Tetanus¶

Chapter 157 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Bacterial

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points¶

Diagnosis is clinical; positive culture of C. tetani from wounds cannot confirm the diagnosis.
Tetanus toxin blocks inhibitory interneurons (GABAergic) via cleavage of vesicle-associated membrane protein 2 (VAMP2).
Human tetanus immunoglobulin (HTIG) is preferred over equine antitoxin due to lower risk of anaphylactoid reactions.
Benzodiazepines and neuromuscular blockers are used to control spasms; mechanical ventilation is often required.
Tetanus Severity Score (TSS) cutoff point ≥8 predicts death with 66% sensitivity and 91% specificity.
Vaccination schedule: 5 doses (0, 4, 6, 15-18 months, 4-6 years) + boosters at 11-12 years and every 10 years thereafter.
Neonatal tetanus prevention relies on maternal vaccination and hygienic umbilical-cord care.
Autonomic nervous system disturbance (ANSD) occurs during the second week of severe tetanus and is a major cause of death.
Recovery typically takes 4-6 weeks; rapid development of symptoms is associated with more severe disease.
Metronidazole is the preferred antibiotic; penicillin is an alternative but may theoretically exacerbate spasms.

📋 Figures in This Chapter¶

#	Type	Description
1	🖼 Figure	Figure / Illustration

1. DEFINITION & OVERVIEW¶

Tetanus is a preventable disease manifested by skeletal muscle spasms and autonomic nervous system disturbance.
It is caused by a powerful neurotoxin produced by the bacterium Clostridium tetani.
The Centers for Disease Control and Prevention (CDC) defines probable tetanus as: 'in the absence of a more likely diagnosis, an acute illness with muscle spasms or hypertonia, and diagnosis of tetanus by a health care provider.'
Neonatal tetanus is defined by the World Health Organization (WHO) as: 'an illness occurring in a child who has the normal ability to suck and cry in the first 2 days of life but who loses this ability between days 3 and 28 of life and becomes rigid and has spasms.'
Maternal tetanus is defined by the WHO as: 'tetanus during pregnancy or within 6 weeks after the end of pregnancy (whether with birth, miscarriage, or abortion).'
The diagnosis of tetanus is based on clinical manifestations with limited supportive laboratory confirmation.
Case definitions are often used to facilitate clinical and epidemiologic assessments.

2. EPIDEMIOLOGY¶

The incidence of tetanus has decreased gradually over the past few decades as vaccine coverage has increased.
This disease is rare in developed countries.
In 2022, 28 tetanus cases were reported in the United States.
Most tetanus cases occur in individuals who have not received recommended tetanus vaccinations and booster shots every 10 years.
In the United States between 2009 and 2017, tetanus cases occurred primarily in those between the ages of 20 and 64 (64%), with only 13% of cases occurring in those younger than 20.
Three cases of neonatal tetanus were reported in this period.
Diabetes and intravenous drug use were associated with increased tetanus risk.
The global incidence of neonatal tetanus has reduced significantly following a concerted elimination program by WHO partnering with the United Nations Children's Fund (UNICEF) and the United Nations Population Fund (UNFPA).
However, approximately 25,000 neonates with tetanus died in 2018.
The incidence of tetanus among older children and adults (who have a high risk of tetanus due to the deterioration of immunity and lack of booster shots) is unknown.
As few countries have good surveillance systems, in 2015, there were estimated to be between 30,000 and 62,000 deaths from tetanus in older children and adults.
The mortality rate of tetanus varies depending on staff skills, clinical practices, and equipment capacity.
Tetanus causes around 50,000 deaths annually worldwide.

3. ETIOLOGY & PATHOPHYSIOLOGY¶

C. tetani is an anaerobic, gram-positive, spore-forming rod whose spores are highly resilient and can survive readily in the environment throughout the world.
The spores resist boiling and many disinfectants.
C. tetani spores and bacilli survive in the intestinal systems of many animals, and fecal carriage is common.
The spores or bacteria enter the body through abrasions, wounds, or the umbilical stump (in the case of neonates).
Once in a suitable anaerobic environment, the organisms grow, multiply, and release tetanus toxin that enters the nervous system and causes disease.
Approximately 20–30% tetanus cases have unclear entry wounds.
Superficial abrasions to the limbs are the most common entry sites in adults.
Deeper injuries or infections (e.g., open fractures, drug injection) are associated with more severe clinical presentations.
Home delivery with unhygienic umbilical cutting and inadequate umbilical-cord care are the main causes of neonatal tetanus.
Circumcision or ear-piercing also can result in neonatal tetanus.
Tetanus occurs when immunity is lacking. Unvaccinated individuals or those with incomplete vaccination history are at increased risk of developing tetanus.
Genome sequencing of C. tetani has allowed identification of several exotoxins and virulence factors.
Only those bacteria producing tetanus toxin can cause tetanus.
Tetanus toxin undergoes retrograde transport into the central nervous system (CNS) and thus produces clinical effects.
Tetanus toxin is a single 150-kDa protein that is cleaved to produce heavy (100-kDa) and light (50-kDa) chains linked by a disulfide bond and noncovalent forces.
The carboxy terminal of the heavy chain binds to specific membrane components in presynaptic α-motor nerve terminals; evidence suggests binding to both polysialogangliosides and membrane proteins.
This binding results in toxin internalization and uptake into the nerves.
Once inside the neuron, the toxin enters a retrograde transport pathway, whereby it is carried proximally to the motor neuron body.
Tetanus toxin exhibits several different pH-dependent conformations and therefore can interact with a variety of different receptors.
During its passage from the periphery to the central nervous system, tetanus toxin can access neuronal trafficking systems and evade degradation.
Following retrograde transport in the motor neuron, the tetanus toxin undergoes translocation across the synapse to the GABA-ergic presynaptic inhibitory interneuron terminals.
Here the light chain, which is a zinc-dependent endopeptidase, cleaves vesicle-associated membrane protein 2 (VAMP2, also known as synaptobrevin).
This molecule is necessary for presynaptic binding and release of neurotransmitter; thus, tetanus toxin prevents transmitter release and effectively blocks inhibitory interneuron discharge.
The result is unregulated activity in the motor nervous system.
Similar activity in the autonomic system accounts for the characteristic features of skeletal muscle spasm and autonomic system disturbance.
The increased circulating catecholamine levels in severe tetanus are associated with cardiovascular complications.
Relatively little is known about the processes of recovery from tetanus.
Recovery can take several weeks.
Peripheral nerve sprouting is involved in recovery from botulism, and similar CNS sprouting may occur in tetanus.
Other evidence suggests toxin degradation as a mechanism of recovery.

4. CLINICAL FEATURES¶

Clinical presentations of tetanus are diverse and are divided into the following categories: generalized, localized, cephalic, and neonatal tetanus.
In the mild form of local tetanus, only isolated areas of the body are affected and only small areas of local muscle spasm may be apparent.
Localized tetanus can progress to generalized tetanus.
If the cranial nerves are involved in localized cephalic tetanus, the pharyngeal or laryngeal muscles may spasm, with consequent aspiration, respiratory failure, or airway obstruction.
Generalized tetanus is the most common form of clinical presentation, characterized by muscle rigidity and generalized spasms.
Neonates with tetanus typically present with an inability to suck, poor feeding, and generalized spasms.
The most common initial symptoms are trismus (lockjaw), which progresses to neck and body muscle rigidity, difficulty swallowing, and pharyngeal and laryngeal spasms.
As the disease progresses, generalized muscle spasms develop and cause pain.
Laryngeal spasm can cause respiratory failure or apnea and is a life-threatening event; without immediate respiratory support, this is the most common cause of death in tetanus.
Autonomic nervous system disturbance (ANSD) occurs during the second week of severe tetanus, and death due to cardiovascular events becomes the major risk.
Clinical symptoms of ANSD include fluctuated heart rate (tachycardia or bradycardia) accompanied by a fluctuation in blood pressure (hypertension or hypotension) resulting from alteration in the activities of the sympathetic or parasympathetic nervous systems.
Autonomic involvement is evidenced by gastrointestinal stasis, sweating, and increased tracheal secretions.
The Ablett score classifications of the clinical presentation of tetanus are outlined in Table 157-1.

Ablett Classification of Severity¶

Grade I: Mild trismus, general spasticity, no respiratory compromise, no spasms, no dysphagia.
Grade II: Moderate trismus, rigidity, short spasms, mild dysphagia, moderate respiratory involvement, respiratory rate >30 breaths/min.
Grade III: Severe trismus, generalized rigidity, prolonged spasms, severe dysphagia, apneic spells, pulse >120 beats/min, respiratory rate >40 breaths/min.
Grade IV: Very severe Grade 3 with autonomic dysfunction.

Table 1 — Table 157-1 Ablett Classification of Severity of Tetanus¶

GRADE	SEVERITY	SYMPTOMS
I	Mild	Mild trismus, general spasticity, no respiratory compromise, no spasms, no dysphagia
II	Moderate	Moderate trismus, rigidity, short spasms, mild dysphagia, moderate respiratory involvement, respiratory rate >30 breaths/min
III	Severe	Severe trismus, generalized rigidity, prolonged spasms, severe dysphagia, apneic spells, pulse >120 beats/min, respiratory rate >40 breaths/min
IV	Very severe	Grade 3 with autonomic dysfunction

5. DIFFERENTIAL DIAGNOSIS¶

A diagnosis of tetanus requires differentiation from other diseases.
The few conditions that mimic generalized tetanus include strychnine poisoning, dystonic reactions to antidopaminergic drugs, somatic symptom disorder, stiff person syndrome, and neuroleptic malignant syndrome.
Abdominal muscle rigidity is characteristically continuous in tetanus and should be differentiated from peritonitis or acute abdominal emergency.
Cephalic tetanus can be confused with trismus because pharyngeal involvement combined with hyperactivity of laryngeal muscles makes endotracheal intubation difficult.
Hypocalcemia and meningoencephalitis are included in the differential diagnosis of neonatal tetanus.
Other etiologies of neonatal tetanus include oropharyngeal infection, cranial nerve diseases, intracranial hemorrhage, submaxillary lymphadenitis, or peritonsillar infections.

6. INVESTIGATIONS & DIAGNOSIS¶

The diagnosis of tetanus is based on clinical findings.
Confirmatory laboratory tests are limited.
Positive culture of C. tetani from wounds cannot confirm a diagnosis of tetanus.
Serum antitetanus immunoglobulin G may also be measured in a sample taken before the administration of antitoxin or immunoglobulin.
Levels >0.1 IU/mL (measured by standard enzyme-linked immunosorbent assay) are deemed protective and do not support the diagnosis of tetanus.
If levels are below this threshold, a bioassay for serum tetanus toxin may be helpful, but a negative result does not exclude the diagnosis, and these levels are not generally performed.
Polymerase chain reaction and recombinase polymerase amplification have been developed to detect the tetanus neurotoxin gene; these techniques have proven promising in recent years.

7. MANAGEMENT & TREATMENT¶

Treatment strategies aim to neutralize remaining unbound toxin, support vital functions, treat symptoms, and control complications until the effects of the toxin have worn off.
Patients usually recover after 4–6 weeks.
If possible, the entry wound should be identified, cleaned, and debrided of necrotic material in order to remove anaerobic foci of infection and prevent further toxin production.
Wound care should be performed several hours after anti-toxin administration.
Failure to remove devitalized tissue and treat infection may result in recurrent or prolonged tetanus.
Metronidazole (400 mg rectally or 500 mg IV every 6 h for 7 days) is preferred for antibiotic therapy.
Although not a first choice for therapy, an alternative is penicillin (100,000–200,000 IU/kg per day); this drug theoretically may exacerbate spasms due to its ability to bind to the GABA receptor and, in one study, was associated with increased mortality.
Antitoxin should be given early in an attempt to deactivate any circulating tetanus toxin and prevent its uptake into the nervous system.
Two preparations are available: human tetanus immunoglobulin (HTIG) and equine antitoxin.
HTIG is the preparation of choice, as it is less likely to be associated with anaphylactoid reactions.
A single IM dose (500–5000 IU) is given.
Equine-derived antitoxin is available widely and is used in low- and middle-income countries; after hypersensitivity testing, 10,000–20,000 U is administered IM.
According to a recent randomized controlled trial in Vietnam, there were no significant differences in the outcome and complications between groups using either intramuscular equine antitoxin or HTIG.
Additional intrathecal antitoxin (HTIG) showed no benefit.
Benzodiazepines are commonly used to control spasms, and patients can tolerate them in high doses.
The use of intermittent or continuous sedation depends on the severity of spasms and the availability of appropriate resources, e.g., mechanical ventilators.
High-dose diazepam may cause hyperosmolarity and lactic acidosis.
Midazolam is another option for controlling spasms in tetanus; it has fewer side effects and can be used continuously.
Infusions of propofol can be used to control spasms and provide sedation; however, consideration should be given to the likely long duration of therapy.
Sedatives should be reduced in the elderly and patients who have liver diseases due to drug accumulation and slow excretion.
When sedatives alone cannot control spasms, a combination of neuromuscular blocking agents is recommended.
Nondepolarizing neuromuscular blockers are used in clinical practice, depending upon availability.
IV magnesium sulfate has been used as a muscle relaxant.
Patients who are using these agents require mechanical ventilation support.
In those settings with limited availability of mechanical ventilators, controlling spasms while maintaining adequate ventilation is problematic.
Patients may require ventilator support for several weeks.
It is important to establish a secure airway early in severe tetanus.
Ideally, patients should be nursed in calm, quiet environments because light and noise can trigger spasms.
Dysphagia due to pharyngeal involvement combined with hyperactivity of laryngeal muscles makes endotracheal intubation difficult.
Tracheostomy is the better option for securing the airway in severe tetanus.
Magnesium sulfate has been used in autonomic nervous system to control high blood pressure and tachycardia; maintaining a plasma concentration of 2–4 mmol/L is recommended.
If magnesium alone cannot control tachycardia, short-acting beta-blockers (labetalol, propranolol, esmolol) or calcium antagonists can be used with strict monitoring.
When the parasympathetic nervous system predominates—resulting in prolonged low blood pressure and bradycardia—vasopressors are required.
A complication arising from treatment with diazepam injection is thrombophlebitis.
Long-term hospitalization with high-dose sedation creates a high risk of hospital-acquired infections (ventilator-associated pneumonia, bloodstream infection, urinary tract infection, sepsis), deep vein thrombosis, pneumonia emboli, myocardiopathy, myocardial infarction, stress ulcers, muscle weakness, and pressure sores.
Many of these patients require long-term rehabilitation.

8. PROGNOSIS & COMPLICATIONS¶

Rapid development of tetanus is associated with more severe disease; it is important to note time of onset and length of incubation period.
More sophisticated modeling has revealed other important predictors of prognosis.
In many adults, particularly in the elderly, surviving tetanus is associated with reduced long-term functional outcome measures.
Studies of children and neonates have suggested a higher incidence of neurologic sequelae.
Neonates may be at increased risk of learning disabilities, behavioral problems, cerebral palsy, and deafness.
Tetanus has a high survival rate if complications can be controlled and interventions conducted promptly.
In assessing prognosis, the incubation period (time from wound to first symptom) and the period of onset (time from first symptom to first generalized spasm or pharyngeal or laryngeal spasm) are of particular significance.
The shorter these periods, the worse is the prognosis.
Among the three main scales available to predict the severity and outcome of tetanus, the Tetanus Severity Score (TSS) (Table 157-2) is superior to the Dakar and Philips scores, with a sensitivity of 66% and a specificity of 91%.

Table 2 — Table 157-2 Tetanus Severity Score (TSS) (Sensitivity 66%, Specificity 91%), Cutoff Point to Predict Death ≥8¶

VARIABLES	SCORE
Age (year)	≤70
	71–80
	>80
	0
	5
	10
Time from first symptom to admission (days)	≤2
	3–5
	>5
	0
	-5
	-6
Difficulty breathing on admission	No
	Yes
	0
	4
Coexisting medical condition	Fit and well
	Minor illness or injury
	Moderately severe illness
	Severe illness not immediately life threatening
	Immediately life-threatening illness
	0
	3
	5
	5
	9
Entry sites	Internal or injection
	Other (including unknown)
	7
	0
Highest systolic blood pressure recorded during first day in hospital (mmHg)	≤130
	131–140
	>140
	0
	2
	4
Highest heart rate recorded during first day in hospital (beats/min)	≤100
	101–110
	111–120
	>120
	0
	1
	2
	4
Lowest heart rate recorded during first day in hospital (beats/min)	≤110
	>110
	0
	-2
Highest temperature recorded during first day in hospital (oC)	≤38.5
	38.6–39
	39.1–40
	>40
	0
	4
	6
	8

9. SPECIAL CONSIDERATIONS¶

Patients must be given a full primary course of immunization as tetanus toxin is poorly immunogenic and the immune response following natural infection is inadequate.
Safe delivery, hygienic umbilical-cord care, and maternal vaccination are recommended to prevent neonatal tetanus.
Individuals sustaining wounds should undergo passive immunization (see 'Treatment of Tetanus,' above) if their vaccination status is incomplete or unknown or if their last booster was given >10 years earlier.
Vaccination programs and recommended prevention measures vary somewhat according to individual countries.
The rate of primary vaccination coverage in infancy (three doses of DTP [diphtheria, pertussis, and tetanus]) is 86%, but rates for the subsequent boosters necessary for long-term protection are unknown.
WHO guidelines for tetanus vaccination consist of a primary course of three doses and should start at 6 weeks of age; the interval between doses is 4 weeks.
The first booster is given from 12–23 months of age.
The second and third boosters are at 4–7 and 9–15 years of age, respectively.
There should be at least 4 years between booster doses.
In 2022, the CDC reported the rate of infants who had received a full primary vaccination course of three doses of the diphtheria, tetanus toxoid (DTP3), and pertussis vaccine was 94%.
There is a lack of data about boosters in older children, adolescents, and adults in many countries.
The CDC recommends five doses of tetanus vaccine for infants and children at 2 months, 4 months, 6 months, 15 through 18 months, and 4 through 6 years of age, an additional booster dose at 11–12 years of age, and every 10 years thereafter.
There are separate schedules for children ages 4 months through 6 years of age and from ages 7 through 18 years of age.
Complete maternal vaccination reduces the incidence of neonatal tetanus by an estimated 94%.
WHO recommends that pregnant women who have not been vaccinated with the tetanus vaccine should receive at least two doses, with an interval of 4 weeks between doses.
The second dose should be given at least 2 weeks before delivery.
The third dose should be received at least 6 months later, with the fourth and fifth doses following an interval of 1 year or during subsequent pregnancies.
A total of five doses can provide long-term immunity.
The CDC provides a special schedule for those with partial vaccination.
In high-risk areas, women of childbearing age should receive a primary course of vaccination and education on safe delivery and postnatal practices.

10. KEY PEARLS & CLINICAL TRAPS¶

Tetanus is a preventable disease.
Treatment should not be delayed once the diagnosis of tetanus is confirmed.
Positive culture of C. tetani from wounds cannot confirm a diagnosis of tetanus.
Serum antitetanus immunoglobulin G levels >0.1 IU/mL are deemed protective and do not support the diagnosis of tetanus.
A negative result for serum tetanus toxin does not exclude the diagnosis.
Tetanus has a high survival rate if complications can be controlled and interventions conducted promptly.
Rapid development of tetanus is associated with more severe disease.
The shorter the incubation period and period of onset, the worse is the prognosis.
Patients usually recover after 4–6 weeks.
Neonates may be at increased risk of learning disabilities, behavioral problems, cerebral palsy, and deafness.

Figures & Illustrations¶

Reproduced from Harrison's 22nd Edition.

Figure 1¶

Clinical manifestations of tetanus including trismus, muscle rigidity, and autonomic...

Caption: Clinical manifestations of tetanus including trismus, muscle rigidity, and autonomic nervous system disturbance, alongside the Tetanus Severity Score (TSS) used to predict mortality risk.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.