Tetanus Toxoid

History of Disease

Tetanus is unique among vaccine-preventable diseases in that it is not communicable. Clostridium tetani , the causative agent of tetanus, is widespread in the environment; many animals, in addition to humans, can harbor and excrete the organism and its spores. When spores of C. tetani are introduced into the anaerobic conditions found in devitalized tissue or punctures, they germinate to vegetative bacilli that elaborate toxin. The clinical presentation results from the actions of this toxin on the central nervous system (CNS). Many animal species besides humans are susceptible to the disease.

The clinical characteristics of tetanus were recognized as distinct early in human history because of the constancy and severity of symptoms. A description of tetanus was found in Egyptian medical papyri from 1550 BC, and detailed descriptions were included in the writings of Hippocrates and other ancient Greeks. ^, After identification and purification of tetanus toxin in 1890, repeated inoculation of animals with minute quantities of toxin led to the production of antibodies in survivors that neutralized the effects of the toxin. Preparations of antibodies derived from animal sera, particularly from horses, became the first means to prevent and treat tetanus; efficacy was demonstrated in World War I by a sharp decline in tetanus cases among wounded soldiers once tetanus antiserum was introduced. ^, In 1924, a chemically inactivated toxin, now termed a toxoid, induced active immunity against the disease before exposure.

In 1901, tetanus fatalities occurred in two historically important incidents. Thirteen children died in St. Louis after receiving diphtheria-antisera obtained from a horse that was infected with tetanus, and 11 persons died in Camden, New Jersey from a tetanus-contaminated smallpox vaccine. These events led to passage of the Biologics Control Act in 1902, also known as the Virus-Toxin Act, which regulated the production of biologic products.

Why the Disease is Important

The original impetus to prevent tetanus through immunization was the striking and highly fatal disease, predominantly associated with injuries to otherwise healthy persons in both high- and low-income nations, and particularly during military conflicts. Prevention of tetanus is now almost universally achievable by use of highly immunogenic and safe tetanus toxoid-containing vaccines (TTCV). In some low-income countries where high tetanus vaccination coverage has not been achieved, tetanus in neonates continues to represent a substantial proportion of the health burden from tetanus. Even with a global standard of routine TTCV administration to infants, tetanus in adolescents and adults has been observed in low- and middle-income countries not providing booster doses following the initial primary infant series. Tetanus disease can be prevented or modified by proper wound care, sterile surgical and obstetrical practices, and use of exogenous antibody. Challenges with access to intensive care and timely antibody therapy result in continued high case fatality rates in many lower-income countries.

Clinical Description

The incubation period for tetanus varies from 1 day to several months after a wound, but most cases occur within 3 days to 3 weeks after exposure. In the United States during 1972–2001, the median interval between the injury and onset of tetanus was 7 days (range: 0–178 days) for 1191 non-neonatal tetanus (non-NT) cases with reported information. The onset of symptoms was within 30 days of injury for 97% of the cases, and within 2 days for 10% of the cases. The incubation period is usually longest after injuries farthest from the CNS; injuries of the head and trunk are generally associated with the shortest incubation periods. ^, The incubation period is inversely related to the severity of illness ^, and has historically been considered one of the best prognostic indicators. ^, Incubation periods of 10 days or more tend to result in milder disease, whereas incubation periods within 7 days of injury tend to result in more severe disease.

Three clinical syndromes are associated with tetanus infection: (1) localized, (2) generalized, and (3) cephalic. Localized tetanus, which is uncommon, consists of spasm of muscles in a confined area surrounding the site of the injury. ^, Painful contractions may persist for several weeks to months before gradually subsiding. Localized disease is thought to occur when transport of toxin produced at the site of the injury is restricted to the local nerves. Although localized tetanus per se is generally mild, with fatality rates of less than 1%, progression to generalized tetanus and its complications can occur.

More than 80% of cases of tetanus are generalized. The most common initial sign is spasm of the muscles of mastication—trismus, or lockjaw—occurring in up to 90% of patients on presentation. ^{, ,} Spasm of the facial muscles produces a characteristic facial expression—risus sardonicus—consisting of raised eyebrows, tight closure of the eyelids, wrinkling of the forehead, and lateral extension of the corners of the mouth. Other early presentations of tetanus include pain and muscle spasm of the neck, shoulders, back, and abdomen. Dysphagia can be the initial symptom, particularly in older adults. ^, Initially, spasms are triggered by external stimuli such as touch or sudden noises, but they occur spontaneously as the disease progresses. Sustained spasm of back muscles gives rise to the arched posture of opisthotonus ( Fig. 59.1 ). Generalized tonic seizure-like tetanospasms consist of sudden excruciating contraction of all muscle groups, resulting in opisthotonus, adduction at the shoulders, flexion of the elbows and wrists, and extension of the legs. Frank convulsions can occur in severely affected patients. Spasm of the glottis can result in immediate death. Patients exhibit generalized hyperreflexia; temperature elevations of 2–4°C are often associated with severe spasms. Cognitive functions are not overtly affected.

Neonatal tetanus (NT) is a form of generalized tetanus occurring in the first month of life, most often as a result of an infected umbilical stump ( Fig. 59.1 ). ^{, ,} Symptoms begin 3–14 days after birth in approximately 90% of cases, but can occur from 1 to 28 days of age. ^, Illness begins with poor sucking and excessive crying in an infant with normal ability to suck in the first 2 days of life. ^{, ,} This is followed by variable degrees of trismus, difficulty swallowing, rigidity, and spasms.

The clinical course of generalized tetanus is highly variable. The disease frequently remains intense for 1–4 weeks and then gradually subsides. Case-fatality rates for reported cases of generalized tetanus have varied from 25% to 70% overall and approach 100% at the extremes of age. ^{, ,} With modern intensive care, mortality can be reduced to <10% to 20% ^, ; however, high mortality persists where intensive care is limited. Relapsing or recurrent cases have been reported.

Cephalic tetanus is a rare manifestation of the disease generally associated with lesions of the head or face ^, and with chronic otitis media. The incubation period is usually 1–2 days after an acute wound. In contrast to generalized tetanus, cephalic tetanus is manifested by atonic cranial nerve palsies involving nerves III, IV, VII, IX, X, and XII, singly or in combination. Nonetheless, trismus can be present. The disease may progress to generalized tetanus and has a similar prognosis if it does. ^,

Complications

Generalized tetanus is frequently accompanied by respiratory failure as a result of chest wall rigidity and spasm, diaphragmatic dysfunction, airway obstruction from laryngeal or glottis spasm, aspiration pneumonia, and fatigue. ^, Before the availability of effective medications to control spasms and mechanical ventilation, respiratory failure was the most common cause of death in patients with tetanus, and it continues to be so in lower income countries. ^, Severe autonomic nervous system abnormalities can develop usually several days after symptom onset, and include labile or sustained systemic arterial hypertension, hypotension, flushing, diaphoresis, tachycardia, bradycardia, and arrhythmias. ^, Development of autonomic dysfunction carries a worse prognosis and has become the most common cause of death in countries where intensive care facilities and respiratory support are available. ^{, , ,} Other complications associated with tetanus include vertebral and long bone fractures, traumatic glossitis, urinary retention, catheter-associated infections, pulmonary embolism, decubitus ulcers, contractures, and, rarely, hematomas due to muscle or blood vessel damage. ^,

Long-term consequences of non-NT—including prolonged muscle fatigue, hyperostosis and osteoarthritis, and difficulties with speech, memory, and mental capacity—have been documented but appear to be uncommon, though data from low-income and middle-income countries is lacking. ^, In survivors of NT, neurologic damage, including spastic paresis/paralysis and severe psychomotor retardation, as well as more subtle intellectual and behavioral abnormalities, have been reported.

Bacteriology

Clostridium tetani is a gram-positive, spore-forming, motile, anaerobic bacillus. Motility is produced by peritrichous flagellae coating the bacterial cell surface. During sporulation, C. tetani loses its flagellae and develops a terminal spore, resulting in a characteristic drumstick-like appearance. C. tetani is a strict anaerobe that grows optimally at 33–37°C; however, growth can occur at 14–43°C, depending on the strain. Growth is usually accompanied by the production of gas and an associated fetid odor.

Sporulation can be promoted at 37°C and in the presence of oleic acid, phosphates, 1–2% sodium chloride, protein, and magnesium. ^, In contrast, acidification, high (≥41°C) or low (≤25°C) temperatures, glucose, assorted saturated fatty acids, antibiotics, and potassium inhibit spore formation. The germination of spores requires anaerobic conditions and is enhanced by the presence of lactic acid and chemicals toxic to cells.

If not exposed to sunlight, C. tetani spores can persist in soil for months to years. ^{, ,} Spores are resistant to boiling and a variety of disinfectants. ^, Inactivation of spores requires 15–24 hours in a solution of phenol (5%), formalin (3%), chloramine (1%), or hydrogen peroxide (6%). Use of aqueous iodine or 2% glutaraldehyde at pH 7.5–8.5 kills spores within 3 hours; autoclaving at a temperature of 120°C and a pressure of 15 pounds per square inch destroys them within 20 minutes. ^{, ,}

Pathogenesis as It Relates to Prevention

C. tetani produces two exotoxins: tetanolysin and tetanospasmin. ^{, ,} Tetanolysin is an oxygen-sensitive hemolysin related to streptolysin and the θ-toxin of Clostridium perfringens . It may play a part in establishing infection at the site of inoculation, but it has no other known role in pathogenesis of the disease. Tetanospasmin, referred to as tetanus toxin, is the neurotoxin that causes the manifestations of tetanus. The highly conserved genes for tetanus toxin and its transcriptional regulator are present on a plasmid. The protein prototoxin is produced intracellularly during the logarithmic phase of bacterial growth and released on autolysis. Once released, the prototoxin is cleaved by bacterial or tissue proteases into its active form, consisting of a 50-kDa light chain and a 100-kDa heavy chain held together by a single disulfide bond; a second disulfide bond connects two heavy chain sites. ^,

Tetanus toxin is one of the most potent known poisons on a weight basis because of its absolute neurospecificity and enzymatic function at the site of action. As little as 1 ng/kg will kill a mouse; 0.3 ng/kg will kill a guinea pig. The estimated minimum human lethal dose is less than 2.5 ng/kg. Various species have different levels of responsiveness to the toxin: cats, dogs, birds, and poikilotherms are relatively resistant; mice, guinea pigs, monkeys, sheep, goats, and particularly horses are sensitive. These differences are the result of specific differences in toxin binding and neurotransmitter blocking activity.

Infection usually begins with the inoculation of spores into wounds, accompanied by tissue injury, necrosis, and the anaerobic conditions necessary for spore germination and bacterial replication. Ionic calcium appears to increase local necrosis and the likelihood of C. tetani infection; its presence in soil contaminating wounds may enhance spore germination and bacterial replication. ^,

Tetanus toxin does not cross the blood-brain barrier; it enters at neuromuscular junctions and neuronal transport is the sole means of entry and dissemination into the CNS ( Fig. 59.2 ). ^, After extracellular release, toxin diffuses to neuromuscular junctions of α-motor neurons in adjacent muscle tissue or to the lymphatic system, which transports the toxin to the bloodstream, leading to systemic dissemination and widespread uptake into α-motor neurons. ^, The carboxy-terminal end of the heavy chain mediates receptor binding and endocytosis. Once tetanospasmin is internalized, the amino-terminal end of the heavy chain mediates axonal retrograde transport via microtubules to the motor neuron cell body. Transcytosis and entry into adjacent inhibitory interneurons in the CNS occurs via synaptic vesicle recycling and endocytosis.

Once in the cytosol of an inhibitory neuron, the disulfide bond between the heavy and light chains is broken, freeing the light chain to begin proteolysis. ^{, , ,} The light chain is a zinc protease that cleaves synaptobrevin, a synaptic vesicle membrane protein necessary for vesicle fusion with the plasma membrane, thereby blocking release of the inhibitory neurotransmitters glycine or γ-aminobutyric acid (GABA). ^, With inhibition blocked, excitatory neuron firing leads to muscle rigidity, and characteristic tetanic spasms. ^{, , , ,}

With local tetanus, transport of toxin is from the neuromuscular junction of the affected muscle without hematogenous dissemination; the predominant effect is on spinal glycinergic inhibitory neurons. ^, In generalized tetanus, hematogenous dissemination of toxin allows more widespread uptake at neuromuscular junctions; the predominant effect is on the GABAergic supraspinal inhibitory neurons. ^, The clinical syndrome appears almost identical to strychnine poisoning, which acts by competitively binding to postsynaptic glycine receptors at the motor neurons. Tetanospasmin can act at peripheral neuromuscular junctions, the spinal cord, the brain, and the autonomic nervous system. ^{, , , , ,} Tetanospasmin also interferes with release of a variety of other neurotransmitters, including acetylcholine in peripheral somatic and autonomic nerves. ^, This accounts for autonomic dysfunction in cases of severe disease, flaccid cranial nerve palsy in cephalic tetanus, and peripheral muscle weakness, that is masked by the manifestations of the central inhibitory blockade. Recovery from tetanus may depend on new functional connections or toxin degradation. More detailed information on tetanus toxin can be found in recent reviews. ^{, , ,}

Modes of Transmission

Acute wounds, particularly puncture wounds and lacerations, account for more than 50% of lesions associated with tetanus in most series (range, 47–82%). The severity of injury varies from superficial and trivial to extensive and deep; often, antecedent conditions are considered too minor to require medical attention. Burns, open fractures, abrasions, and excoriations also are commonly associated with tetanus. ^{, ,}

Tetanus also is associated with a wide variety of nontraumatic conditions, including chronic skin ulcers, abscesses, gangrene, dental infections, insect and animal bites, snake and stingray envenomations, and carcinomas. ^{, , ,} In South Asia and Africa, otitis media is a common cause of tetanus in children, accounting for up to half of cases in some pediatric tetanus series. Tungiasis (skin inflammation and secondary bacterial infection caused by Tunga penetrans flea infestation) is often associated with tetanus in Africa, South America, and the Caribbean, especially in children. ^{, , , ,}

Medical procedures, including surgeries and injections, were frequent causes of tetanus in high-income countries prior to the use of sterilized equipment, solutions, and dressings; they continue to account for a significant proportion of cases in low-income countries. ^{, ,} Even vaccination, especially against smallpox, was associated with tetanus. Intramuscular quinine injections are associated with especially high mortality, likely related to quinine-induced muscle necrosis that enhances bacterial growth and toxin production. ^{, ,} Tetanus associated with deliveries and abortions (maternal tetanus) has been a frequent cause of maternal mortality where unclean deliveries and abortions are common, accounting for up to 5% of maternal mortality. ^, Circumcision, both in the neonatal period and at older ages (male and female) has been associated with tetanus. Tetanus also has been identified following voluntary male medical circumcision for HIV prevention. Traditional surgeries, such as uvulectomy, ear piercing, and ritual scarification, also are associated with tetanus. ^{, , ,} In the United States, cases associated with body piercing and tattoos have been reported. ^, Injection drug use has long been appreciated as a significant tetanus risk factor, ^{, ,} related to contaminated injection drug supplies. Failure to identify an antecedent wound or condition is not uncommon; up to 25% of tetanus cases in published series have no known associated cause.

Diagnosis

The diagnosis of tetanus is established primarily on clinical grounds and secondarily supported by epidemiologic setting. ^{, ,} A history of a wound contaminated by soil or other material and the presence of a local skin infection are helpful in the diagnosis but are not always present. Bacterial cultures are usually negative, even though characteristic gram-positive bacilli, some with terminal or subterminal spores, occasionally may be seen in aspirates from the affected area. ^, Conversely, detection of the organism at a wound site does not confirm the clinical diagnosis. ^{, ,} Low or undetectable levels of circulating antitoxin (antibodies that neutralize toxin) at the time of onset of symptoms are compatible with the diagnosis; however, there are a number of case reports in which moderately high levels of antitoxin were noted when the patient sought treatment. ^, Changes in antitoxin levels in convalescence are not reliably seen. Given the mild nature of some presentations, electromyography has been suggested to aid in the diagnosis, and elicitation of trismus by posterior pharyngeal stimulation (“spatula test”) has been reported to help in clinical differentiation.

The differential diagnosis depends on the clinical form of tetanus and the presenting symptoms. Trismus has a variety of causes, including dental infection, tonsillitis, peritonsillar abscess, temporomandibular joint dysfunction, parotitis, and, rarely, Stiff Person Syndrome. ^, Patients with rabies can also have hyperreflexia; however, rabies is more likely to be associated with hallucinations, hydrophobia, mania, stupor, and a history of an animal bite, and is unlikely to be accompanied by trismus. In addition, seizures with rabies are usually clonic, whereas tetanospasms are prolonged and tonic. Encephalitis is rarely associated with trismus and is much more likely to be accompanied by disturbances of consciousness than is tetanus. Because of nuchal rigidity, bacterial meningitis could be confused with tetanus. Cephalic tetanus may be confused with Bell’s palsy and trigeminal neuritis. However, cephalic tetanus often is accompanied by other cranial nerve symptoms, including dysphagia, and signs of trismus and nuchal rigidity. ^,

A variety of metabolic conditions and poisonings can resemble tetanus. Although muscle spasm may be seen with hypocalcemic tetany, it is not generally associated with trismus. A determination of low serum calcium can confirm tetany. Strychnine poisoning mimics generalized tetanus but is rarely associated with persistent trismus and is characterized by greater muscle relaxation between spasms and normal body temperature; the presence of detectable strychnine in gastric contents or in urine confirms the diagnosis. Phenothiazine toxicity may be associated with a variety of dystonias, including trismus. Detection of phenothiazines in the blood or amelioration by treatment with diphenhydramine confirms the diagnosis. Conversion disorder can mimic tetanus; however, such patients usually relax during prolonged observation or when they are distracted, and are more likely to display clonic rather than tonic spasms.

Because of the distinctive presentation of NT, verbal autopsy—collection of a postmortem history determining the nature and timing of symptoms with verification that the child was normal at birth and the presence of other NT risk factors—permits accurate classification of tetanus as the cause of death with a high degree of probability. ^, The World Health Organization (WHO) defines neonatal tetanus as an illness occurring in a child who has the normal ability to suck and cry in the first 2 days of life, loses this ability between 3 and 28 days of life, and becomes rigid or has convulsions. Misdiagnosed cases of NT are most commonly meningitis, sepsis (including umbilical sepsis) or birth defects, for which trismus is absent; in NT, there is no bulging of the fontanelle, and the child is conscious during spasms, which are often brought on by stimuli.

Treatment

The purposes of tetanus therapy are: (1) to inactivate circulating toxin, (2) to prevent further toxin production by eliminating the organism, and (3) to give supportive care for the duration of the illness. Patients with tetanus may initially have few signs and symptoms, but these will generally progress over subsequent days. ^, The primary indicators of rapid progression in the most recent severity scale developed to predict prognosis and the need for aggressive management of tetanus include age, time from first symptom to admission, entry site, and hemodynamic indicators on the first day.

Human tetanus immunoglobulin (TIG), given with the purpose to neutralize circulating toxin, should be administered intramuscularly *

* TIG, according to the product label, cannot be given intravenously in the United States.

at the time of diagnosis. ^{, , , ,} When TIG became available in the 1960s, a dosage range of 3,000–6,000 units was recommended based on calculations of the quantity of immunoglobulin necessary to achieve higher than minimally protective antibody levels. ^, Subsequent analyses suggested that 500 units of TIG is as effective as higher dosages in reducing mortality. ^, In addition, administration of 500 units of antitoxin requires fewer injections thereby reducing spasm-inducing stimuli. Thus, 500 units of TIG is now commonly recommended for tetanus treatment. ^{, , , , ,}

Equine antitoxin can be given intravenously but is associated with serious allergic side effects such as anaphylaxis and serum sickness. Use of equine antitoxin is not recommended when TIG is available because there is no evidence that it is more efficacious than intramuscularly administered human TIG. Intravenous immunoglobulin (IVIg) has been proposed as an alternative to TIG when TIG is unavailable or when intramuscular injections must be avoided. Although the quantity of tetanus antitoxin in IVIg produced by different manufacturers varies, commercial IVIg preparations contain sufficient antitetanus antibody to achieve protective levels when given in dosages of 200–450 mg/kg. ^{, ,} However, IVIg is not licensed for this indication in the United States.

Systemically administered antibody does not cross the blood–brain barrier and intrathecal administration of antitoxin has been proposed to help neutralize extracellular toxin in the CNS. ^, However, the results of studies evaluating the benefits of intrathecal therapy are conflicting. ^{, ,} TIG is not licensed for this indication in the United States.

When patients with tetanus have identifiable sites of ongoing infection, careful surgical drainage or debridement and appropriate antimicrobial therapy are indicated to prevent continued production of tetanus toxin. In the absence of active infection, the utility of antibiotics in treating tetanus is unclear. ^{, , ,} In the past, penicillin (procaine penicillin or aqueous crystalline penicillin G) was the antibiotic of choice in tetanus patients. Because penicillin is a central GABA antagonist and may potentiate the effects of tetanus toxin, metronidazole (intravenously or orally) has been preferred more recently. ^, However, the results of controlled trials evaluating use of metronidazole compared with penicillin have been inconsistent. ^, Other antibiotics that are effective against C. tetani include macrolides, tetracyclines, and clindamycin. ^,

Pharmacologic treatment of hypertonicity and spasms depends on the severity of disease. The objective is to control spasms and increased tone without impairing all voluntary movement, consciousness, or spontaneous respiration. Because tetanospasmin blocks GABA release from inhibitory neurons in the CNS, ^{, ,} GABA _A agonists, such as benzodiazepines, are standard treatment for tetanus patients. ^{, ,} Other possible treatments include muscle relaxants, although evidence of their benefit is limited, ^{, , ,} and magnesium sulfate, a presynaptic neuromuscular blocker. ^, Short-acting barbiturates can be used when benzodiazepines are not available, but they are more likely to result in respiratory depression and coma than benzodiazepines. ^{, ,} If conservative therapy fails to control muscle spasms, or if severe spasms compromise respiration, neuromuscular blockade with assisted ventilation is indicated. Vecuronium is now the agent of choice because it causes minimal autonomic instability; an alternative is atracurium. ^{, ,}

Autonomic dysfunction should be treated with labetalol or morphine. ^{, , ,} Beta-blockers should not be given in isolation, because their use can result in unopposed α-adrenergic activity leading to severe hypertension. Other agents used for managing autonomic dysfunction include continuous intravenous magnesium sulfate, clonidine, and fentanyl. ^{, , , , ,}

Meticulous supportive care is critical to the treatment of patients with tetanus. ^{, ,} To minimize spasms, the patient should be kept in a quiet, dimly lit room equipped to avoid sudden environmental stimuli. Moderate or severe tetanus often results in high metabolic demands and a protein-catabolic state; parenteral alimentation is sometimes required. ^{, ,} Other supportive measures include prophylaxis for thromboemboli, gastrointestinal hemorrhage, and pressure sores.

Prior to discharge, all patients suspected to have tetanus at the time of diagnosis should receive a TTCV dose(s) if unvaccinated or under-vaccinated, or, if up-to-date with TTCV doses, should receive a booster dose; the quantity of toxin sufficient to produce clinical tetanus is so minute that an immune response may not be elicited by the disease.

Incidence—US, Europe, Rest of World

Tetanus Epidemiology in the United States

The epidemiology in the United States illustrates patterns occurring in all high-income countries. Death certificate data from the early 1900s and national surveillance data starting in 1947 document a relatively constant decline in the annual rate of deaths from tetanus ( Fig. 59.3 ). The decline accelerated somewhat in the mid-1920s with introduction of equine antitoxin for prophylaxis and treatment, as well as with improvements in living standards and medical care. In 1947, when national reporting began, 560 cases were reported, corresponding to an incidence of 0.39 per 100,000 population. By the early 1990s, overall incidence had declined to 0.01 per 100,000 population and has remained stable since 2000 (CDC, unpublished data). Declines in incidence occurred in all age groups ( Fig. 59.4 ), with the greatest proportional reductions in infants and those older than age 60 years. Over the last two decades (2000–2019), 23–41 tetanus cases were reported annually ( https://www.cdc.gov/mmwr/mmwr_nd/index.html ).

Among tetanus cases reported from 1992 to 2019, incidence increased with age. Fifty-nine percent of cases were in males, and the overall incidence of tetanus was slightly higher for males than females (0.013 per 100,000 and 0.009 per 100,000, respectively). Immunization histories were available for 25% (235/931) of the non-NT cases reported during this time: 63 (27%) had received at least a three-dose primary series of TTCV, while the remainder had fewer than 3 doses (CDC, unpublished data). Among the 63 patients who reported having had at least a three-dose primary series of TTCV, one death occurred (case-fatality rate: 2%); this patient had received his last dose of TTCV 10 years before the onset of tetanus. All other deaths (62) occurred among 868 patients with fewer than three doses of TTCV or with unknown vaccination history (case-fatality rate: 7%) (CDC, unpublished data).

Tetanus among children and adolescents in the United States is now rare with an incidence of 0.004 per 100,000 population over the last 20 years (2000–2019); sporadic cases are reported (CDC, unpublished data). A case in an unimmunized 6-year-old child was recently described: onset of tetanus occurred following a laceration, and the child required 57 days of acute inpatient care costing $811,929 before fully recovering; additional tetanus toxoid immunizations were declined by his parents. In a review of neonatal and pediatric tetanus cases from 1992 to 2000, 85% of the children were unprotected because of parental religious or philosophic objection to vaccination.

During 1985–2019, only seven cases of NT were reported in the United States: one each in 1989, 1995, 1998, 2001, 2011, 2012, and 2016 (CDC, unpublished data). Three of the seven mothers were foreign-born women who were undervaccinated or had unknown vaccine status; three were U.S.-born and declined tetanus vaccination on religious or philosophic grounds; one had unknown birth place and vaccination status. These cases highlight the importance of obtaining vaccination histories from all pregnant women, and of counseling women who decline vaccination about the risk of NT.

Tetanus Epidemiology Worldwide

Tetanus generally follows a seasonal pattern in temperate countries, with a midsummer peak that may reflect soil and spore conditions as well as agricultural and other outdoor activities associated with injuries during warmer months. ^{, , , , ,} In tropical climates, tetanus tends to occur year round, although in some areas an increase in cases is seen during the wet season.

Geographic distribution is uneven, with a higher incidence in lowland areas with a moist, warm climate and fertile soil, especially where land is used for cultivation or to pasture domestic animals, ^{, ,} although cases have been documented in desert environments. High altitude has been associated with lower tetanus rates, although not consistently. ^, The highest rates of tetanus are found in rural communities, particularly those lying nearest the equator. ^{, ,}

After more than 60 years of use of TTCV in higher-income countries, and more than 40 years in lower-income countries, the number of tetanus cases and deaths has decreased dramatically (see Fig. 59.5 ). ^, Other factors that contributed to the decline included urbanization, mechanization of agriculture, adoption of aseptic surgical and medical techniques, hygienic childbirth and wound care practices, and use of prophylactic tetanus antitoxin and antibiotics. ^{, ,}

Data on tetanus cases and deaths are not reliable due to weaknesses in tetanus surveillance systems and lack of non-NT surveillance in many low-income countries. Even in developed countries, tetanus reporting efficiency is 60% or less. ^{, , , , ,} In 2019, the Global Burden of Disease study estimated 73,662 total tetanus cases (95% uncertainty interval (UI) 53,346–101,149) and 27,170 neonatal tetanus cases (95% UI: 16,449–43,334) worldwide. The estimated total tetanus incidence was 0.95 cases per 100,000 population (95% UI: 0.69–1.31 per 100,000) with a higher incidence estimated in males (1.2 per 100,000) than females (0.9 per 100,000). Tetanus incidence was estimated at 0.03 per 100,000 population in high-income countries compared to over 2 per 100,000 in low-income countries.

Tetanus is also becoming rare in low- and middle-income countries with well-established immunization programs delivering both primary and booster TTCV doses. ^, Countries where primary immunization coverage has lagged, or where booster doses have not yet been introduced, have tetanus incidence rates of over 20 per 100,000 population. In such countries, tetanus still accounts for a significant proportion of hospital admissions and deaths. ^{, ,}

In low-income countries, coverage with three doses of DTP (diphtheria and tetanus toxoids and pertussis vaccine) in infancy (DTP3) and TTCV (tetanus toxoid) for pregnant and childbearing-age women has steadily improved (see Fig. 59.5 ); consequently, tetanus in young children is rare and is increasingly uncommon in women. Data from a longitudinal study of tetanus in a major medical center in Ho Chi Minh City, Vietnam, demonstrate this impact. Vietnam has had high DTP3 coverage since the late 1980s, exceeding 90% since the early 1990 and TTCV is widely implemented for pregnant and childbearing-age women. The age- and sex-specific pattern of tetanus admissions during 1993–2002 showed a small proportion of cases in children younger than 10 years of age (5.8%) and a 90% reduction in cases among adult women over the study period (10% of cases in 1993; 1% in 2002), whereas tetanus incidence in older children and adult men remained unchanged. The same pattern has been documented in other Asian and some African countries: the most affected groups are persons in their 20s and 30s, with a male predominance. ^, The few tetanus serosurveys available from low income countries mirror this pattern: loss of protection is apparent in older childhood and, by adolescence and young adulthood, the prevalence of seroprotection is below 65%, except among women who receive TTCV to prevent NT. Where booster doses in childhood and adolescence are used, the median age of patients with tetanus shifts to mid- and late-adulthood and male predominance is more modest.

In many published community- and hospital-based studies, a male predominance in NT incidence has been observed (1.5 : 1 male-to-female ratio or higher). However, this has not been a universal finding or, when found, is often minor and consistent with the known slightly higher frequency of male births (~1.05 : 1). ^, The male predominance among NT cases could be attributed to culturally based differences in care seeking or recall bias resulting in better case/death detection in males; ^{, , ,} other possible explanations are a true male predominance in NT incidence and death attributable to sex-related differences in cord care practices and neonatal male circumcision, ^, or biologic differences, including later cord separation in males. ^{, ,}

High-Risk Groups

Tetanus has become rare wherever systematic use of tetanus toxoid has been implemented in large proportions of the population over many birth cohorts. In high-income countries, the proportion of cases predominates in older adults who are unvaccinated or undervaccinated. ^{, , , , , , ,} Other important risk groups are immigrants from countries with less developed vaccination programs, or persons with religious or philosophic objections to immunization. ^{, , , ,} This distribution is remarkably consistent in higher-income countries, and is mirrored in population-based serosurveys. ^,

PWID are at high risk of tetanus as the injection of street drugs is a risk factor for anaerobic infections. Injection drug use has accounted for 15% to 89% of tetanus cases in recent series from more affluent countries. ^{, , , , ,} Patients with a history of injection drug use accounted for 16% of cases reported in the United States from 1992 to 2019. ^{, , , ,} Substantial clusters of tetanus among PWID have occurred in California and England.

People with diabetes are also at increased risk of tetanus, which might be due to injection practices or low serum concentrations of tetanus antibodies among this population. In the United States, 15% (67/432) of non-NT cases reported from 1992–2019 (with information available) reported diabetes as an underlying illness; these cases accounted for 29% of the tetanus deaths in that period (CDC, unpublished data).

Historically, tetanus was a dreaded consequence of war, with incidence rates on the order of two cases per 1,000 injured troops ^, ; similarly high rates were described in wounded civilians in Asia during World War II. Large clusters of tetanus cases also have occurred in conjunction with natural disasters resulting in mass casualties, including the 2004 tsunami in Aceh, Indonesia (106 cases, 20 deaths) and the earthquakes in Pakistan (2005: 139 cases, 41 deaths) ^, and Indonesia (2006: 71 cases, 26 deaths).

In low-resource settings, increased NT risk is associated with home deliveries with unclean birthing surfaces, untrained birth attendants, lack of attendant hand washing, unclean tools used to cut the umbilical cord, and the use of traditional substances on the umbilical stump. ^{, , , ,} In African and South Asian countries where animal dung was commonly used for postpartum cord care (to confer “strength” or “purity”), NT mortality was particularly high; when culturally acceptable cleaner alternatives were introduced, rates decreased dramatically. ^, NT is more common in places where domestic animals are prevalent, especially, if animals are kept close to or inside homes. ^{, ,} Use of dried cow dung as fuel may result in contamination of hands and substances placed on the umbilical stump. ^, Traditional surgeries or piercings are also associated with NT. ^{, , , ,}

Reservoirs of Infection

The most common source of environmental exposure to C. tetani bacilli and spores is soil, where the organism is widely but variably distributed. It is difficult to compare studies of the distribution of the organism in nature because of methodological differences. Most studies suggest that viable spores are more common in soils with an alkaline pH and in nutrient-rich soils in warm, moist climates that could more easily support multiplication of the bacillus. ^, In the contiguous United States, however, a limited study in 1975 found spores in 30% of samples without any apparent geographic or chemical influence on the distribution.

Animals are also C. tetani reservoirs. Both herbivores and omnivores can harbor tetanus bacilli and spores in their intestines, disseminating the organism in their feces. Fecal carriage has been reported in 10% to 20% of horses and 25% to 30% of dogs and guinea pigs; fecal specimens from several other species, including sheep, cattle, and small mammals, also were found to contain C. tetani . ^, Attempts to quantify the frequency of human intestinal colonization have produced varied results ranging from 0% to 40%. ^, Rural residents tend to have higher rates of intestinal carriage than city dwellers. C. tetani spores have also been detected in street dust and the dust and air of surgical operating theaters. ^,