skin infection. Rheumatic fever and toxic shock syndrome are both consequences of local infection at the skin. Tetanus organisms cause systemic illness unrelated to their direct skin effects. Illness results from the remote effects of tetanus toxin, released by the organism after successful infection of anaerobic spaces beneath the skin.

Central nervous system infections

The brain and spinal cord can be attacked by microorganisms in three distinct patterns of illness—meningitis, encephalitis, and abscess. The most common of these, meningitis, is an inflammation of the brain’s lining and suspending fluids. Patients have severe headaches and are unwilling to stretch or fold these covering membranes by such activities as bending their necks or even turning their eyes. The brain itself shows normal function until late in the course of infection, when there is possible damage to the nervous tissue, affecting thought, movement, and behavior. Making the diagnosis requires finding evidence of infection in samples of spinal fluid.

Encephalitis involves a direct attack of a microorganism into the nervous tissue of the brain. It usually occurs in a diffuse pattern throughout the brain’s substance. Some patients suffer damage in only one cerebral area, with symptoms relating to the specific brain structures involved. Since the brain is a fragile and shielded structure, diagnosis usually requires indirect testing, such as evaluation of cerebrospinal fluid or computerized brain imaging.

An abscess in the brain represents a circumscribed collection of infected material that not only causes local damage but also, as it expands, causes compression of the brain as a whole, trapped in the skull’s rigid compartment. This is a rare illness that requires specific treatment, possibly including drainage to empty the area where the infection is localized.

Gastroenteritis and dysentery

The presence of disruptive organisms in the upper gastrointestinal tract can result in painful abdominal distension and discomfort, caused by irritation of the gastric and esophageal lining. It can also cause reflex reactions from the brain, manifested as nausea, vomiting, and loss of appetite. In the lower intestinal tract, the presence of infection by pathogenic microorganisms can lead to different forms of diarrhea. If the organisms—or, more commonly, their secreted toxins—merely interfere with the intestine’s ability to resorb liquid, then the patient suffers a watery diarrhea. Dehydration and electrolyte imbalance may result. This type of infection is often difficult to confirm, because the organism is not easily available for laboratory identification. If the infection actually attacks the intestine’s wall, the patient loses more than the usual colonic contents. Dysentery is recognized by the presence of blood, inflammatory cells, and mucus in the stool. In this form of illness, invasive microorganisms are more likely to be successfully identified in laboratory evaluation.

“Flu-like illness”

Many illnesses with important consequences initially manifest themselves with widespread symptoms that are nonspecific and not easily diagnosed. Even though the clinical picture may be different from the specific illness of influenza, whenever patients have prominent respiratory symptoms, the phrase flu-like illness will be applied to almost any fever-associated syndrome. The symptoms most often recognized to be “flu like” are body aches, chills, stiffness, mild to moderate fever, headache, and fatigue. The term is rarely applied to illness with only respiratory symptoms, such as cough, nasal congestion, or sore throat.

Upper respiratory allergy

Allergy to ragweed pollen (“hay fever”) is a common environmental respiratory allergy. Symptoms of this disorder are identical to those of allergy caused by other airborne proteins and result from direct contact of inhaled particles with the respiratory mucosa. Manifestations of exposure include increased production of tears and a continuous clear nasal discharge. The lining of the nasal passages may swell, resulting in obstruction. Patients commonly experience sneezing, along with itching of the eyes and throat.

Lower respiratory allergy

Asthma is an episodic illness. Symptoms result from constriction of muscle-lined air passages in the lungs. The ability to exhale air is limited. Patients experience spells of shortness of breath, chest tightness, and possibly cough. Wheezing may be audible or noted only with a stethoscope or if measured with a flow meter. The inability to achieve adequate air exchange results in a diminished blood level of oxygen.

Patients with acute hypersensitivity pneumonitis also commonly experience shortness of breath and cough. Unlike asthma, symptoms include chills, high fever, and muscle aches, which are signs of widespread reaction to active inflammation. Symptoms generally resolve after a brief illness lasting several hours, but some patients experience milder symptoms for several days. This illness may be confused with an infectious pneumonia caused by organisms actually present in the lung. Careful evaluation and a high degree of clinical suspicion are required to arrive at the correct diagnosis.

Skin reactions

Immunologic skin reactions are extremely varied and can often be confusing. However, the classic lesion associated with allergic contact dermatitis is the rash associated with poison ivy and poison oak. This red, itchy rash contains small, clear, fluid-filled raised blisters. For other allergic skin eruptions, the clinical findings are frequently much less specific, with evidence of only redness and possibly scaling.

The skin may also be active as part of a systemic response to ingestion or injection of antigens. One such manifestation may be widespread edema (swelling of soft tissues as a result of excess fluid accumulation) and diffuse hives accompanied by pale swelling and itching. In severe cases, this reaction may be associated with leakage of circulating blood plasma into peripheral tissues and consequent shock. Emergency medical treatment is required in these cases.

Another skin response is similar to that seen with the intradermal injection of purified protein derivative (PPD) used diagnostically for tuberculosis skin testing. The skin becomes firm and raised as a result of local cellular infiltration responding to a secondary exposure to this foreign protein. The specific reaction does not appear for 2–3 days following re-exposure.

Irritations

Nonimmunologic individual variation in the response to other biological stimuli is also widely recognized. Wood and tobacco smoke and other irritants usually do not act as specific allergens and do not provoke the illness mechanisms described above. Nonetheless, variation among the doses tolerated by the human population is considerable. Even though irritation occurs without specific antibodies or immunologic mechanisms, there are sensitive individuals who react to many stimuli (including odors) with more severe symptoms than the general population, sometimes with easily recognized objective clinical findings.

Microscopic visualization of the organism

The most rapid means for disease recognition is direct microbial identification in stained biological specimens. In pneumonia, for example, sputum samples are smeared onto a glass slide and allowed to dry. Specific stains and selective rinses are then applied before careful microscopic examination. Expert evaluation can reveal the nature and number of the organisms present and even indicate whether the microorganisms are pathogens or colonizers, based on whether they are seen engulfed by the host’s defensive cells. This technique not only provides a glimpse into the nature of the disease but also discloses the possibility of mixed infection by several organisms and indicates the intensity of the battle between the microbes and the host cells.

For general bacterial evaluation, the Gram stain is used. This technique provides useful information regarding the organism’s shape and the type of cell membrane of the microbes present. The Gram stain procedure is designed for a primary pigment to be selectively removed from the interior of certain Gram-negative bacteria, permitting the loss of the dark color and permitting staining only by the last stage, a light pink universal stain. The darkly stained bacteria are recognized as Gram positive, whereas the paler organisms are Gram negative. The organism’s shape offers additional diagnostic clues. Rectangular and elongated bacteria are characterized as rods; circles, coffee bean shapes, and clusters are cocci.

Special stains are required for certain organisms and situations. The acid-fast reaction is a special stain that provides the classic means to recognize mycobacteria (e.g., tuberculosis). Silver-based staining is used to identify microscopic protozoa, fungi, and spirochetal bacteria (e.g., syphilis and pneumocystis). Viruses, which are much smaller and necessarily intracellular, are more difficult to visualize by direct microscopic evaluation. Usually, the identity of the exact virus must be inferred from the clinical circumstances and the source tissue being evaluated. Viral organisms can sometimes be confirmed with special staining techniques or electron microscopy.

The most targeted stains use specifically created antibodies against individual organisms. Once these antibodies attach to their targets, they are linked to fluorescent compounds that allow microscopic detection. This technique, called immunofluorescence, allows precise confirmation of actual microbial identity without the delay required for cultures to grow or the host’s own antibodies to emerge.

Growth and identification of microbial colonies

The organism’s ability to multiply in the host tissue is the most common disease mechanism. Culture techniques use this same capability to identify organisms that would otherwise be missed by amplifying their numbers in specific artificial environments called media. Once isolated and flourishing in the microbiological laboratory, pathogenic colonies can be tested for additional information regarding their precise speciation, antibiotic sensitivity, and biochemical activity. Molecular markers may be useful for epidemiologic evaluation.

The greatest weakness of culture as investigative tool is the delay before the organisms are sufficiently numerous to be detected. For bacteria, the lag is usually 24 hours. Most viruses fail to grow in laboratory settings, but even where it is possible, there is a similar delay. For fungi and mycobacteria, although a positive sample might be reported earlier, a sample cannot be considered “no growth” until it has been incubated for a full 6 weeks.

In addition, there are many occasions when a sample will fail to yield any growth, even in the presence of infection confirmed by other means. To protect the microorganisms they contain, samples must be spared any risk of heat, cold, or drying. If the patient has taken antibiotics, if the sample is mishandled, or if nonpathogenic organisms are present that inhibit the pathogen’s in vitro behavior, then the culture will not only be slow to diagnose the illness but will also yield false-negative results.

After collecting a specimen with viable microbes, the next step in microbiological culture preparation is selection of the appropriate growth medium. This requires specific broths or agar gels with nutrients and cofactors designed to encourage the growth of even particularly fastidious organisms. In addition, when specimens are collected from a source known to be contaminated with selective nonpathogenic organisms (e.g., from the throat), antibacterial chemicals must be included to suppress their competitive growth.

Finally, the environment for culture growth must be selected. When the organism sought is a tissue-invading bacterial pathogen, 37°C is used to simulate the human host. However, when an allergen is cultivated, its disease-producing biology is different, since the mechanism of disease involves the organism’s growth at ambient temperature and the subsequent release into the environment. Environmental samples should be cultured at a temperature that accurately reflects the biology of the area where they were collected.

The results from cultures, especially environmental, do not necessarily constitute a clinical diagnosis. For each biological sample, there are guidelines for culture isolates. For sputum, culture interpretation requires knowledge of whether the specimen included host cells that prove its origin from lung tissue (as opposed to mere oral saliva). For urinary cultures, microscopic identification of cells from the vagina makes diagnosis from culture results suspect. Because most infections are caused by only a single species, growth of even small numbers of organisms from just one species constitutes stronger support for the presence of an important microbiological presence.

Even when a pure sample is achieved, the concentration of viable colonies can be an important interpretative fact. Rare stray organisms found in urine specimens do not constitute proof of disease. Useful culture reports must indicate, for example, that the culture showed 100 000 colonies of Escherichia coli per milliliter of sampled fluid. Clearly, there are many times when the mere identification of an organism in a sample does constitute a conclusive diagnosis of disease. Where a material is ordinarily sterile, the presence of a single colony is persuasive. Such samples include spinal fluid, liver biopsy material, and urine obtained via sterile catheter. In those cases, every microorganism must be considered a pathogen.

In other circumstances, the presence of any microbial colonies is sufficient proof for a firm diagnosis where the infecting agent is never part of the benign normal flora. The mere isolation of any of these organisms constitutes a firm diagnosis, regardless of concentration, coexisting organisms, and whether the specimen was otherwise contaminated by other body materials. These agents include Neisseria gonorrhoeae (the gonorrhea organism), Mycobacterium tuberculosis, and the herpes simplex virus.

Diagnostic evaluation by immunity testing

For many infections, the responsible organisms cannot be identified by direct visualization or by culture because they are too fastidious or too few, or because they are located in unreachable anatomic sites. In these cases, including those caused by many viral organisms and several atypical bacteria, the best way to identify an illness is to monitor the patient’s immune response to the microbe as indirect evidence of its presence.

A basic concept in biology is that each individual’s immunity is developed as a consequence of its own exposure and infection experience. The immune system serves as a data bank for the aggregate history of the host’s exposures. Each foreign protein and macromolecule serves as a unique immune stimulus (called an antigen). Each exposure to a new antigen constitutes a new immunization and results in a uniquely responsive set of precise cellular and antibody reactions. These reactions create permanent changes in the way that the host reacts to the antigen on any future exposure. The sum of these learned reactions is retained in the organism’s immunologic “memory.” This represents a catalog of identifiable exposures, each of which resulted from a prior exposure and each of which can be tested and identified for proof of prior contact. As an example, when a patient is effectively exposed to the mumps virus, a characteristic set of targeted proteins called antibodies are produced that react specifically to the viral proteins. Whether the exposure arrives as a vaccine or is the consequence of an actual infection, the result is the lifelong presence of identifiable circulating antibodies specifically reactive to this microbe.

Most immune testing evaluates the existence, quantity, and type of circulating antibodies. The presence of each specific antibody proves prior exposure and infection. Because the production of immunoglobulins of differing types occurs in predictable sequential fashion, this pattern of response can reveal the timing of an infection. The classes of antibody are named with single-letter suffixes, for example, immunoglobulin M (IgM). IgM is an antibody subtype with a transitory role, lasting only a few weeks until immunoglobulin G (IgG) is synthesized. Because of its transient presence, the identification of IgM against a microbe is itself proof of recent disease. Evidence of recent immune activation may also be obtained by demonstrating a recent rise in antibody concentration. Antibody levels are usually expressed as titers, referring to serial dilutions of serum that still demonstrate a positive reaction. For example, if four twofold dilutions of a sample produced a positive test result but the fifth did not, the result would be reported as positive at 1 : 16. Two samples collected 6 weeks apart (labeled acute and convalescent) constitute a matched set for analytic purposes. The customary threshold for a significant antibody elevation is a fourfold titer increase. Since the clinical consequences are likely to have run their course, the intervening delay is usually too long for clinical decisions concerning an affected patient. However, it may provide important documentation for workplace or public health use.

Immunoglobulins are also utilized in other diagnostic tests. Fluorescent compounds chemically linked to antibodies can be used to stain specific proteins for immunohistologic microscopic examination. This technique of linking a detectable moiety to an antibody is also used in enzyme-linked immunosorbent assay (ELISA). When an antigen from the biological substrate of interest binds to the ELISA antibody, the linked enzyme generates a measurable product. This product may be a fluorescent compound or another easily measured chemical.

Although ELISA provides a rapid and relatively simple technique for antigen detection, results are not highly specific. A positive ELISA may need to be confirmed by antibody electrophoresis testing (e.g., the Western blot assay). This more expensive and time-consuming assay increases specificity by recognition of the size and the electric charge characteristic of the detected antibody.

Polymerase chain reaction testing

Biotechnology techniques have provided new opportunities to specifically identify microorganisms. Based on the same means used for gene cloning and synthesis, methods now exist to identify segments of either DNA or RNA that represent specific identifiable microbial genes. Identification is accomplished by a process that amplifies any genetic material present. This technique can prove the presence of infecting organisms without relying on the immune system’s response and without requiring successful growth of the organism outside the infected host. It replaces whole-pathogen cultures with the detection of recognizable species-specific genes and gene segments. There are several advantages to this elegant laboratory tool. Confirming the presence of microbial DNA or RNA, even when the organism itself is too weak or too slow growing to be cultured, enables the identification of organisms whose culture has never been possible. It can also provide results more rapidly than other diagnostic methods. However, there is concern about the possibility of genetic contamination, where random bits of genetic material erroneously suggest that a particular microbe is present. Clinical experience is rapidly accumulating to where this technique might achieve the reliability and standardization now available with traditional culture or antibody testing.

Allergy testing with skin prick tests

The mechanism by which traditional allergy occurs involves mast cell activation by the binding of a high-molecular-weight compound to the cell-attached IgE antibodies. The classical allergy test involves placing a drop of a dilute antigenic solution onto the skin, pricking the skin shallowly with a clean pin, and awaiting an immediate reaction. The response, when one occurs, shows the effects of the activated mast cell’s release of histamine and other mediators, causing a localized reaction of swelling, reddening, and notable itching.

When properly administered, this testing procedure is useful and reliable. Results are skewed by varying circumstances, including nonspecific skin reactions, antihistamine use, and many complex issues involving the applied solution. An experienced clinician should perform this test.

IgE evaluations with RAST testing

Because the actual mechanism of classical allergic symptoms involves IgE, diagnostic tools have focused on measuring circulating levels of this molecular class. Measurement of total IgE may be useful in some cases (e.g., allergic bronchopulmonary aspergillosis). The concentration of IgE antibody directed against specific allergens can also be quantitated.

The technology most commonly used is called radioallergosorbent test (RAST) (because the test involves radioactive methods in the laboratory). These tests are capable of accurately measuring very small concentrations of IgE antibodies in the serum of allergic patients. The resulting information has proven highly comparable with the results from skin testing. While both tests correlate with clinical diagnoses of allergy, evaluations can be positive without clinical meaning.

Patch testing and intradermal skin testing

Cellular-mediated immunity is also called delayed hypersensitivity, because it represents a slower mechanism of response. Although the recognition of the foreign agent still depends on the lymphocytes’ molecular memory, the response utilizes an entirely different class of activated cells, and the disease is manifested by different mechanisms.

Because delayed hypersensitivity involves several cellular classes working together, testing currently requires measurement of the response by the intact host rather than any cellular extract or circulating antibody. Thus, the diagnostic tests require applying the potential offending allergen directly onto the patient’s skin and waiting 48 hours for cellular infiltration. The response considered to be diagnostic results from the arrival of enough immune-activated cells to produce a circular area of irritation and stiffening (induration).

Patch testing is performed to evaluate suspected cases of contact dermatitis. An extremely dilute antigen solution is applied to a gauze pad and held in place with a shallow aluminum protector during the test’s incubation. To ascertain the reactions’ specificity, skin tests are always done simultaneously with control solutions. These include antigens known to produce positive results in the population at large as well as the saline preservative solution used for the allergen’s dilution to reveal nonspecific responses. These skin test batteries thus often require an entire grid of applied patches, sometimes covering the patient’s entire back for the 2-day waiting period.

When the tissue response in question involves organs other than the skin (including possible inapparent tuberculosis), more invasive dosing is performed, depositing 0.1 mL of the solution directly into the skin with a tiny needle (intradermal testing). In this case, the number of applied solutions is limited by the patient’s discomfort, but control solutions may still be used. Many patients with suppressed immune response (including corticosteroid treatment, HIV infection, or even overwhelming systemic infection) will be unable to mount any cellular response, thus producing a false-negative result termed anergy. By including simultaneous doses of antigens with universal response (mumps, Trichophyton, Candida), the skin test battery can be self-validating.

For intradermal skin tests, the puncture site becomes the center of a spreading firm area. Reading the test simply involves measurement of the firm region’s greatest diameter after a delay of 48–72 hours. The medical interpretation of skin testing requires additional consideration of the setting and the patient. Even the most common of intradermal skin tests, the purified protein derivative (PPD) for tuberculosis, can be called positive at 5, 10, or 15 mm of induration, depending upon the clinical setting (see Chapter 23).

Exposure challenge testing

In cases where the clinician tries to evaluate environmental disease potentially explained by mechanisms of hypersensitivity, objective measures of dose may be totally misleading. Responses by allergic individuals are frequently many orders of magnitude more sensitive than the best industrial hygiene techniques, especially when others who share the exposure show no symptoms at all. Investigators of potentially allergenic environments must therefore cope with an obvious temptation—direct patient challenge.

There is a significant danger in sending potentially affected individuals into situations where they are suspected to be allergic to an airborne agent. Depending on the patient’s prior reactions, such experiments must be done with ample opportunity for rescue and medical attention. They should only be done when the prior illness has been mild (e.g., skin rash) and when the symptoms are easily reversible. The exposure testing must progress in a stepwise fashion, where earliest exposures should be chosen to produce no response at all.

Exposure testing should be used only when no other means of evaluation is available and only with both medical guidance and the fully informed permission of the patient. It should be considered the choice of last resort in diagnostic techniques.

Unusual job activities

The health consequences of many workplaces can be predicted and prevented with planning and conscientious concern, but despite such measures, some employee populations remain at increased risk. Healthcare workers have direct contact with patients with transmissible illnesses. For organisms spread by airborne contagion (e.g., influenza or tuberculosis), the risk of contracting disease is greater for these workers than for the population as a whole, because the disease is more concentrated among their clients. For other illnesses, healthcare workers are uniquely susceptible where exposure requires deposit or liberation of an infective organism. Infection usually occurs as an untoward consequence of an invasive procedure (e.g., exposure to blood-borne pathogens).

In these settings, clinicians and safety professionals must remain aware of the opportunity for illness to transform care providers into patients. Routine preventive measures, including vaccination against expected exposures (e.g., influenza and hepatitis), universal precautions with blood and body fluids, and routine hand washing, are essential.

Animal workers

Unfortunately, workers with direct contact with other species are at risk for both allergy and infection. The proteins released from animal urine, skin, and other tissues can easily become airborne, resulting in rashes, hives, allergic nasal and ocular symptoms, and even asthma. This form of hypersensitivity usually occurs immediately after exposure, facilitating the diagnosis. However, conditions such as asthma may be delayed. The lack of an immediate response does not automatically exclude an occupational association.

For infections, the parameters of risk attribution are reversed. Infection resulting from other species is rare and poorly identified. Clinicians often fail to recognize the nature of illness and may not even know what microbial agents to suspect or what treatment is needed. When an agent is identified by culture or serologic means, it is not hard to determine that this unusual pathogen must have arisen as a consequence of work exposure. Populations at risk include workers at abattoirs, zoological parks, and veterinary clinics and those involved in biology research. Pet owners also have large exposures to the possibility for allergy and for infection. Since many animal workers are also pet owners, both occupational and home environmental exposures need to be investigated when evaluating suspicious illnesses.

Workers handling waste and sewage

Before proper sanitation and sterilized water supplies, numerous infections associated with human waste posed community-wide dangers. The risk for diseases prevented by these techniques are now concentrated among the workers with potential exposure, usually in municipal water treatment centers. These agents include both viral organisms and bacteria. Recognition of disease in these workers is important to provide proper treatment and to minimize identified exposures for their coworkers.

Travelers

Geographic dislocation may result in environmental illnesses through a variety of mechanisms. Many areas of the world, including regions in the United States, contain unique pathogens in such high environmental quantities that the rate of pediatric infection is universal while the danger to adults exists only among new arrivals to the community. Usually fungal in nature, examples include histoplasmosis and coccidioidomycosis, endemic in the Ohio River valley and in the American southwest, respectively. Even “traveler’s diarrhea” can sometimes be explained by organisms that produce no symptoms among local inhabitants because they were naturally immunized years earlier.

Many illnesses are climate specific and thus are seen in industrialized societies only among returning travelers, new immigrants, and visitors. Malaria, yellow fever, and Zika infection represent important concerns for travelers to tropical areas, where insects act as potent vectors for disease. For these diagnoses, the link to foreign travel is essential. In addition to the area of the world, some consideration is required for the traveler’s choice of accommodation. Urban life, with its air-conditioned hotels and restaurant meals, represents a drastically reduced risk for tropical disease compared to traveling to remote villages and spending long, unprotected hours in the wilderness.

Sanitation and public health measures in other cultures are often less thorough than the norms in European and American societies. Water and food supplies are often the source of infection for adventurous travelers who sample local edibles contaminated with viable organisms that would not be present in their home food markets. Vibrio organisms and Shigella are much more common in settings where food and water regulations are lax for reasons of poverty, societal disruption, or crowding.

Travelers may also contract contagious illness from their new human contacts. The geographic migration of many illnesses (including measles, Ebola, HIV, and resistant gonorrhea) requires migrating human hosts. Thus, an infection may result just as easily from contact with a newly arrived immigrant to the domestic environment as from visits to foreign regions.

Hypersensitivity is not usually related to travel. A period of several weeks to years is required for exposure to produce the necessary antibodies that create allergy, and travelers have by then become residents. Additionally, when travelers develop hypersensitivity-related illness, the best therapy is removal from exposure, which is easily accomplished when a visit is short term by its nature.

Unusual clusters of disease events

Even among workers with unremarkable job activities, some evaluation is required in response to what appears to be an outbreak or disease cluster. Even for illnesses that are common in our society, there is a poorly defined threshold when an investigation is required to explain the simultaneous development of numerous similar medical problems within a worker community. The rarity and nature of the illness, its prevalence within the at-risk workforce, and the pattern of its occurrence and spread are important criteria in evaluating these situations.

In the office setting, occupational health professionals may be asked to evaluate health complaints that the occupants have ascribed to “sick building syndrome.” Symptoms reported commonly include headache; irritation of the eyes, nose, and throat; fatigue; and sensitivity to odors. Employees may report that symptoms occur only while they are in the building. Although controversy persists as to the most common etiology of this syndrome, it appears unlikely that a specific biological organism causes such nonspecific symptoms. Extensive searches for biological sources of illness are usually not warranted. A systematic review of employee complaints is an important first step in understanding the problem. If indicated, an evaluation of the ventilation system should be undertaken. Efforts should be directed toward providing adequate airflow and air exchanges, as well as appropriate regulation of temperature and humidity. Altering these physical aspects of the ambient environment may reduce occupant complaints. Psychosocial factors, including a variety of workplace stressors, may also contribute to health complaints. An evaluation of the role of psychosocial issues should be conducted contemporaneously with the rest of the evaluation.

By contrast, “building-related illness” describes a situation where building occupants suffer specific clinically diagnosable illnesses, such as hypersensitivity pneumonitis. Biological organisms may either cause or contribute to these illnesses. A thorough evaluation for potential sources of contamination should be pursued. Molds (usually fungal colonies and spores) are commonplace. Although they are found even in well-maintained office settings, their environmentally released dose is greatly magnified wherever imperfect ventilation and filtration are permitted. Clusters of symptomatic workers with “hay fever” symptoms (nasal congestion, tearing, sneezing, and coughing) should prompt an assessment of the air purity for potential contamination with invisible microbes and proteins. Evidence of either water condensation or prior flooding makes it even more likely that the symptoms can be explained by occupational exposures. These factors suggest a need for special testing for environmental flora that may be present either on surfaces or in the air.

Situations involving hypersensitivity pneumonitis (such as “farmer’s lung”) present a rarer but more critical problem. Because of the delayed onset of their illness, the sensitive workers do not develop immediate symptoms; therefore, they may not notice an association with any particular activity. Several episodes of illness, either in just a single worker or among a work team, may occur before a connection can be made to the work environment. In these cases, the evaluation of the environment and the patient should be coordinated, with open communication between the clinician and the environmental health professional.

There are occasions when work-related controls must be considered for an epidemic of infection as a result of a common source illness. Food-related illnesses can be introduced into the workplace by any common eating opportunity, including vending machines, in-house cafeterias, or popular neighborhood restaurants. Direct contagion must be considered for outbreaks of conjunctivitis (“pinkeye”) among workers using shared optical devices, such as microscopes.

Rare or severe diseases

In some cases, the patient’s diagnosis is sufficiently unusual on its own that the occupational environment must be considered to explain the source of disease. Just as with chemical exposures, where the development of peripheral neuropathy or bladder cancer requires a thoughtful assessment of the potential for environmentally triggered illness, there are certain diagnoses where occupational and environmental causes must be conscientiously sought, even without explicit hints or leads.

Recurrent asthma and respiratory compromise, even in just one worker, represent such a commonly environmentally mediated danger that an investigation of workplace environment is a reasonable supplement to medical management. An inspection for potential organic contaminants or dusts is a prudent adjunct to the treatment of this hazardous and progressive condition. A diagnosis of Legionnaires’ disease should prompt a consideration of where the pathogen was acquired.

Tuberculosis in a worker should prompt an assessment of coworkers who might have provided or received the organism in the work setting. This public health response is similar for those with a shared home environment and is usually performed by the same governmental prevention specialists. The need to identify those with recent exposure and early infection is very important, both to the individual and to the rest of the work community, since curative treatment abolishes the risk of further exposure in only a few days.

Further Reading

1. Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 8th edn. Philadelphia, PA: Saunders, 2015.
2. Kasper DL, Fauci AS, Longo DL, et al., eds. Harrison’s Principles of Internal Medicine, 19th edn. New York: McGraw-Hill, 2015.