Bacteria

Background and Importance

In the fifth century bce , Hippocrates first described what was likely diphtheria, characterized by sore throat, membrane formation, and death from suffocation. In 1821, Pierre Bretonneau named the condition diphtherite (Greek for leather), describing the characteristic pharyngeal membrane. In 1890, von Behring and Kitasato created the first diphtheria antitoxin (DAT) and 1 year later administered the first dose of antitoxin to a human with diphtheria. Immunization dramatically decreased the incidence of diphtheria in the United States from 206,000 cases in 1921 with 15,520 deaths to only 2 cases between 2004 and 2017. ^,

Humans are the only known reservoir for Cornybacterium diphtheriae. Spread is person-to-person through respiratory droplets or by direct contact with secretions, skin lesion exudates, or rarely fomites or food. Transmission is associated with crowded living conditions. Individuals may spread the disease when they are actively ill, in the convalescent stage, or as asymptomatic carriers. ^{, ,}

Immunization against diphtheria is highly effective ( Fig. 118.1 ). Before widespread immunization in the United States, the incidence of diphtheria exceeded 100 cases per 100,000 population, and the disease predominantly affected children. Most people acquired natural immunity to diphtheria by age 15, and recurrent exposure to toxigenic strains of the bacteria acted as a booster. Because childhood immunization nearly eliminates toxigenic strains in a population, adult immunity wanes, so more adults in industrialized nations are susceptible to diphtheria. By the 1980s the Centers for Disease Control and Prevention (CDC) reported 0 to 5 cases per year nationwide. Currently, sporadic cases occur primarily in inadequately immunized adolescents and adults. Even in industrialized nations with high childhood vaccination rates, more than 50% of adults older than 40 years old lack protective antibodies. Recent reemergence due to disruption of national vaccination programs has led to outbreaks in Yemen and Venezuela, with a recent death in Spain from a traveling passenger from that region.

Anatomy, Physiology, and Pathophysiology

Diphtheria is caused by C. diphtheriae, an unencapsulated, nonmotile, gram-positive bacillus named for its shape ( korynee, for “club”) and its characteristic clinical presentation ( diphtheria, for “leather,” describing the leathery pharyngeal membrane).

Infection with C. diphtheriae can occur at various sites of the respiratory tract or the skin. Respiratory diphtheria includes faucial (pharyngeal or tonsillar), nasal, and laryngeal (tracheobronchial) types, named for the primary location of infection. Cutaneous diphtheria can occur as a primary skin infection or as a secondary infection of a preexisting wound. ^,

Toxigenic strains of C. diphtheriae bacterium are lysogenized with the bacteriophage and produce an exotoxin that inhibits cellular protein synthesis. The diphtheritic membrane, composed of leukocytes, erythrocytes, fibrin, epithelial cells, and bacteria, results from necrosis caused by local effects of the exotoxin. Initially, the pharynx appears erythematous, but as necrosis occurs, grayish white patches appear and eventually coalesce. The membrane causes surrounding edema and cervical adenitis. The initial grayish white, filmy appearance changes to a thick, grayish black membrane with sharply defined borders. This membrane adheres to the underlying tissue, and bleeding occurs if removal is attempted.

Circulating exotoxin causes the systemic symptoms of diphtheria, most profoundly affecting the nervous system, heart, and kidneys. ^, The degree of local and systemic toxicity depends on the location and extent of membrane formation. Pharyngeal diphtheria has the greatest toxicity and cutaneous diphtheria the least. As the exotoxin disrupts cellular protein synthesis, it causes peripheral neuropathy manifested by muscle weakness. About 5% of patients with respiratory infection develop polyneuritis; 75% of patients with severe disease have some form of neuropathy. The muscles of the palate are usually affected first. Other cranial nerves, peripheral nerves, and the spinal cord may be affected. Degenerative lesions develop in dorsal root and ventral horn ganglia of the spinal cord and in cranial nerve nuclei. Cortical cells are spared. Proximal muscle groups are affected first. In severe cases, paralysis may develop in the first few days of illness. Paralysis typically does not last more than 10 days, but may last up to 3 months. Complete recovery over a longer time is the rule.

The exotoxin directly damages myocardial cells. Cardiac dysfunction may appear 1 to 2 weeks after the onset of illness, but may arise earlier in severe cases. Electrocardiographic (ECG) changes suggestive of myocarditis occur in up to two-thirds of patients, but clinical manifestations of myocarditis occur in only 10% to 25% of cases.

Background and Importance

Pertussis is an acute respiratory disease first described in 1578 when an epidemic swept through Paris. Pertussis means “violent cough.” It is also called whooping cough because the severe episodes of coughing are followed by forceful inspiration, which creates a characteristic “whoop” sound. Bordet and Gengou identified the causative organism in 1900. Pertussis was a major cause of mortality among infants and children in the United States in the prevaccination era. A vaccine was developed in the 1940s, but pertussis remains a significant cause of morbidity and mortality worldwide.

Pertussis is a highly contagious respiratory illness transmitted by aerosolized droplets. It can occur at any age but is predominantly a pediatric and adolescent illness. Infection rates are greater than 80% in adults exposed more than 12 years after completing a vaccination series and up to 90% in susceptible individuals with household exposure. Half of the cases in the United States occur from June through September. The average incubation period is 7 to 10 days (range less than 1 week to 3 weeks). Neither vaccination nor prior infection confers lifelong immunity.

Pertussis is prevalent worldwide. The World Health Organization (WHO) estimated over 24.1 million cases in 2017 with 160,700 annual deaths. In the United States, annual pertussis rates declined sharply after the introduction of the vaccine, reaching a nadir of 1010 cases in 1976. There has been a steady increase since, with 11,647 cases reported in 2003 and more than 28,000 cases in 2014 ( Fig. 118.2A and B). The incidence is highest in infants who have not received the entire vaccine series (see Fig. 118.2C ). Waning immunity in the adult population and increased reporting may be contributing factors, but the emergence of the antivaccination movement is a leading factor.

A 1991 report found a possible relationship between the vaccine and acute encephalopathy. Although there appears to be no relationship between the vaccine and long-term neurologic complications, the report resulted in a decline in the use of the whole-cell pertussis vaccine. The acellular pertussis vaccine has been approved in the United States since 1991 for persons 15 months to 64 years and since 1997 for infants.

Anatomy, Physiology, and Pathophysiology

Pertussis is caused by organisms of the Bordetella genus, which are small, aerobic, gram-negative coccobacilli. Bordetella pertussis and Bordetella parapertussis are responsible for human disease. The organisms are fastidious and require a medium containing charcoal, blood, or starch, and an optimal temperature of 95° to 98.6°F (35° to 37°C) to grow. Bordetella bronchiseptica, a flagellated, motile organism, causes illness in animals, including kennel cough, and may rarely cause respiratory infection in immunocompromised humans. Bordetella adheres preferentially to ciliated respiratory epithelial cells, but does not invade beyond the submucosa and is seldom recovered in the bloodstream. It elaborates several toxins that act locally and systemically, including pertussis toxin, dermonecrotic toxin, adenylate cyclase toxin, and tracheal cytotoxin. Local tissue damage consists of inflammatory changes in the respiratory mucosa. Secondary pneumonia and otitis media may occur. Systemic effects of pertussis toxin include sensitization to the lethal effects of histamine and increased excretion of insulin. This hyperinsulinemia can cause hypoglycemia, particularly in young infants potentially leading to seizures.

Acute Treatment

Treatment of pertussis is supportive and includes oxygen, frequent suctioning, appropriate hydration, parenteral nutrition as needed, and avoidance of respiratory irritants. Patients with suggested pertussis and associated pneumonia, hypoxia, CNS complications, or those experiencing severe paroxysms should be hospitalized. Children younger than 1 year old should also be admitted, because they are not yet fully immunized and have the greatest risk for morbidity and mortality. Neonates with pertussis should be admitted to a neonatal intensive care unit (NICU) because apnea and significant cardiac complications can occur without warning. ^,

Antibiotic treatment does not reduce the severity or duration of illness at any phase. The goal of antibiotic therapy is to decrease infectivity and carriage. The CDC recommends macrolides; erythromycin, clarithromycin, and azithromycin are preferred for pertussis in persons 1 month of age and older. Erythromycin estolate ester 40 to 50 mg/kg/day (maximum of 2 g/day) has previously been recommended for four divided doses for 14 days, but a 7-day course of erythromycin estolate ester at 1 g/day is just as effective at eradicating B. pertussis with better compliance. Azithromycin 10 mg/kg/day for 5 days is recommended in infants younger than 1-year-old because of an association between oral erythromycin and infantile hypertrophic pyloric stenosis (IHPS). Alternative treatments include azithromycin (10 mg/kg on day 1, followed by 5 mg/kg on days 2 to 5) or clarithromycin (15 mg/kg/day; maximum of 1 g/day in two divided doses). Trimethoprim-sulfamethoxazole (8 mg/kg/day of trimethoprim) is an alternative for macrolide-allergic patients two months of age or older, but efficacy is unproven. Patients should be considered infectious for 3 weeks after the onset of the paroxysmal phase or until at least 5 days after antibiotics are started. Droplet isolation is recommended during this period.

Corticosteroids, especially in young critically ill infants, may reduce the severity and course of illness, but effectiveness has not been established. Inhaled beta ₂ -adrenergic agonists do not reduce the frequency or severity of paroxysmal coughing episodes but may help patients with reactive airway disease. Past trials with pertussis immune globulin are limited and do not show benefit. Standard cough suppressants and antihistamines are ineffective.

Postexposure prophylaxis with an appropriate macrolide is recommended for those at high risk for developing severe pertussis, including household contacts of a pertussis case, infants and women in their third trimester of pregnancy, persons with preexisting health conditions that may be exacerbated by a pertussis infection, and close contact with any of the above-listed people. This includes but is not limited to those who work in NICUs, childcare settings, and maternity wards. Women in their third trimester of pregnancy may be a source of pertussis to their newborn infant.

Vaccination

Whole-cell and acellular pertussis vaccines are distributed in combination with diphtheria and tetanus toxoids as DPT and DTaP, respectively. The whole-cell vaccine is 70% to 90% effective at preventing serious pertussis infection. Pediatric recipients have fever, irritability, behavioral changes, and local discomfort at the site of inoculation. Moderately severe reactions are uncommon but include temperature above 104°F (40°C), persistent, high-pitched crying, and seizures. Severe neurologic complications (prolonged seizures and encephalopathy) occur rarely but led to decreased use of the whole-cell form of the vaccine and the development of DTaP.

The acellular pertussis vaccines contain inactivated pertussis toxin and one or more other bacterial components; they are less effective than the whole-cell vaccine but have fewer reported adverse reactions. ^, DTaP has replaced DPT for childhood immunizations in the United States and is approved for children ages 6 weeks to 6 years old. ^, Current American Academy of Pediatrics (AAP) guidelines state that acellular pertussis vaccinations are as safe as whole-cell vaccines, but new data suggest the latter provide a better, longer-lasting serologic response. There has also been a correlation between acellular vaccination and food allergies. Further studies are needed to guide future recommendations.

Pertussis immunity wanes 5 to 10 years after immunization and 15 years after natural infection, resulting in an increased incidence in people older than 15 years. Tetanus, diphtheria, acellular pertussis (Tdap) (with reduced diphtheria toxoid and pertussis antigens) is indicated as a booster vaccine in persons 11 to 18 years old. It is safe and effective in adults, including pregnant women and those over 65 years of age. Persons older than 65 years old who have never received Tdap and anticipate close contact with infants younger than 12 months old should receive a single dose of Tdap, regardless of interval since last Td vaccination. A live attenuated nasal vaccine has completed phase one trials in humans showing greater than 99.9 nasopharyngeal colonization and is undergoing further clinical development.

Background and Importance

Tetanus is a toxin-mediated disease characterized by severe uncontrolled skeletal muscle spasms. Respiratory muscle involvement leads to hypoventilation, hypoxia, and death. Dramatic descriptions of this disease date to ancient Egypt, when physicians recognized a frequent relationship between tissue injury and subsequent fatal spasm. Prophylactic injection of tetanus antitoxin provided passive immunity to wounded soldiers during World War I. In 1924, an effective vaccine was developed, and large-scale testing during World War II indicated that the tetanus toxoid confers a high degree of protection against disease. Despite the availability of an effective vaccine, tetanus remains endemic worldwide. It is more common in warm, damp climates and relatively rare in cold regions. The global annual incidence of reported cases of tetanus has declined with the introduction of vaccination programs ( Fig. 118.3A ). The WHO reported 15,103 cases of tetanus in 2018 but estimates that thousands of unreported cases occur annually resulting in approximately 34,000 neonatal deaths. Most of these cases occur in countries with low immunization rates.

Since the introduction of vaccination programs in the United States, the incidence of tetanus has steadily declined from 4 cases per million population in the 1940s to fewer than 0.01 cases per million population in 2010 (see Fig. 118.3B ). The highest incidence occurs in people older than 65 years old (0.23 case per million population). Half of cases occur in injection drug users. The overall case fatality rate is 18% but approaches 50% in patients over 70 years old ( Fig. 118.4 ). Cases have been reported in fully vaccinated patients, but no deaths occurred.

Tetanus classically occurs as a result of a deep penetrating wound. A history of injury is present in more than 70% of patients, but the injury may be trivial. The remainder may have another identifiable condition or no apparent source. The most common portals of entry are puncture wounds, lacerations, and abrasions. Tetanus has also been reported in association with chronic skin ulcers, abscesses, otitis media, foreign bodies, corneal abrasions, childbirth, and dental procedures. Postoperative tetanus has been reported in patients who have undergone intestinal operations and abortions. In these cases, the source of bacteria is probably endogenous because up to 10% of humans harbor Clostridium tetani in the colon. Inadequate primary immunization and waning immunity continue to be the primary risk factors for tetanus in the United States. As tetanus vaccination of children has improved, older people have accounted for an increasing percentage of reported cases.

Anatomy, Physiology, and Pathophysiology

C. tetani is a spore-forming, motile, rod-shaped, obligate anaerobic bacillus. It stains gram-positive in fresh culture but has a variable staining pattern in culture and tissue samples. C. tetani is ubiquitous in soil and dust and is also found in the feces of animals and humans. Spores are resistant to heating and chemical disinfectants and can survive in the soil for months to years. When introduced into a wound, spores may not germinate for weeks because of unfavorable tissue conditions. When injury favors anaerobic growth, the spores germinate into mature bacilli, which form a single spherical terminal endospore to produce a characteristic drumstick appearance. Only these mature bacilli produce the tetanus toxin that causes clinical disease.

C. tetani is a noninvasive organism. The development of clinical disease requires a portal of entry and tissue conditions that promote germination and growth in a susceptible host. Tetanus-prone wounds have damaged or devitalized tissue, foreign bodies, or other bacteria. Under these conditions, C. tetani produces the neurotoxin that causes clinical illness. Germination and replication of C. tetani can occur without clinical signs of wound infection.

C. tetani produces the neurotoxin tetanospasmin at the site of tissue injury. Tetanospasmin binds the motor nerve ending and moves by retrograde axonal transport and trans-synaptic spread to the CNS. It binds preferentially to inhibitory (GABAergic and glycinergic) neurons and blocks the presynaptic release of these neurotransmitters. Interneurons afferent to alpha motor neurons are affected first. Without inhibitory control, the motor neurons undergo sustained excitatory discharge, resulting in the muscle spasm characteristic of tetanus. Tetanospasmin may also affect preganglionic sympathetic neurons and parasympathetic centers, resulting in autonomic nervous system dysfunction. The clinical manifestations include dysrhythmias and wide fluctuations in blood pressure and heart rate. The binding of tetanospasmin at the synapse is irreversible; recovery occurs only when a new axonal terminal is produced.

Generalized Tetanus

Generalized tetanus, the most common form of the disease, results in spasms of agonist and antagonist muscle groups throughout the body. The classic presenting symptom is trismus or “lockjaw,” caused by masseter muscle spasm, and is present in 50% to 75% of patients. As the other facial muscles become involved, a characteristic sardonic smile (risus sardonicus) appears. Other early symptoms include irritability, weakness, myalgias, muscle cramps, dysphagia, hydrophobia, and drooling. As the disease progresses, generalized uncontrollable muscle spasms occur spontaneously or as a result of minor stimuli, such as touch or noise. Spasms can cause vertebral and long-bone fractures and tendon rupture. Opisthotonos is prolonged tonic contraction that resembles decorticate posturing. Spasms of laryngeal and respiratory muscles can cause ventilatory failure and death. Autonomic dysfunction is the major cause of death in patients who survive the acute phase and is manifested by tachycardia, hypertension, hyperpyrexia, cardiac dysrhythmias, and diaphoresis. The illness progresses over 2 weeks. If the patient survives, recovery is complete after 4 weeks or more. Throughout this illness, patients remain completely lucid unless they are chemically sedated.