# Respiratory System Infections

## Bacterial Infections of the Respiratory Tract

### Learning Objectives

By the end of this section, you will be able to:
1. Identify the most common bacteria that can cause infections of the upper and lower respiratory tract
2. Compare the major characteristics of specific bacterial diseases of the  respiratory tract
The respiratory tract can be infected by a variety of bacteria, both gram positive and gram negative. Although the diseases that they cause may range from mild to severe, in most cases, the microbes remain localized within the respiratory system. Fortunately, most of these infections also respond well to antibiotic therapy.

### Streptococcal Infections

A common upper respiratory infection, streptococcal pharyngitis (strep throat) is caused by . This gram-positive bacterium appears as chains of cocci, as seen in . Rebecca Lancefield serologically classified streptococci in the 1930s using carbohydrate antigens from the bacterial cell walls. S. pyogenes is the sole member of the Lancefield group A streptococci and is often referred to as GAS, or group A strep.
Similar to streptococcal infections of the skin, the mucosal membranes of the pharynx are damaged by the release of a variety of exoenzymes and exotoxins by this extracellular pathogen. Many strains of S. pyogenes can degrade connective tissues by using hyaluronidase, collagenase and streptokinase. Streptokinase activates plasmin, which leads to degradation of fibrin and, in turn, dissolution of blood clots, which assists in the spread of the pathogen. Released toxins include streptolysins that can destroy red and white blood cells. The classic signs of streptococcal pharyngitis are a fever higher than 38 °C (100.4 °F); intense pharyngeal pain; erythema associated with pharyngeal inflammation; and swollen, dark-red palatine tonsils, often dotted with patches of pus; and petechiae (microcapillary hemorrhages) on the soft or hard palate (roof of the mouth) (). The submandibular lymph nodes beneath the angle of the jaw are also often swollen during strep throat.
Some strains of group A streptococci produce erythrogenic toxin. This exotoxin is encoded by a temperate bacteriophage (bacterial virus) and is an example of phage conversion (see The Viral Life Cycle). The toxin attacks the plasma membranes of capillary endothelial cells and leads to scarlet fever (or scarlatina), a disseminated fine red rash on the skin, and strawberry tongue, a red rash on the tongue (). Severe cases may even lead to streptococcal toxic shock syndrome (STSS), which results from massive superantigen production that leads to septic shock and death.
S. pyogenes can be easily spread by direct contact or droplet transmission through coughing and sneezing. The disease can be diagnosed quickly using a rapid enzyme immunoassay for the group A antigen. However, due to a significant rate of false-negative results (up to 30%WL Lean et al. “Rapid Diagnostic Tests for Group A Streptococcal Pharyngitis: A Meta-Analysis.” ), culture identification is still the gold standard to confirm pharyngitis due to S. pyogenes. S. pyogenes can be identified as a catalase-negative, beta hemolytic bacterium that is susceptible to 0.04 units of bacitracin. Antibiotic resistance is limited for this bacterium, so most β-lactams remain effective; oral amoxicillin and intramuscular penicillin G are those most commonly prescribed.

### Sequelae of S. pyogenes Infections

One reason strep throat infections are aggressively treated with antibiotics is because they can lead to serious sequelae, later clinical consequences of a primary infection. It is estimated that 1%–3% of untreated S. pyogenes infections can be followed by nonsuppurative (without the production of pus) sequelae that develop 1–3 weeks after the acute infection has resolved. Two such sequelae are acute rheumatic fever and acute glomerulonephritis.
Acute rheumatic fever can follow pharyngitis caused by specific rheumatogenic strains of S. pyogenes (strains 1, 3, 5, 6, and 18). Although the exact mechanism responsible for this sequela remains unclear, molecular mimicry between the M protein of rheumatogenic strains of S. pyogenes and heart tissue is thought to initiate the autoimmune attack. The most serious and lethal clinical manifestation of rheumatic fever is damage to and inflammation of the heart (carditis). Acute glomerulonephritis also results from an immune response to streptococcal antigens following pharyngitis and cutaneous infections. Acute glomerulonephritis develops within 6–10 days after pharyngitis, but can take up to 21 days after a cutaneous infection. Similar to acute rheumatic fever, there are strong associations between specific nephritogenic strains of S. pyogenes and acute glomerulonephritis, and evidence suggests a role for antigen mimicry and autoimmunity. However, the primary mechanism of acute glomerulonephritis appears to be the formation of immune complexes between S. pyogenes antigens and antibodies, and their deposition between endothelial cells of the glomeruli of kidney. Inflammatory response against the immune complexes leads to damage and inflammation of the glomeruli (glomerulonephritis).

### Acute Otitis Media

An infection of the middle ear is called acute otitis media (AOM), but often it is simply referred to as an earache. The condition is most common between ages 3 months and 3 years. In the United States, AOM is the second-leading cause of visits to pediatricians by children younger than age 5 years, and it is the leading indication for antibiotic prescription.G. Worrall. “Acute Otitis Media.”
AOM is characterized by the formation and accumulation of pus in the middle ear. Unable to drain, the pus builds up, resulting in moderate to severe bulging of the tympanic membrane and otalgia (ear pain). Inflammation resulting from the infection leads to swelling of the eustachian tubes, and may also lead to fever, nausea, vomiting, and diarrhea, particularly in infants. Infants and toddlers who cannot yet speak may exhibit nonverbal signs suggesting AOM, such as holding, tugging, or rubbing of the ear, as well as uncharacteristic crying or distress in response to the pain.
AOM can be caused by a variety of bacteria. Among neonates, S. pneumoniae is the most common cause of AOM, but , Enterococcus spp., and group B  species can also be involved. In older infants and children younger than 14 years old, the most common bacterial causes are S. pneumoniae, , or . Among S. pneumoniae infections, encapsulated strains are frequent causes of AOM. By contrast, the strains of H. influenzae and M. cattarhalis that are responsible for AOM do not possess a capsule. Rather than direct tissue damage by these pathogens, bacterial components such as lipopolysaccharide (LPS) in gram-negative pathogens induce an inflammatory response that causes swelling, pus, and tissue damage within the middle ear ().
Any blockage of the eustachian tubes, with or without infection, can cause fluid to become trapped and accumulate in the middle ear. This is referred to as otitis media with effusion (OME). The accumulated fluid offers an excellent reservoir for microbial growth and, consequently, secondary bacterial infections often ensue. This can lead to recurring and chronic earaches, which are especially common in young children. The higher incidence in children can be attributed to many factors. Children have more upper respiratory infections, in general, and their eustachian tubes are also shorter and drain at a shallower angle. Young children also tend to spend more time lying down than adults, which facilitates drainage from the nasopharynx through the eustachian tube and into the middle ear. Bottle feeding while lying down enhances this risk because the sucking action on the bottle causes negative pressure to build up within the eustachian tube, promoting the movement of fluid and bacteria from the nasopharynx.
Diagnosis is typically made based on clinical signs and symptoms, without laboratory testing to determine the specific causative agent. Antibiotics are frequently prescribed for the treatment of AOM. High-dose amoxicillin is the first-line drug, but with increasing resistance concerns, macrolides and cephalosporins may also be used. The pneumococcal conjugate vaccine (PCV13) contains serotypes that are important causes of AOM, and vaccination has been shown to decrease the incidence of AOM. Vaccination against influenza has also been shown to decrease the risk for AOM, likely because viral infections like influenza predispose patients to secondary infections with S. pneumoniae. Although there is a conjugate vaccine available for the invasive serotype B of H. influenzae, this vaccine does not impact the incidence of H. influenzae AOM. Because unencapsulated strains of H. influenzae and M. catarrhalis are involved in AOM, vaccines against bacterial cellular factors other than capsules will need to be developed.

### Bacterial Rhinosinusitis

The microbial community of the nasopharynx is extremely diverse and harbors many opportunistic pathogens, so it is perhaps not surprising that infections leading to rhinitis and sinusitis have many possible causes. These conditions often occur as secondary infections after a viral infection, which effectively compromises the immune defenses and allows the opportunistic bacteria to establish themselves. Bacterial sinusitis involves infection and inflammation within the paranasal sinuses. Because bacterial sinusitis rarely occurs without rhinitis, the preferred term is rhinosinusitis. The most common causes of bacterial rhinosinusitis are similar to those for AOM, including S. pneumoniae, H. influenzae, and M. catarrhalis.

### Diphtheria

The causative agent of diphtheria, , is a club-shaped, gram-positive rod that belongs to the phylum Actinobacteria. Diphtheroids are common members of the normal nasopharyngeal microbiota. However, some strains of C. diphtheriae become pathogenic because of the presence of a temperate bacteriophage-encoded protein—the diphtheria toxin. Diphtheria is typically a respiratory infection of the oropharynx but can also cause impetigo-like lesions on the skin. Although the disease can affect people of all ages, it tends to be most severe in those younger than 5 years or older than 40 years. Like strep throat, diphtheria is commonly transmitted in the droplets and aerosols produced by coughing. After colonizing the throat, the bacterium remains in the oral cavity and begins producing the diphtheria toxin. This protein is an A-B toxin that blocks host-cell protein synthesis by inactivating elongation factor (EF)-2 (see Virulence Factors of Bacterial and Viral Pathogens). The toxin’s action leads to the death of the host cells and an inflammatory response. An accumulation of grayish exudate consisting of dead host cells, pus, red blood cells, fibrin, and infectious bacteria results in the formation of a pseudomembrane. The pseudomembrane can cover mucous membranes of the nasal cavity, tonsils, pharynx, and larynx (). This is a classic sign of diphtheria. As the disease progresses, the pseudomembrane can enlarge to obstruct the fauces of the pharynx or trachea and can lead to suffocation and death. Sometimes, intubation, the placement of a breathing tube in the trachea, is required in advanced infections. If the diphtheria toxin spreads throughout the body, it can damage other tissues as well. This can include myocarditis (heart damage) and nerve damage that may impair breathing.
The presumptive diagnosis of diphtheria is primarily based on the clinical symptoms (i.e., the pseudomembrane) and vaccination history, and is typically confirmed by identifying bacterial cultures obtained from throat swabs. The diphtheria toxin itself can be directly detected in vitro using polymerase chain reaction (PCR)-based, direct detection systems for the diphtheria tox gene, and immunological techniques like radial immunodiffusion or Elek’s immunodiffusion test.
Broad-spectrum antibiotics like penicillin and erythromycin tend to effectively control C. diphtheriae infections. Regrettably, they have no effect against preformed toxins. If toxin production has already occurred in the patient, antitoxins (preformed antibodies against the toxin) are administered. Although this is effective in neutralizing the toxin, the antitoxins may lead to serum sickness because they are produced in horses (see Hypersensitivities).
Widespread vaccination efforts have reduced the occurrence of diphtheria worldwide. There are currently four combination toxoid vaccines available that provide protection against diphtheria and other diseases: DTaP, Tdap, DT, and Td. In all cases, the letters “d,” “t,” and “p” stand for diphtheria, tetanus, and pertussis, respectively; the “a” stands for acellular. If capitalized, the letters indicate a full-strength dose; lowercase letters indicate reduced dosages. According to current recommendations, children should receive five doses of the DTaP vaccine in their youth and a Td booster every 10 years. Children with adverse reactions to the pertussis vaccine may be given the DT vaccine in place of the DTaP.

### Bacterial Pneumonia

Pneumonia is a general term for infections of the lungs that lead to inflammation and accumulation of fluids and white blood cells in the alveoli. Pneumonia can be caused by bacteria, viruses, fungi, and other organisms, although the vast majority of pneumonias are bacterial in origin. Bacterial pneumonia is a prevalent, potentially serious infection; it caused more 50,000 deaths in the United States in 2014.KD Kochanek et al. “Deaths: Final Data for 2014.”  As the alveoli fill with fluids and white blood cells (consolidation), air exchange becomes impaired and patients experience respiratory distress (). In addition, pneumonia can lead to pleurisy, an infection of the pleural membrane surrounding the lungs, which can make breathing very painful. Although many different bacteria can cause pneumonia under the right circumstances, three bacterial species cause most clinical cases: , , and . In addition to these, we will also examine some of the less common causes of pneumonia.

### Pneumococcal Pneumonia

The most common cause of community-acquired bacterial pneumonia is Streptococcus pneumoniae. This gram-positive, alpha hemolytic streptococcus is commonly found as part of the normal microbiota of the human respiratory tract. The cells tend to be somewhat lancet-shaped and typically appear as pairs (). The pneumococci initially colonize the bronchioles of the lungs. Eventually, the infection spreads to the alveoli, where the microbe’s polysaccharide capsule interferes with phagocytic clearance. Other virulence factors include autolysins like Lyt A, which degrade the microbial cell wall, resulting in cell lysis and the release of cytoplasmic virulence factors. One of these factors, pneumolysin O, is important in disease progression; this pore-forming protein damages host cells, promotes bacterial adherence, and enhances pro-inflammatory cytokine production. The resulting inflammatory response causes the alveoli to fill with exudate rich in neutrophils and red blood cells. As a consequence, infected individuals develop a productive cough with bloody sputum.
Pneumococci can be presumptively identified by their distinctive gram-positive, lancet-shaped cell morphology and diplococcal arrangement. In blood agar cultures, the organism demonstrates alpha hemolytic colonies that are autolytic after 24 to 48 hours. In addition, S. pneumoniae is extremely sensitive to optochin and colonies are rapidly destroyed by the addition of 10% solution of sodium deoxycholate. All clinical pneumococcal isolates are serotyped using the quellung reaction with typing antisera produced by the CDC. Positive quellung reactions are considered definitive identification of pneumococci.
Antibiotics remain the mainstay treatment for pneumococci. β-Lactams like penicillin are the first-line drugs, but resistance to β-lactams is a growing problem. When β-lactam resistance is a concern, macrolides and fluoroquinolones may be prescribed. However, S. pneumoniae resistance to macrolides and fluoroquinolones is increasing as well, limiting the therapeutic options for some infections. There are currently two pneumococcal vaccines available: pneumococcal conjugate vaccine (PCV13) and pneumococcal polysaccharide vaccine (PPSV23). These are generally given to the most vulnerable populations of individuals: children younger than 2 years and adults older than 65 years.

### Haemophilus Pneumonia

Encapsulated strains of  are known for causing meningitis, but nonencapsulated strains are important causes of pneumonia. This small, gram-negative coccobacillus is found in the pharynx of the majority of healthy children; however, Haemophilus pneumonia is primarily seen in the elderly. Like other pathogens that cause pneumonia, H. influenzae is spread by droplets and aerosols produced by coughing. A fastidious organism, H. influenzae will only grow on media with available factor X (hemin) and factor V (NAD), like chocolate agar (). Serotyping must be performed to confirm identity of H. influenzae isolates.
Infections of the alveoli by H. influenzae result in inflammation and accumulation of fluids. Increasing resistance to β-lactams, macrolides, and tetracyclines presents challenges for the treatment of Haemophilus pneumonia. Resistance to the fluoroquinolones is rare among isolates of H. influenzae but has been observed. As discussed for AOM, a vaccine directed against nonencapsulated H. influenzae, if developed, would provide protection against pneumonia caused by this pathogen.

### Mycoplasma Pneumonia (Walking Pneumonia)

Primary atypical pneumonia is caused by . This bacterium is not part of the respiratory tract’s normal microbiota and can cause epidemic disease outbreaks. Also known as walking pneumonia,  infections are common in crowded environments like college campuses and military bases. It is spread by aerosols formed when coughing or sneezing. The disease is often mild, with a low fever and persistent cough. These bacteria, which do not have cell walls, use a specialized attachment organelle to bind to ciliated cells. In the process, epithelial cells are damaged and the proper function of the cilia is hindered ().
Mycoplasma grow very slowly when cultured. Therefore, penicillin and thallium acetate are added to agar to prevent the overgrowth by faster-growing potential contaminants. Since M. pneumoniae does not have a cell wall, it is resistant to these substances. Without a cell wall, the microbial cells appear pleomorphic. M. pneumoniae infections tend to be self-limiting but may also respond well to macrolide antibiotic therapy. β-lactams, which target cell wall synthesis, are not indicated for treatment of infections with this pathogen.

### Chlamydial Pneumonias and Psittacosis

Chlamydial pneumonia can be caused by three different species of bacteria:  (formerly known as Chlamydia pneumoniae),  (formerly known as Chlamydia psittaci), and . All three are obligate intracellular pathogens and cause mild to severe pneumonia and bronchitis. Of the three, Chlamydophila pneumoniae is the most common and is transmitted via respiratory droplets or aerosols. C. psittaci causes psittacosis, a zoonotic disease that primarily affects domesticated birds such as parakeets, turkeys, and ducks, but can be transmitted from birds to humans. Psittacosis is a relatively rare infection and is typically found in people who work with birds. Chlamydia trachomatis, the causative agent of the sexually transmitted disease chlamydia, can cause pneumonia in infants when the infection is passed from mother to baby during birth.
Diagnosis of chlamydia by culturing tends to be difficult and slow. Because they are intracellular pathogens, they require multiple passages through tissue culture. Recently, a variety of PCR- and serologically based tests have been developed to enable easier identification of these pathogens. Tetracycline and macrolide antibiotics are typically prescribed for treatment.

### Health Care-Associated Pneumonia

A variety of opportunistic bacteria that do not typically cause respiratory disease in healthy individuals are common causes of health care-associated pneumonia. These include , , and proteobacteria such as species of Escherichia, Proteus, and Serratia. Patients at risk include the elderly, those who have other preexisting lung conditions, and those who are immunocompromised. In addition, patients receiving supportive therapies such as intubation, antibiotics, and immunomodulatory drugs may also be at risk because these interventions disrupt the mucociliary escalator and other pulmonary defenses. Invasive medical devices such as catheters, medical implants, and ventilators can also introduce opportunistic pneumonia-causing pathogens into the body.SM Koenig et al. “Ventilator-Associated Pneumonia: Diagnosis, Treatment, and Prevention.”
Pneumonia caused by K. pneumoniae is characterized by lung necrosis and “currant jelly sputum,” so named because it consists of clumps of blood, mucus, and debris from the thick polysaccharide capsule produced by the bacterium. K. pneumoniae is often multidrug resistant. Aminoglycoside and cephalosporin are often prescribed but are not always effective. Klebsiella pneumonia is frequently fatal even when treated.

### Pseudomonas Pneumonia

 is another opportunistic pathogen that can cause serious cases of bacterial pneumonia in patients with cystic fibrosis (CF) and hospitalized patients assisted with artificial ventilators. This bacterium is extremely antibiotic resistant and can produce a variety of exotoxins. Ventilator-associated pneumonia with P. aeruginosa is caused by contaminated equipment that causes the pathogen to be aspirated into the lungs. In patients with CF, a genetic defect in the cystic fibrosis transmembrane receptor (CFTR) leads to the accumulation of excess dried mucus in the lungs. This decreases the effectiveness of the defensins and inhibits the mucociliary escalator. P. aeruginosa is known to infect more than half of all patients with CF. It adapts to the conditions in the patient’s lungs and begins to produce alginate, a viscous exopolysaccharide that inhibits the mucociliary escalator. Lung damage from the chronic inflammatory response that ensues is the leading cause of mortality in patients with CF.R. Sordé et al. “Management of Refractory

### Tuberculosis

Tuberculosis (TB) is one of the deadliest infectious diseases in human history. Although tuberculosis infection rates in the United States are extremely low, the CDC estimates that about one-third of the world’s population is infected with , the causal organism of TB, with 9.6 million new TB cases and 1.5 million deaths worldwide in 2014.Centers for Disease Control and Prevention. “Tuberculosis (TB). Data and Statistics.” http://www.cdc.gov/tb/statistics/default.htm
M. tuberculosis is an acid-fast, high G + C, gram-positive, nonspore-forming rod. Its cell wall is rich in waxy mycolic acids, which make the cells impervious to polar molecules. It also causes these organisms to grow slowly. M. tuberculosis causes a chronic granulomatous disease that can infect any area of the body, although it is typically associated with the lungs. M. tuberculosis is spread by inhalation of respiratory droplets or aerosols from an infected person. The infectious dose of M. tuberculosis is only 10 cells.D. Saini et al. “Ultra-Low Dose of
After inhalation, the bacteria enter the alveoli (). The cells are phagocytized by macrophages but can survive and multiply within these phagocytes because of the protection by the waxy mycolic acid in their cell walls. If not eliminated by macrophages, the infection can progress, causing an inflammatory response and an accumulation of neutrophils and macrophages in the area. Several weeks or months may pass before an immunological response is mounted by T cells and B cells. Eventually, the lesions in the alveoli become walled off, forming small round lesions called tubercles. Bacteria continue to be released into the center of the tubercles and the chronic immune response results in tissue damage and induction of apoptosis (programmed host-cell death) in a process called liquefaction. This creates a caseous center, or air pocket, where the aerobic M. tuberculosis can grow and multiply. Tubercles may eventually rupture and bacterial cells can invade pulmonary capillaries; from there, bacteria can spread through the bloodstream to other organs, a condition known as miliary tuberculosis. The rupture of tubercles also facilitates transmission of the bacteria to other individuals via droplet aerosols that exit the body in coughs. Because these droplets can be very small and stay aloft for a long time, special precautions are necessary when caring for patients with TB, such as the use of face masks and negative-pressure ventilation and filtering systems.
Eventually, most lesions heal to form calcified Ghon complexes. These structures are visible on chest radiographs and are a useful diagnostic feature. But even after the disease has apparently ended, viable bacteria remain sequestered in these locations. Release of these organisms at a later time can produce reactivation tuberculosis (or secondary TB). This is mainly observed in people with alcoholism, the elderly, or in otherwise immunocompromised individuals ().
Because TB is a chronic disease, chemotherapeutic treatments often continue for months or years. Multidrug resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains of M. tuberculosis are a growing clinical concern. These strains can arise due to misuse or mismanagement of antibiotic therapies. Therefore, it is imperative that proper multidrug protocols are used to treat these infections. Common antibiotics included in these mixtures are isoniazid, rifampin, ethambutol, and pyrazinamide.
A TB vaccine is available that is based on the so-called bacillus Calmette-Guérin (BCG) strain of M. bovis commonly found in cattle. In the United States, the BCG vaccine is only given to health-care workers and members of the military who are at risk of exposure to active cases of TB. It is used more broadly worldwide. Many individuals born in other countries have been vaccinated with BCG strain. BCG is used in many countries with a high prevalence of TB, to prevent childhood tuberculous meningitis and miliary disease.
The Mantoux tuberculin skin test () is regularly used in the United States to screen for potential TB exposure (see Hypersensitivities). However, prior vaccinations with the BCG vaccine can cause false-positive results. Chest radiographs to detect Ghon complex formation are required, therefore, to confirm exposure.

### Pertussis (Whooping Cough)

The causative agent of pertussis, commonly called whooping cough, is , a gram-negative coccobacillus. The disease is characterized by mucus accumulation in the lungs that leads to a long period of severe coughing. Sometimes, following a bout of coughing, a sound resembling a “whoop” is produced as air is inhaled through the inflamed and restricted airway—hence the name whooping cough. Although adults can be infected, the symptoms of this disease are most pronounced in infants and children. Pertussis is highly communicable through droplet transmission, so the uncontrollable coughing produced is an efficient means of transmitting the disease in a susceptible population.
Following inhalation, B. pertussis specifically attaches to epithelial cells using an adhesin, filamentous hemagglutinin. The bacteria then grow at the site of infection and cause disease symptoms through the production of exotoxins. One of the main virulence factors of this organism is an A-B exotoxin called the pertussis toxin (PT). When PT enters the host cells, it increases the cyclic adenosine monophosphate (cAMP) levels and disrupts cellular signaling. PT is known to enhance inflammatory responses involving histamine and serotonin. In addition to PT, B. pertussis produces a tracheal cytotoxin that damages ciliated epithelial cells and results in accumulation of mucus in the lungs. The mucus can support the colonization and growth of other microbes and, as a consequence, secondary infections are common. Together, the effects of these factors produce the cough that characterizes this infection.
A pertussis infection can be divided into three distinct stages. The initial infection, termed the catarrhal stage, is relatively mild and unremarkable. The signs and symptoms may include nasal congestion, a runny nose, sneezing, and a low-grade fever. This, however, is the stage in which B. pertussis is most infectious. In the paroxysmal stage, mucus accumulation leads to uncontrollable coughing spasms that can last for several minutes and frequently induce vomiting. The paroxysmal stage can last for several weeks. A long convalescence stage follows the paroxysmal stage, during which time patients experience a chronic cough that can last for up to several months. In fact, the disease is sometimes called the 100-day cough.
In infants, coughing can be forceful enough to cause fractures to the ribs, and prolonged infections can lead to death. The CDC reported 20 pertussis-related deaths in 2012,Centers for Disease Control and Prevention. “2012 Final Pertussis Surveillance Report.” 2015. http://www.cdc.gov/pertussis/downloads/pertuss-surv-report-2012.pdf. Accessed July 6, 2016. but that number had declined to five by 2015.Centers for Disease Control and Prevention. “2015 Provisional Pertussis Surveillance Report.” 2016. http://www.cdc.gov/pertussis/downloads/pertuss-surv-report-2015-provisional.pdf. Accessed July 6, 2016.
During the first 2 weeks of infection, laboratory diagnosis is best performed by culturing the organism directly from a nasopharyngeal (NP) specimen collected from the posterior nasopharynx. The NP specimen is streaked onto Bordet-Gengou medium. The specimens must be transported to the laboratory as quickly as possible, even if transport media are used. Transport times of longer than 24 hours reduce the viability of B. pertussis significantly.
Within the first month of infection, B. pertussis can be diagnosed using PCR techniques. During the later stages of infection, pertussis-specific antibodies can be immunologically detected using an enzyme-linked immunosorbent assay (ELISA).
Pertussis is generally a self-limiting disease. Antibiotic therapy with erythromycin or tetracycline is only effective at the very earliest stages of disease. Antibiotics given later in the infection, and prophylactically to uninfected individuals, reduce the rate of transmission. Active vaccination is a better approach to control this disease. The DPT vaccine was once in common use in the United States. In that vaccine, the P component consisted of killed whole-cell B. pertussis preparations. Because of some adverse effects, that preparation has now been superseded by the DTaP and Tdap vaccines. In both of these new vaccines, the “aP” component is a pertussis toxoid.
Widespread vaccination has greatly reduced the number of reported cases and prevented large epidemics of pertussis. Recently, however, pertussis has begun to reemerge as a childhood disease in some states because of declining vaccination rates and an increasing population of susceptible children.

### Legionnaires Disease

An atypical pneumonia called Legionnaires disease (also known as legionellosis) is caused by an aerobic gram-negative bacillus, . This bacterium infects free-living amoebae that inhabit moist environments, and infections typically occur from human-made reservoirs such as air-conditioning cooling towers, humidifiers, misting systems, and fountains. Aerosols from these reservoirs can lead to infections of susceptible individuals, especially those suffering from chronic heart or lung disease or other conditions that weaken the immune system.
When L. pneumophila bacteria enter the alveoli, they are phagocytized by resident macrophages. However, L. pneumophila uses a secretion system to insert proteins in the endosomal membrane of the macrophage; these proteins prevent lysosomal fusion, allowing L. pneumophila to continue to proliferate within the phagosome. The resulting respiratory disease can range from mild to severe pneumonia, depending on the status of the host’s immune defenses. Although this disease primarily affects the lungs, it can also cause fever, nausea, vomiting, confusion, and other neurological effects.
Diagnosis of Legionnaires disease is somewhat complicated. L. pneumophila is a fastidious bacterium and is difficult to culture. In addition, since the bacterial cells are not efficiently stained with the Gram stain, other staining techniques, such as the Warthin-Starry silver-precipitate procedure, must be used to visualize this pathogen. A rapid diagnostic test has been developed that detects the presence of Legionella antigen in a patient’s urine; results take less than 1 hour, and the test has high selectivity and specificity (greater than 90%). Unfortunately, the test only works for one serotype of L. pneumophila (type 1, the serotype responsible for most infections). Consequently, isolation and identification of L. pneumophila from sputum remains the defining test for diagnosis.
Once diagnosed, Legionnaire disease can be effectively treated with fluoroquinolone and macrolide antibiotics. However, the disease is sometimes fatal; about 10% of patients die of complications.Centers for Disease Control and Prevention. “ There is currently no vaccine available.

### Q Fever

The zoonotic disease Q fever is caused by a rickettsia, . The primary reservoirs for this bacterium are domesticated livestock such as cattle, sheep, and goats. The bacterium may be transmitted by ticks or through exposure to the urine, feces, milk, or amniotic fluid of an infected animal. In humans, the primary route of infection is through inhalation of contaminated farmyard aerosols. It is, therefore, largely an occupational disease of farmers. Humans are acutely sensitive to C. burnetii—the infective dose is estimated to be just a few cells.WD Tigertt et al. “Airborne Q Fever.”  In addition, the organism is hardy and can survive in a dry environment for an extended time. Symptoms associated with acute Q fever include high fever, headache, coughing, pneumonia, and general malaise. In a small number of patients (less than 5%Centers for Disease Control and Prevention. “Q fever. Symptoms, Diagnosis, and Treatment.” 2013. http://www.cdc.gov/qfever/symptoms/index.html. Accessed July 6, 2016.), the condition may become chronic, often leading to endocarditis, which may be fatal.
Diagnosing rickettsial infection by cultivation in the laboratory is both difficult and hazardous because of the easy aerosolization of the bacteria, so PCR and ELISA are commonly used. Doxycycline is the first-line drug to treat acute Q fever. In chronic Q fever, doxycycline is often paired with hydroxychloroquine.

### Key Concepts and Summary

1. A wide variety of bacteria can cause respiratory diseases; most are treatable with antibiotics or preventable with vaccines.
2. Streptococcus pyogenes causes strep throat, an infection of the pharynx that also causes high fever and can lead to scarlet fever, acute rheumatic fever, and acute glomerulonephritis.
3. Acute otitis media is an infection of the middle ear that may be caused by several bacteria, including Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. The infection can block the eustachian tubes, leading to otitis media with effusion.
4. Diphtheria, caused by Corynebacterium diphtheriae, is now a rare disease because of widespread vaccination. The bacteria produce exotoxins that kill cells in the pharynx, leading to the formation of a pseudomembrane; and damage other parts of the body.
5. Bacterial pneumonia results from infections that cause inflammation and fluid accumulation in the alveoli. It is most commonly caused by S. pneumoniae or H. influenzae. The former is commonly multidrug resistant.
6.  results from infection by Mycoplasma pneumoniae; it can spread quickly, but the disease is mild and self-limiting.
7. Chlamydial pneumonia can be caused by three pathogens that are obligate intracellular parasites. Chlamydophila pneumoniae is typically transmitted from an infected person, whereas C. psittaci is typically transmitted from an infected bird. Chlamydia trachomatis, may cause pneumonia in infants.
8. Several other bacteria can cause pneumonia in immunocompromised individuals and those with cystic fibrosis.
9. Tuberculosis is caused by Mycobacterium tuberculosis. Infection leads to the production of protective tubercles in the alveoli and calcified Ghon complexes that can harbor the bacteria for a long time. Antibiotic-resistant forms are common and treatment is typically long term.
10. Pertussis is caused by Bordetella pertussis. Mucus accumulation in the lungs leads to prolonged severe coughing episodes (whooping cough) that facilitate transmission. Despite an available vaccine, outbreaks are still common.
11. Legionnaires disease is caused by infection from environmental reservoirs of the Legionella pneumophila bacterium. The bacterium is endocytic within macrophages and infection can lead to pneumonia, particularly among immunocompromised individuals.
12. Q fever is caused by Coxiella burnetii, whose primary hosts are domesticated mammals (zoonotic disease). It causes pneumonia primarily in farm workers and can lead to serious complications, such as endocarditis.

### Multiple Choice

### Fill in the Blank

### Short Answer

### Critical Thinking


# Respiratory System Infections

## Viral Infections of the Respiratory Tract

### Learning Objectives

By the end of this section, you will be able to:
1. Identify the most common viruses that can cause infections of the upper and lower respiratory tract
2. Compare the major characteristics of specific viral diseases of the  respiratory tract
Viruses are the most frequent cause of respiratory tract infections. Unlike the bacterial pathogens, we have few effective therapies to combat viral respiratory infections. Fortunately, many of these diseases are mild and self-limiting. A few respiratory infections manifest their primary symptoms at other locations in the body.

### The Common Cold

The common cold is a generic term for a variety of mild viral infections of the nasal cavity. More than 200 different viruses are known to cause the common cold. The most common groups of cold viruses include rhinoviruses, coronaviruses, and adenoviruses. These infections are widely disseminated in the human population and are transmitted through direct contact and droplet transmission. Coughing and sneezing efficiently produce infectious aerosols, and rhinoviruses are known to persist on environmental surfaces for up to a week.AG L’Huillier et al. “Survival of Rhinoviruses on Human Fingers.”
Viral contact with the nasal mucosa or eyes can lead to infection. Rhinoviruses tend to replicate best between 33 °C (91.4 °F) and 35 °C (95 °F), somewhat below normal body temperature (37 °C [98.6 °F]). As a consequence, they tend to infect the cooler tissues of the nasal cavities. Colds are marked by an irritation of the mucosa that leads to an inflammatory response. This produces common signs and symptoms such as nasal excess nasal secretions (runny nose), congestion, sore throat, coughing, and sneezing. The absence of high fever is typically used to differentiate common colds from other viral infections, like influenza. Some colds may progress to cause otitis media, pharyngitis, or laryngitis, and patients may also experience headaches and body aches. The disease, however, is self-limiting and typically resolves within 1–2 weeks.
There are no effective antiviral treatments for the common cold and antibacterial drugs should not be prescribed unless secondary bacterial infections have been established. Many of the viruses that cause colds are related, so immunity develops throughout life. Given the number of viruses that cause colds, however, individuals are never likely to develop immunity to all causes of the common cold.

### Influenza

Commonly known as the flu, influenza is a common viral disease caused by an orthomyxovirus that primarily affects the upper respiratory tract but can also extend into the lower respiratory tract. Influenza is pervasive worldwide and causes 3,000–50,000 deaths each year in the United States. The annual mortality rate can vary greatly depending on the virulence of the strain(s) responsible for seasonal epidemics. Centers for Disease Control and Prevention. “Estimating Seasonal Influenza-Associated Deaths in the United States: CDC Study Confirms Variability of Flu.” 2016. http://www.cdc.gov/flu/about/disease/us_flu-related_deaths.htm. Accessed July 6, 2016.
Influenza infections are most typically characterized by fever, chills, and body aches. This is followed by symptoms similar to the common cold that may last a week or more.  compares the signs and symptoms of influenza and the common cold.
In general, influenza is self-limiting. However, serious cases can lead to pneumonia and other complications that can be fatal. Such cases are more common in the very young and the elderly; however, certain strains of influenza virus (like the 1918–1919 variant discussed later in this chapter) are more lethal to young adults than to the very young or old. Strains that affect young adults are believed to involve a cytokine storm—a positive feedback loop that forms between cytokine production and leukocytes. This cytokine storm produces an acute inflammatory response that leads to rapid fluid accumulation in the lungs, culminating in pulmonary failure. In such cases, the ability to mount a vigorous immune response is actually detrimental to the patient. The very young and very old are less susceptible to this effect because their immune systems are less robust.
A complication of influenza that occurs primarily in children and teenagers is Reye syndrome. This sequela causes swelling in the liver and brain, and may progress to neurological damage, coma, or death. Reye syndrome may follow other viral infections, like chickenpox, and has been associated with the use of aspirin. For this reason, the CDC and other agencies recommend that aspirin and products containing aspirin never be used to treat viral illnesses in children younger than age 19 years.ED Belay et al. “Reye’s Syndrome in the United States From 1981 Through 1997.”
The influenza virus is primarily transmitted by direct contact and inhalation of aerosols. The RNA genome of this virus exists as seven or eight segments, each coated with ribonucleoprotein and encoding one or two specific viral proteins. The influenza virus is surrounded by a lipid membrane envelope, and two of the main antigens of the influenza virus are the spike proteins hemagglutinin (H) and neuraminidase (N), as shown in . These spike proteins play important roles in the viral infectious cycle.
Following inhalation, the influenza virus uses the hemagglutinin protein to bind to sialic acid receptors on host respiratory epithelial cells. This facilitates endocytosis of the viral particle. Once inside the host cell, the negative strand viral RNA is replicated by the viral RNA polymerase to form mRNA, which is translated by the host to produce viral proteins. Additional viral RNA molecules are transcribed to produce viral genomic RNA, which assemble with viral proteins to form mature virions. Release of the virions from the host cell is facilitated by viral neuraminidase, which cleaves sialic-acid receptors to allow progeny viruses to make a clean exit when budding from an infected cell.
There are three genetically related influenza viruses, called A, B, and C. The influenza A viruses have different subtypes based on the structure of their hemagglutinin and neuraminidase proteins. There are currently 18 known subtypes of hemagglutinin and 11 known subtypes of neuraminidase. Influenza viruses are serologically characterized by the type of H and N proteins that they possess. Of the nearly 200 different combinations of H and N, only a few, such as the H1N1 strain, are associated with human disease. The influenza viruses A, B, and C make up three of the five major groups of orthomyxoviruses. The differences between the three types of influenza are summarized in . The most virulent group is the influenza A viruses, which cause seasonal pandemics of influenza each year. Influenza A virus can infect a variety of animals, including pigs, horses, and even whales and dolphins. Influenza B virus is less virulent and is sometimes associated with epidemic outbreaks. Influenza C virus generally produces the mildest disease symptoms and is rarely connected with epidemics. Neither influenza B virus nor influenza C virus has significant animal reservoirs.
Influenza virus infections elicit a strong immune response, particularly to the hemagglutinin protein, which would protect the individual if they encountered the same virus. Unfortunately, the antigenic properties of the virus change relatively rapidly, so new strains are evolving that immune systems previously challenged by influenza virus cannot recognize. When an influenza virus gains a new hemagglutinin or neuraminidase type, it is able to evade the host’s immune response and be successfully transmitted, often leading to an epidemic.
There are two mechanisms by which these evolutionary changes may occur. The mechanisms of antigen drift and antigenic shift for influenza virus have been described in Virulence Factors of Bacterial and Viral Pathogens. Of these two genetic processes, it is viruses produced by antigenic shift that have the potential to be extremely virulent because individuals previously infected by other strains are unlikely to produce any protective immune response against these novel variants.
The most lethal influenza pandemic in recorded history occurred from 1918 through 1919. Near the end of World War I, an antigenic shift involving the recombination of avian and human viruses is thought to have produced a new H1N1 virus. This strain rapidly spread worldwide and is commonly claimed to have killed as many as 40 million to 50 million people—more than double the number killed in the war. Although referred to as the Spanish flu, this disease is thought to have originated in the United States. Regardless of its source, the conditions of World War I greatly contributed to the spread of this disease. Crowding, poor sanitation, and rapid mobilization of large numbers of personnel and animals facilitated the dissemination of the new virus once it appeared.
Several of the most important influenza pandemics of modern times have been associated with antigenic shifts. A few of these are summarized in .
Laboratory diagnosis of influenza is typically performed using a variety of RIDTs. These tests are inoculated by point-of-care personnel and give results within 15–20 minutes. Unfortunately, these tests have variable sensitivity and commonly yield false-negative results. Other tests include hemagglutination of erythrocytes (due to hemagglutinin action) or complement fixation. Patient serum antibodies against influenza viruses can also be detected in blood samples. Because influenza is self-limiting disease, diagnosis through these more time-consuming and expensive methods is not typically used.
Three drugs that inhibit influenza neuraminidase activity are available: inhaled zanamivir, oral oseltamivir, and intravenous peramivir. If taken at the onset of symptoms, these drugs can shorten the course of the disease. These drugs are thought to impair the ability of the virus to efficiently exit infected host cells. A more effective means of controlling influenza outbreaks, though, is vaccination. Every year, new influenza vaccines are developed to be effective against the strains expected to be predominant. This is determined in February by a review of the dominant strains around the world from a network of reporting sites; their reports are used to generate a recommendation for the vaccine combination for the following winter in the northern hemisphere. In September, a similar recommendation is made for the winter in the southern hemisphere.World Health Organization. “WHO Report on Global Surveillance of Epidemic-Prone Infectious Diseases.” 2000. http://www.who.int/csr/resources/publications/surveillance/Influenza.pdf. Accessed July 6, 2016. These recommendations are used by vaccine manufacturers to formulate each year’s vaccine. In most cases, three or four viruses are selected—the two most prevalent influenza A strains and one or two influenza B strains. The chosen strains are typically cultivated in eggs and used to produce either an inactivated or a live attenuated vaccine (e.g., FluMist). For individuals 18 years or older with an allergy to egg products, a recombinant egg-free trivalent vaccine is available. Most of the influenza vaccines over the past decade have had an effectiveness of about 50%.Centers of Disease Control and Prevention. “Vaccine Effectiveness - How Well Does the Flu Vaccine Work?” 2016. http://www.cdc.gov/flu/about/qa/vaccineeffect.htm. Accessed July 6, 2016.

### Viral Pneumonia

Viruses cause fewer cases of pneumonia than bacteria; however, several viruses can lead to pneumonia in children and the elderly. The most common sources of viral pneumonia are adenoviruses, influenza viruses, parainfluenza viruses, and respiratory syncytial viruses. The signs and symptoms produced by these viruses can range from mild cold-like symptoms to severe cases of pneumonia, depending on the virulence of the virus strain and the strength of the host defenses of the infected individual. Occasionally, infections can result in otitis media.
Respiratory syncytial virus (RSV) infections are fairly common in infants; most people have been infected by the age of 2 years. During infection, a viral surface protein causes host cells to fuse and form multinucleated giant cells called syncytia. There are no specific antiviral therapies or vaccines available for viral pneumonia. In adults, these infections are self-limiting, resemble the common cold, and tend to resolve uneventfully within 1 or 2 weeks. Infections in infants, however, can be life-threatening. RSV is highly contagious and can be spread through respiratory droplets from coughing and sneezing. RSV can also survive for a long time on environmental surfaces and, thus, be transmitted indirectly via fomites.

### SARS and MERS

Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) are two acute respiratory infections caused by coronaviruses. In both cases, these are thought to be zoonotic infections. Bats and civet cats are thought to have been the reservoirs for SARS; camels seem to be the reservoir for MERS.
SARS originated in southern China in the winter of 2002 and rapidly spread to 37 countries. Within about 1 year, more than 8,000 people experienced influenza-like symptoms and nearly 800 people died. The rapid spread and severity of these infections caused grave concern at the time. However, the outbreak was controlled in 2003 and no further cases of SARS have been recorded since 2004.Y. Huang. “The SARS Epidemic and Its Aftermath in China: A Political Perspective.” In  Signs and symptoms of SARS include high fever, headache, body aches, and cough, and most patients will develop pneumonia.
MERS was first reported in Saudi Arabia in 2013. Although some infected individuals will be asymptomatic or have mild cold-like symptoms, most will develop a high fever, aches, cough and a severe respiratory infection that can progress to pneumonia. As of 2015, over 1,300 people in 27 countries have been infected. About 500 people have died. There are no specific treatments for either MERS or SARS. In addition, no vaccines are currently available. Several recombinant vaccines, however, are being developed.

### Viral Respiratory Diseases Causing Skin Rashes

Measles, rubella (German measles), and chickenpox are three important viral diseases often associated with skin rashes. However, their symptoms are systemic, and because their portal of entry is the respiratory tract, they can be considered respiratory infections.

### Measles (Rubeola)

The measles virus (MeV) causes the highly contagious disease measles, also known as rubeola, which is a major cause of childhood mortality worldwide. Although vaccination efforts have greatly reduced the incidence of measles in much of the world, epidemics are still common in unvaccinated populations in certain countries.Centers for Disease Control and Prevention. “Global Health - Measles, Rubella, and CRS, Eliminating Measles, Rubella & Congenital Rubella Syndrome (CRS) Worldwide.” 2015. http://www.cdc.gov/globalhealth/measles/. Accessed July 7, 2016.
The measles virus is a single-stranded, negative-strand RNA virus and, like the influenza virus, it possesses an envelope with spikes of embedded hemagglutinin. The infection is spread by direct contact with infectious secretions or inhalation of airborne droplets spread by breathing, coughing, or sneezing. Measles is initially characterized by a high fever, conjunctivitis, and a sore throat. The virus then moves systemically through the bloodstream and causes a characteristic rash. The measles rash initially forms on the face and later spreads to the extremities. The red, raised macular rash will eventually become confluent and can last for several days. At the same time, extremely high fevers (higher than 40.6 °C [105 °F]) can occur. Another diagnostic sign of measles infections is Koplik’s spots, white spots that form on the inner lining of inflamed cheek tissues ().
Although measles is usually self-limiting, it can lead to pneumonia, encephalitis, and death. In addition, the inhibition of immune system cells by the measles virus predisposes patients to secondary infections. In severe infections with highly virulent strains, measles fatality rates can be as high as 10% to 15%. There were more than 145,000 measles deaths (mostly young children) worldwide in 2013.World Health Organization. “Measles Factsheet.” 2016. http://www.who.int/mediacentre/factsheets/fs286/en/. Accessed July 7, 2016.
The preliminary diagnosis of measles is typically based on the appearance of the rash and Koplik’s spots. Hemagglutination inhibition tests and serological tests may be used to confirm measles infections in low-prevalence settings.
There are no effective treatments for measles. Vaccination is widespread in developed countries as part of the measles, mumps, and rubella (MMR) vaccine. As a result, there are typically fewer than 200 cases of measles in the United States annually.Centers for Disease Control and Prevention. “Measles Cases and Outbreaks.” 2016. http://www.cdc.gov/measles/cases-outbreaks.html. Accessed July 7, 2016. When it is seen, it is often associated with children who have not been vaccinated.

### Rubella (German Measles)

Rubella, or the German measles, is a relatively mild viral disease that produces a rash somewhat like that caused by the measles, even though the two diseases are unrelated. The rubella virus is an enveloped RNA virus that can be found in the respiratory tract. It is transmitted from person to person in aerosols produced by coughing or sneezing. Nearly half of all infected people remain asymptomatic. However, the virus is shed and spread by asymptomatic carriers. Like rubeola, rubella begins with a facial rash that spreads to the extremities (). However, the rash is less intense, shorter lived (2–3 days), not associated with Koplik’s spots, and the resulting fever is lower (101 °F [38.3 °C]).
Congenital rubella syndrome is the most severe clinical complication of the German measles. This occurs if a woman is infected with rubella during pregnancy. The rubella virus is teratogenic, meaning it can cause developmental defects if it crosses the placenta during pregnancy. There is a very high incidence of stillbirth, spontaneous abortion, or congenital birth defects if the mother is infected before 11 weeks of pregnancy and 35% if she is infected between weeks 13–16; after this time the incidence is low.E. Miller et al. “Consequences of Confirmed Maternal Rubella at Successive Stages of Pregnancy.”  For this reason, prenatal screening for rubella is commonly practiced in the United States. Postnatal infections are usually self-limiting and rarely cause severe complications.
Like measles, the preliminary diagnosis of rubella is based on the patient’s history, vaccination records, and the appearance of the rash. The diagnosis can be confirmed by hemagglutinin inhibition assays and a variety of other immunological techniques. There are no antiviral therapies for rubella, but an effective vaccine (MMR) is widely available. Vaccination efforts have essentially eliminated rubella in the United States; fewer than a dozen cases are reported in a typical year.

### Chickenpox and Shingles

Chickenpox, also known as varicella, was once a common viral childhood disease. The causative agent of chickenpox, the varicella-zoster virus, is a member of the herpesvirus family. In children, the disease is mild and self-limiting, and is easily transmitted by direct contact or inhalation of material from the skin lesions. In adults, however, chickenpox infections can be much more severe and can lead to pneumonia and birth defects in the case of infected pregnant women. Reye syndrome, mentioned earlier in this chapter, is also a serious complication associated with chickenpox, generally in children.
Once infected, most individuals acquire a lifetime immunity to future chickenpox outbreaks. For this reason, parents once held “chickenpox parties” for their children. At these events, uninfected children were intentionally exposed to an infected individual so they would contract the disease earlier in life, when the incidence of complications is very low, rather than risk a more severe infection later.
After the initial viral exposure, chickenpox has an incubation period of about 2 weeks. The initial infection of the respiratory tract leads to viremia and eventually produces fever and chills. A pustular rash then develops on the face, progresses to the trunk, and then the extremities, although most form on the trunk (). Eventually, the lesions burst and form a crusty scab. Individuals with chickenpox are infectious from about 2 days before the outbreak of the rash until all the lesions have scabbed over.
Like other herpesviruses, the varicella-zoster virus can become dormant in nerve cells. While the pustular vesicles are developing, the virus moves along sensory nerves to the dorsal ganglia in the spinal cord. Once there, the varicella-zoster virus can remain latent for decades. These dormant viruses may be reactivated later in life by a variety of stimuli, including stress, aging, and immunosuppression. Once reactivated, the virus moves along sensory nerves to the skin of the face or trunk. This results in the production of the painful lesions in a condition known as shingles (). These symptoms generally last for 2–6 weeks, and may recur more than once. Postherpetic neuralgia, pain signals sent from damaged nerves long after the other symptoms have subsided, is also possible. In addition, the virus can spread to other organs in immunocompromised individuals. A person with shingles lesions can transmit the virus to a nonimmune contact, and the newly infected individual would develop chickenpox as the primary infection. Shingles cannot be transmitted from one person to another.
The primary diagnosis of chickenpox in children is mainly based on the presentation of a pustular rash of the trunk. Serological and PCR-based tests are available to confirm the initial diagnosis. Treatment for chickenpox infections in children is usually not required. In patients with shingles, acyclovir treatment can often reduce the severity and length of symptoms, and diminish the risk of postherpetic neuralgia. An effective vaccine is now available for chickenpox. A vaccine is also available for adults older than 60 years who were infected with chickenpox in their youth. This vaccine reduces the likelihood of a shingles outbreak by boosting the immune defenses that are keeping the latent infection in check and preventing reactivation.

### Key Concepts and Summary

1. Viruses cause respiratory tract infections more frequently than bacteria, and most viral infections lead to mild symptoms.
2. The common cold can be caused by more than 200 viruses, typically rhinoviruses, coronaviruses, and adenoviruses, transmitted by direct contact, aerosols, or environmental surfaces.
3. Due to its ability to rapidly mutate through antigenic drift and antigenic shift, influenza remains an important threat to human health. Two new influenza vaccines are developed annually.
4. Several viral infections, including respiratory syncytial virus infections, which frequently occur in the very young, can begin with mild symptoms before progressing to viral pneumonia.
5. SARS and MERS are acute respiratory infections caused by coronaviruses, and both appear to originate in animals. SARS has not been seen in the human population since 2004 but had a high mortality rate during its outbreak. MERS also has a high mortality rate and continues to appear in human populations.
6. Measles, rubella, and chickenpox are highly contagious, systemic infections that gain entry through the respiratory system and cause rashes and fevers. Vaccines are available for all three. Measles is the most severe of the three and is responsible for significant mortality around the world. Chickenpox typically causes mild infections in children but the virus can reactivate to cause painful cases of shingles later in life.

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# Respiratory System Infections

## Respiratory Mycoses

### Learning Objectives

By the end of this section, you will be able to:
1. Identify the most common fungi that can cause infections of the respiratory tract
2. Compare the major characteristics of specific fungal diseases of the  respiratory tract
Fungal pathogens are ubiquitous in the environment. Serological studies have demonstrated that most people have been exposed to fungal respiratory pathogens during their lives. Yet symptomatic infections by these microbes are rare in healthy individuals. This demonstrates the efficacy of the defenses of our respiratory system. In this section, we will examine some of the fungi that can cause respiratory infections.

### Histoplasmosis

Histoplasmosis is a fungal disease of the respiratory system and most commonly occurs in the Mississippi Valley of the United States and in parts of Central and South America, Africa, Asia, and Australia. The causative agent, , is a dimorphic fungus. This microbe grows as a filamentous mold in the environment but occurs as a budding yeast during human infections. The primary reservoir for this pathogen is soil, particularly in locations rich in bat or bird feces.
Histoplasmosis is acquired by inhaling microconidial spores in the air; this disease is not transmitted from human to human. The incidence of histoplasmosis exposure is high in endemic areas, with 60%–90% of the population having anti-Histoplasma antibodies, depending on location;NE Manos et al. “Geographic Variation in the Prevalence of Histoplasmin Sensitivity.”  however, relatively few individuals exposed to the fungus actually experience symptoms. Those most likely to be affected are the very young, the elderly, and immunocompromised people.
In many ways, the course of this disease is similar to that of tuberculosis. Following inhalation, the spores enter the lungs and are phagocytized by alveolar macrophages. The fungal cells then survive and multiply within these phagocytes (see ). Focal infections cause the formation of granulomatous lesions, which can lead to calcifications that resemble the Ghon complexes of tuberculosis, even in asymptomatic cases. Also like tuberculosis, histoplasmosis can become chronic and reactivation can occur, along with dissemination to other areas of the body (e.g., the liver or spleen).
Signs and symptoms of pulmonary histoplasmosis include fever, headache, and weakness with some chest discomfort. The initial diagnosis is often based on chest radiographs and cultures grown on fungal selective media like Sabouraud's dextrose agar. Direct fluorescence antibody staining and Giemsa staining can also be used to detect this pathogen. In addition, serological tests including a complement fixation assay and histoplasmin sensitivity can be used to confirm the diagnosis. In most cases, these infections are self-limiting and antifungal therapy is not required. However, in disseminated disease, the antifungal agents amphotericin B and ketoconazole are effective; itraconazole may be effective in immunocompromised patients, in whom the disease can be more serious.

### Coccidioidomycosis

Infection by the dimorphic fungus  causes coccidioidomycosis. Because the microbe is endemic to the San Joaquin Valley of California, the disease is sometimes referred to as Valley fever. A related species that causes similar infections is found in semi-arid and arid regions of the southwestern United States, Mexico, and Central and South America.DR Hospenthal. “Coccioidomycosis.” Medscape. 2015. http://emedicine.medscape.com/article/215978-overview. Accessed July 7, 2016.
Like histoplasmosis, coccidioidomycosis is acquired by inhaling fungal spores—in this case, arthrospores formed by hyphal fragmentation. Once in the body, the fungus differentiates into spherules that are filled with endospores. Most C. immitis infections are asymptomatic and self-limiting. However, the infection can be very serious for immunocompromised patients. The endospores may be transported in the blood, disseminating the infection and leading to the formation of granulomatous lesions on the face and nose (). In severe cases, other major organs can become infected, leading to serious complications such as fatal meningitis.
Coccidioidomycosis can be diagnosed by culturing clinical samples. C. immitis readily grows on laboratory fungal media, such as Sabouraud's dextrose agar, at 35 °C (95 °F). Culturing the fungus, however, is rather dangerous. C. immitis is one of the most infectious fungal pathogens known and is capable of causing laboratory-acquired infections. Indeed, until 2012, this organism was considered a “select agent” of bioterrorism and classified as a BSL-3 microbe. Serological tests for antibody production are more often used for diagnosis. Although mild cases generally do not require intervention, disseminated infections can be treated with intravenous antifungal drugs like amphotericin B.

### Blastomycosis

Blastomycosis is a rare disease caused by another dimorphic fungus, . Like Histoplasma and Coccidioides, Blastomyces uses the soil as a reservoir, and fungal spores can be inhaled from disturbed soil. The pulmonary form of blastomycosis generally causes mild flu-like symptoms and is self-limiting. It can, however, become disseminated in immunocompromised people, leading to chronic cutaneous disease with subcutaneous lesions on the face and hands (). These skin lesions eventually become crusty and discolored and can result in deforming scars. Systemic blastomycosis is rare, but if left untreated, it is always fatal.
Preliminary diagnosis of pulmonary blastomycosis can be made by observing the characteristic budding yeast forms in sputum samples. Commercially available urine antigen tests are now also available. Additional confirmatory tests include serological assays such as immunodiffusion tests or EIA. Most cases of blastomycosis respond well to amphotericin B or ketoconazole treatments.

### Mucormycosis

A variety of fungi in the order Mucorales cause mucormycosis, a rare fungal disease. These include bread molds, like Rhizopus and ; the most commonly associated species is  (see ). These fungi can colonize many different tissues in immunocompromised patients, but often infect the skin, sinuses, or the lungs.
Although most people are regularly exposed to the causative agents of mucormycosis, infections in healthy individuals are rare. Exposure to spores from the environment typically occurs through inhalation, but the spores can also infect the skin through a wound or the gastrointestinal tract if ingested. Respiratory mucormycosis primarily affects immunocompromised individuals, such as patients with cancer or those who have had a transplant.Centers for Disease Control and Prevention. “Fungal Diseases. Definition of Mucormycosis.” 2015 http://www.cdc.gov/fungal/diseases/mucormycosis/definition.html. Accessed July 7, 2016.
After the spores are inhaled, the fungi grow by extending hyphae into the host’s tissues. Infections can occur in both the upper and lower respiratory tracts. Rhinocerebral mucormycosis is an infection of the sinuses and brain; symptoms include headache, fever, facial swelling, congestion, and tissue necrosis causing black lesions in the oral cavity. Pulmonary mucormycosis is an infection of the lungs; symptoms include fever, cough, chest pain, and shortness of breath. In severe cases, infections may become disseminated and involve the central nervous system, leading to coma and death.Centers for Disease Control and Prevention. “Fungal Diseases. Symptoms of Mucormycosis.” 2015 http://www.cdc.gov/fungal/diseases/mucormycosis/symptoms.html. Accessed July 7, 2016.
Diagnosing mucormycosis can be challenging. Currently, there are no serological or PCR-based tests available to identify these infections. Tissue biopsy specimens must be examined for the presence of the fungal pathogens. The causative agents, however, are often difficult to distinguish from other filamentous fungi. Infections are typically treated by the intravenous administration of amphotericin B, and superficial infections are removed by surgical debridement. Since the patients are often immunocompromised, viral and bacterial secondary infections commonly develop. Mortality rates vary depending on the site of the infection, the causative fungus, and other factors, but a recent study found an overall mortality rate of 54%.MM Roden et al. “Epidemiology and Outcome of Zygomycosis: A Review of 929 Reported Cases.”

### Aspergillosis

 is a common filamentous fungus found in soils and organic debris. Nearly everyone has been exposed to this mold, yet very few people become sick. In immunocompromised patients, however, Aspergillus may become established and cause aspergillosis. Inhalation of spores can lead to asthma-like allergic reactions. The symptoms commonly include shortness of breath, wheezing, coughing, runny nose, and headaches. Fungal balls, or aspergilloma, can form when hyphal colonies collect in the lungs (). The fungal hyphae can invade the host tissues, leading to pulmonary hemorrhage and a bloody cough. In severe cases, the disease may progress to a disseminated form that is often fatal. Death most often results from pneumonia or brain hemorrhages.
Laboratory diagnosis typically requires chest radiographs and a microscopic examination of tissue and respiratory fluid samples. Serological tests are available to identify Aspergillus antigens. In addition, a skin test can be performed to determine if the patient has been exposed to the fungus. This test is similar to the Mantoux tuberculin skin test used for tuberculosis. Aspergillosis is treated with intravenous antifungal agents, including itraconazole and voriconazole. Allergic symptoms can be managed with corticosteroids because these drugs suppress the immune system and reduce inflammation. However, in disseminated infections, corticosteroids must be discontinued to allow a protective immune response to occur.

### Pneumocystis Pneumonia

A type of pneumonia called  (PCP) is caused by . Once thought to be a protozoan, this organism was formerly named P. carinii but it has been reclassified as a fungus and renamed based on biochemical and genetic analyses. Pneumocystis is a leading cause of pneumonia in patients with acquired immunodeficiency syndrome (AIDS) and can be seen in other compromised patients and premature infants. Respiratory infection leads to fever, cough, and shortness of breath. Diagnosis of these infections can be difficult. The organism is typically identified by microscopic examination of tissue and fluid samples from the lungs (). A PCR-based test is available to detect P. jirovecii in asymptomatic patients with AIDS. The best treatment for these infections is the combination drug trimethoprim-sulfamethoxazole (TMP/SMZ). These sulfa drugs often have adverse effects, but the benefits outweigh these risks. Left untreated, PCP infections are often fatal.

### Cryptococcosis

Infection by the encapsulated yeast  causes cryptococcosis. This fungus is ubiquitous in the soil and can be isolated from bird feces. Immunocompromised people are infected by inhaling basidiospores found in aerosols. The thick polysaccharide capsule surrounding these microbes enables them to avoid clearance by the alveolar macrophage. Initial symptoms of infection include fever, fatigue, and a dry cough. In immunocompromised patients, pulmonary infections often disseminate to the brain. The resulting meningitis produces headaches, sensitivity to light, and confusion. Left untreated, such infections are often fatal.
Cryptococcus infections are often diagnosed based on microscopic examination of lung tissues or cerebrospinal fluids. India ink preparations () can be used to visualize the extensive capsules that surround the yeast cells. Serological tests are also available to confirm the diagnosis. Amphotericin B, in combination with flucytosine, is typically used for the initial treatment of pulmonary infections. Amphotericin B is a broad-spectrum antifungal drug that targets fungal cell membranes. It can also adversely impact host cells and produce side effects. For this reason, clinicians must carefully balance the risks and benefits of treatments in these patients. Because it is difficult to eradicate cryptococcal infections, patients usually need to take fluconazole for up to 6 months after treatment with amphotericin B and flucytosine to clear the fungus. Cryptococcal infections are more common in immunocompromised people, such as those with AIDS. These patients typically require life-long suppressive therapy to control this fungal infection.

### Key Concepts and Summary

1. Fungal pathogens rarely cause respiratory disease in healthy individuals, but inhalation of fungal spores can cause severe pneumonia and systemic infections in immunocompromised patients.
2. Antifungal drugs like amphotericin B can control most fungal respiratory infections.
3. Histoplasmosis is caused by a mold that grows in soil rich in bird or bat droppings. Few exposed individuals become sick, but vulnerable individuals are susceptible. The yeast-like infectious cells grow inside phagocytes.
4. Coccidioidomycosis is also acquired from soil and, in some individuals, will cause lesions on the face. Extreme cases may infect other organs, causing death.
5. Blastomycosis, a rare disease caused by a soil fungus, typically produces a mild lung infection but can become disseminated in the immunocompromised. Systemic cases are fatal if untreated.
6. Mucormycosis is a rare disease, caused by fungi of the order Mucorales. It primarily affects immunocompromised people. Infection involves growth of the hyphae into infected tissues and can lead to death in some cases.
7. Aspergillosis, caused by the common soil fungus Aspergillus, infects immunocompromised people. Hyphal balls may impede lung function and hyphal growth into tissues can cause damage. Disseminated forms can lead to death.
8.  is caused by the fungus P. jirovecii. The disease is found in patients with AIDS and other immunocompromised individuals. Sulfa drug treatments have side effects, but untreated cases may be fatal.
9. Cryptococcosis is caused by Cryptococcus neoformans. Lung infections may move to the brain, causing meningitis, which can be fatal.

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# Urogenital System Infections

## Introduction

The urogenital system is a combination of the urinary tract and reproductive system. Because both systems are open to the external environment, they are prone to infections. Some infections are introduced from outside, whereas others result from imbalances in the microbiota of the urogenital tract.
Urinary tract infections (UTIs) are one the most common bacterial infections worldwide, affecting over 100 million people each year. During 2007 in the United States, doctor office visits for UTIs exceeded 10 million, and an additional 2–3 million emergency department visits were attributed to UTIs. Sexually transmitted infections (STIs) also primarily affect the urogenital system and are an important cause of patient morbidity. The Centers for Disease Control and Prevention (CDC) estimates that there are approximately 20 million new cases of reportable STIs annually in the United States, half of which occur in people aged 15–24 years old. When STIs spread to the reproductive organs, they can be associated with severe morbidity and loss of fertility.
Because males and females have different urogenital anatomy, urogenital infections may affect males and females differently. In this chapter, we will discuss the various microbes that cause urogenital disease and the factors that contribute to their pathogenicity.


# Urogenital System Infections

## Anatomy and Normal Microbiota of the Urogenital Tract

### Learning Objectives

By the end of this section, you will be able to:
1. Compare the anatomy, function, and normal microbiota associated with the male and female urogenital systems
2. Explain how microorganisms, in general, overcome the defenses of the urogenital system to cause infection
3. Name, describe, and differentiate between general signs and symptoms associated with infections of the urogenital tract
The urinary system filters blood, excretes wastes, and maintains an appropriate electrolyte and water balance. The reproductive system is responsible for the production of gametes and participates in conception and, in females, development of offspring. Due to their proximity and overlap, these systems are often studied together and referred to as the urogenital system (or genitourinary system).

### Anatomy of the Urinary Tract

The basic structures of the urinary tract are common in males and females. However, there are unique locations for these structures in females and males, and there is a significant amount of overlap between the urinary and genital structures in males.  illustrates the urinary anatomy common to females and males.
The kidneys carry out the urinary system’s primary functions of filtering the blood and maintaining water and electrolyte balance. The kidneys are composed of millions of filtration units called nephrons. Each nephron is in intimate contact with blood through a specialized capillary bed called the glomerulus (plural glomeruli). Fluids, electrolytes, and molecules from the blood pass from the glomerulus into the nephron, creating the filtrate that becomes urine (). Urine that collects in each kidney empties through a ureter and drains to the urinary bladder, which stores urine. Urine is released from the bladder to the urethra, which transports it to be excreted from the body through the urinary meatus, the opening of the urethra.

### Anatomy of the Reproductive System

The male reproductive system () is located in close proximity to the urinary system, and the urethra is part of both systems. The testes are responsible for the production of sperm. The epididymis is a coiled tube that collects sperm from the testes and passes it on to the vas deferens. The epididymis is also the site of sperm maturation after they leave the testes. The seminal vesicles and prostate are accessory glands that produce fluid that supports sperm. During ejaculation, the vas deferens releases this mixture of fluid and sperm, called semen, into the urethra, which extends to the end of the penis.
The female reproductive system is located near the urinary system (). The external genitalia (vulva) in females open to the vagina, a muscular passageway that connects to the cervix. The cervix is the lower part of the uterus (the organ where a fertilized egg will implant and develop). The cervix is a common site of infection, especially for viruses that may lead to cervical cancer. The uterus leads to the fallopian tubes and eventually to the ovaries. Ovaries are the site of ova (egg) production, as well as the site of estrogen and progesterone production that are involved in maturation and maintenance of reproductive organs, preparation of the uterus for pregnancy, and regulation of the menstrual cycle.

### Normal Microbiota of the Urogenital System

The normal microbiota of different body sites provides an important nonspecific defense against infectious diseases (see Physical Defenses), and the urogenital tract is no exception. In both men and women, however, the kidneys are sterile. Although urine does contain some antibacterial components, bacteria will grow in urine left out at room temperature. Therefore, it is primarily the flushing action that keeps the ureters and bladder free of microbes.
Below the bladder, the normal microbiota of the male urogenital system is found primarily within the distal urethra and includes bacterial species that are commonly associated with the skin microbiota. In women, the normal microbiota is found within the distal one third of the urethra and the vagina. The normal microbiota of the vagina becomes established shortly after birth and is a complex and dynamic population of bacteria that fluctuates in response to environmental changes. Members of the vaginal microbiota play an important role in the nonspecific defense against vaginal infections and sexually transmitted infections by occupying cellular binding sites and competing for nutrients. In addition, the production of lactic acid by members of the microbiota provides an acidic environment within the vagina that also serves as a defense against infections. For the majority of women, the lactic-acid–producing bacteria in the vagina are dominated by a variety of species of . For women who lack sufficient lactobacilli in their vagina, lactic acid production comes primarily from other species of bacteria such as  spp.,  spp., and . Lactobacillus spp. use glycogen from vaginal epithelial cells for metabolism and production of lactic acid. This process is tightly regulated by the hormone estrogen. Increased levels of estrogen correlate with increased levels of vaginal glycogen, increased production of lactic acid, and a lower vaginal pH. Therefore, decreases in estrogen during the menstrual cycle and with menopause are associated with decreased levels of vaginal glycogen and lactic acid, and a higher pH. In addition to producing lactic acid, Lactobacillus spp. also contribute to the defenses against infectious disease through their production of hydrogen peroxide and bacteriocins (antibacterial peptides).

### General Signs and Symptoms of Urogenital Infections

Infections of the urinary tract most commonly cause inflammation of the bladder (cystitis) or of the urethra (urethritis). Urethritis can be associated with cystitis, but can also be caused by sexually transmitted infections. Symptoms of urethritis in men include burning sensation while urinating, discharge from the penis, and blood in the semen or the urine. In women, urethritis is associated with painful and frequent urination, vaginal discharge, fever, chills, and abdominal pain. The symptoms of cystitis are similar to those of urethritis. When urethritis is caused by a sexually transmitted pathogen, additional symptoms involving the genitalia can occur. These can include painful vesicles (blisters), warts, and ulcers. Ureteritis, a rare infection of the ureter, can also occur with cystitis. These infections can be acute or chronic.
Pyelonephritis and glomerulonephritis are infections of the kidney that are potentially serious. Pyelonephritis is an infection of one or both of the kidneys and may develop from a lower urinary tract infection; the upper urinary tract, including the ureters, is often affected. Signs and symptoms of pyelonephritis include fever, chills, nausea, vomiting, lower back pain, and frequent painful urination. Pyelonephritis usually only becomes chronic in individuals who have malformations in or damage to the kidneys.
Glomerulonephritis is an inflammation of the glomeruli of the nephrons. Symptoms include excessive protein and blood in urine, increased blood pressure, and fluid retention leading to edema of face, hands, and feet. Glomerulonephritis may be an acute infection or it can become chronic.
Infections occurring within the reproductive structures of males include epididymitis, orchitis, and prostatitis. Bacterial infections may cause inflammation of the epididymis, called epididymitis. This inflammation causes pain in the scrotum, testicles, and groin; swelling, redness, and warm skin in these areas may also be observed. Inflammation of the testicle, called orchitis, is usually caused by a bacterial infection spreading from the epididymis, but it can also be a complication of mumps, a viral disease. The symptoms are similar to those of epididymitis, and it is not uncommon for them both to occur together, in which case the condition is called epididymo-orchitis. Inflammation of the prostate gland, called prostatitis, can result from a bacterial infection. The signs and symptoms of prostatitis include fever, chills, and pain in the bladder, testicles, and penis. Patients may also experience burning during urination, difficulty emptying the bladder, and painful ejaculation.
Because of its proximity to the exterior, the vagina is a common site for infections in women. The general term for any inflammation of the vagina is vaginitis. Vaginitis often develops as a result of an overgrowth of bacteria or fungi that normally reside in the vaginal microbiota, although it can also result from infections by transient pathogens. Bacterial infections of the vagina are called bacterial vaginosis, whereas fungal infections (typically involving Candida spp.) are called yeast infections. Dynamic changes affecting the normal microbiota, acid production, and pH variations can be involved in the initiation of the microbial overgrowth and the development of vaginitis. Although some individuals may have no symptoms, vaginosis and vaginitis can be associated with discharge, odor, itching, and burning.
Pelvic inflammatory disease (PID) is an infection of the female reproductive organs including the uterus, cervix, fallopian tubes, and ovaries. The two most common pathogens are the sexually transmitted bacterial pathogens  and . Inflammation of the fallopian tubes, called salpingitis, is the most serious form of PID. Symptoms of PID can vary between women and include pain in the lower abdomen, vaginal discharge, fever, chills, nausea, diarrhea, vomiting, and painful urination.

### General Causes and Modes of Transmission of Urogenital Infections

Hormonal changes, particularly shifts in estrogen in women due to pregnancy or menopause, can increase susceptibility to urogenital infections. As discussed earlier, estrogen plays an important role in regulating the availability of glycogen and subsequent production of lactic acid by Lactobacillus species. Low levels of estrogen are associated with an increased vaginal pH and an increased risk of bacterial vaginosis and yeast infections. Estrogen also plays a role in maintaining the elasticity, strength, and thickness of the vaginal wall, and keeps the vaginal wall lubricated, reducing dryness. Low levels of estrogen are associated with thinning of the vaginal wall. This thinning increases the risk of tears and abrasions, which compromise the protective barrier and increase susceptibility to pathogens.
Another common cause of urogenital infections in females is fecal contamination that occurs because of the close proximity of the anus and the urethra. , an important member of the digestive tract microbiota, is the most common cause of urinary tract infections (urethritis and cystitis) in women; it generally causes infection when it is introduced to the urethra in fecal matter. Good hygiene can reduce the risk of urinary tract infections by this route. In men, urinary tract infections are more commonly associated with other conditions, such as an enlarged prostate, kidney stones, or placement of a urinary catheter. All of these conditions impair the normal emptying of the bladder, which serves to flush out microbes capable of causing infection.
Infections that are transmitted between individuals through sexual contact are called sexually transmitted infections (STIs) or sexually transmitted diseases (STDs). (The CDC prefers the term STD, but WHO prefers STI,World Health Organization. “Guidelines for the Management of Sexually Transmitted Infections.” World Health Organization, 2003. http://www.who.int/hiv/pub/sti/en/STIGuidelines2003.pdf. which encompasses infections that result in disease as well as those that are subclinical or asymptomatic.) STIs often affect the external genitalia and skin, where microbes are easily transferred through physical contact. Lymph nodes in the genital region may also become swollen as a result of infection. However, many STIs have systemic effects as well, causing symptoms that range from mild (e.g., general malaise) to severe (e.g., liver damage or serious immunosuppression).

### Key Concepts and Summary

1. The urinary system is responsible for filtering the blood, excreting wastes, and helping to regulate electrolyte and water balance.
2. The urinary system includes the kidneys, ureters, urinary bladder, and urethra; the bladder and urethra are the most common sites of infection.
3. Common sites of infection in the male reproductive system include the urethra, as well as the testes, prostate and epididymis.
4. The most commons sites of infection in the female reproductive system are the vulva, vagina, cervix, and fallopian tubes.
5. Infections of the urogenital tract can occur through colonization from the external environment, alterations in microbiota due to hormonal or other physiological and environmental changes, fecal contamination, and sexual transmission (STIs).

### Multiple Choice

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### Short Answer

### Critical Thinking