Tetanus (Clostridium tetani Infection)

Etiology

C tetani are obligate anaerobic, gram-positive, spore-forming bacilli found ubiquitously in the environment, persisting in soil, domestic animal and human feces, dust, and the gastrointestinal (GI) tract.[1] They appear gram-positive in fresh cultures but may appear gram-variable in mature cultures. Mature bacilli possess a terminal spore resembling tennis and squash racquets.[9] Utilizing the mnemonic association of “tetanus” and “tennis” based on their similar sounds can be helpful when interpreting micrographic images of bacilli.

Spores in the environment germinate into bacteria when inoculated into injured tissue. The spores exhibit remarkable stability and resist eradication from exposure to formalin, ethanol, household disinfectants, boiling, and freezing. Exposure to iodine, hydrogen peroxide, glutaraldehyde, and autoclaving at high temperatures and pressure can render them non-infectious. In clinical practice, culture results lack diagnostic value, as the organism is challenging to culture.[10] Positive culture results may reflect the presence of nontoxigenic strains, and even immunized individuals may show positive cultures of C tetani without disease.

Traumatic wounds are the primary source of infection in most cases, while tetanus can also arise from burn injuries, surgical abscesses, intravenous drug use, circumcision, or gangrene. Occasionally, the source of infection remains unidentified. Incomplete immunization or lack of vaccination is often associated with tetanus cases.

Neonatal tetanus frequently results from home deliveries with unsanitary cutting of the umbilical cord.[11] Immunity from the tetanus vaccine tends to decline with age in most individuals. Thus, vaccination or booster shots are required for prevention.[1][3][10][12]

Epidemiology

Most instances of tetanus occur in developing countries where immunity is deficient, particularly in areas affected by natural disasters.[12] In resource-rich countries, the unvaccinated and those with waning vaccine immunity are at risk. Among this group, surveillance data highlights individuals who inject drugs and those with insulin-dependent diabetes as particularly vulnerable.[7]

The spores of C tetani are present in the environment irrespective of geographical location, residing in the soil and entering through openings in the skin. Wounds containing devitalized tissue pose the highest risk, making all age groups susceptible to infection. Without high-quality medical care, the case-fatality rate can approach 100%, while with optimal care, the case-fatality ratio ranges from 10% to 20%.[3] Neonates face an increased risk in resource-poor regions when nonhygienic deliveries are performed, nonsterilized materials are used to cut the umbilical cord, or contaminated dressings are applied to the umbilical stump.[11] In 2015, the World Health Organization (WHO) estimated that approximately 34,000 neonates died from neonatal tetanus.[13]

Tetanus is a vaccine-preventable disease, and tetanus toxoid-containing vaccines (TTCV) are included in the routine childhood immunization schedule. The average annual incidence of tetanus in the US from 2001 to 2008 was 0.01 per 100,000 population.[7] From 2009 to 2015, there were 197 reported tetanus cases and 16 associated deaths reported in the US.[14] The age groups at the highest risk are newborns and older individuals. The tetanus toxoid vaccine was first produced in 1924 and used extensively among soldiers during World War II. The pentavalent vaccine, which protects against diphtheria, tetanus, pertussis, Hib, and hepatitis B (DTP-Hib-HepB), is the most commonly used childhood vaccine worldwide.[3] Infection from C tetani does not confer immunity and is not transmitted from person to person.

Pathophysiology

Inoculation of wounds with C tetani spores facilitates germination of bacilli. These bacteria produce 2 toxins: tetanospasmin (tetanus toxin) and tetanolysin. Tetanospasmin circulates through lymphatics and the bloodstream, binding to receptors in the peripheral nervous system at neuromuscular junctions. Subsequently, it is endocytosed and retrogradely transported in the peripheral nerve axons to inhibitory interneurons within the central nervous system (CNS). Within the CNS, tetanospasmin blocks the release of the neurotransmitters gamma amino butyric acid (GABA) and glycine from inhibitory interneurons within the spinal cord and brain stem. In addition, it blocks the release of the inhibitory neurotransmitters within the sympathetic nervous system. The absence of inhibitory signals allows excitatory neurotransmitters to act unchecked, resulting in muscle spasms and hypersympathetic activity. The role of tetanolysin in the pathogenesis of tetanus remains unclear. The unopposed release of excitatory neurotransmitters causes the involuntary muscle spasms of tetanus.[15] 

Hypersympathetic activity results from the uninhibited release of catecholamines by the adrenals.[16] Toxin binding at the neuromuscular junction is irreversible.

History and Physical

A history of a deep penetrating wound resulting in devitalized tissue is often, but not always, evident in tetanus cases. Minor trauma, post-surgical infection, injection drug use, intramuscular injections, compound fractures, decubitus ulcers, and no identifiable inoculation have also been reported.[15][17] In neonates born to unvaccinated women, tetanus can develop from contamination of the umbilical stump.[11] 

The incubation period for tetanus ranges from 1 day to several months after wound inoculation. A shorter incubation period is associated with more severe disease, likely influenced by the inoculum size and a short axonal transport distance. Tetanus typically spans 2 weeks, with full recovery often taking several months, a process probably related to the growth of new axon nerve terminals.

Generalized tetanus is the most prevalent form of the disease, typically beginning with trismus (lockjaw) and orbicularis oris muscle rigidity (risus sardonicus), followed by generalized painful muscle contractions. Hyperextension of back and leg muscles and flexion of arm muscles (opisthotonus) can resemble decorticate posturing. Dysphagia caused by pharyngeal muscle spasms is a common symptom and may be the patient's initial complaint.[18][2] Airway obstruction can arise from neck muscles and diaphragm spasms. The painful spasms can persist for several weeks due to the presence of toxins within axons. The spasms may be provoked by noise, touch, and simple nursing care procedures. Hypersympathetic activity and autonomic dysfunction can manifest with labile blood pressure and cardiac arrhythmias. Notably, the sensorium remains intact in the absence of coexisting brain dysfunction. Morbidity and mortality are significantly influenced by underlying comorbidities and iatrogenic complications that may arise during prolonged hospitalization.

Localized tetanus is rare and tends to be limited to an extremity where the initial injury occurred. This form can progress into the generalized form of the disease. Moreover, localized tetanus resulting from injury to the face or scalp can evolve into cephalic tetanus involving the cranial nerve musculature.

Cephalic tetanus presents with cranial nerve dysfunction potentially resembling stroke symptoms.[5] This form of tetanus can evolve into generalized tetanus.

Neonatal tetanus can arise from the contamination of the umbilical stump in offspring born to unvaccinated mothers.[11] The incubation period is around 7 days. Affected infants develop symptoms such as failure to suckle followed by generalized rigidity, often leading to opisthotonus. Mortality is high as infants frequently succumb to complications such as apnea and sepsis.

Evaluation

The diagnosis of tetanus is primarily clinical, and reliance on radiology, hematology, clinical chemistry, and microbiology is generally insufficient for confirmation.[1][4][12][15] Obtaining a patient's immunization status and history of a recent traumatic wound should be sought, although obtaining reliable information may be challenging.[19] In neonatal cases, information regarding the mother's immunization status is key, as well as considering the possibility of unsanitary practices during delivery.

Treatment / Management

The approach to treatment requires a collaborative effort between infectious disease clinicians and critical care intensivists. Acute tetanus management should focus on toxin mitigation and aggressive symptom management.[6][20] Immediate cleansing and debridement of tetanus-prone wounds are essential for eradicating spores and preventing the further spread of toxins from tissue to the bloodstream. Patients exhibiting signs and symptoms of tetanus should be closely monitored, preferably in an intensive care unit (ICU).[21] Efforts to minimize noise, bright light, and tactile stimuli should be attempted in ICU and non-ICU settings. Close observation for signs of impending airway compromise is imperative, and intubation should be anticipated.(B3)

It is important to note that many aspects of treatment are based on small case series, case reports, and relatively few randomized trials. Furthermore, literature reports are often confounded by differences in disease severity. 

Tetanospasmin binds irreversibly at the neuromuscular junction, so neutralization focuses on unbound toxins circulating in the bloodstream. Passive immunization involving the intramuscular administration of human tetanus immune globulin (HTIG) is recommended as soon as tetanus is suspected and has been shown to shorten the course and reduce the severity of the disease.

In resource-poor countries where HTIG may not be available, intravenous administration of equine antitetanus serum is an alternative, with the caveat that anaphylactic reactions may develop. Skin testing should be performed before administering equine antitetanus serum. Currently, conflicting data exist regarding the benefits of intrathecal administration of antisera, and no definitive recommendation can be made.[8][20] If human and equine antitetanus antisera are unavailable, administering pooled human immunoglobulin is recommended.(A1)

Sedation and control of spasms and hypersympatheic activity are crucial in managing tetanus. Benzodiazepines, offering sedative, muscle relaxant, and anxiolytic effects, play an important role. The critical care team should anticipate that the doses required can produce oversedation, respiratory suppression, and coma. Neuromuscular blocking agents such as vecuronium have been reported to be effective in patients with severe tetanus who are not responding to benzodiazepines.[21]

There is limited data concerning the use of intravenous magnesium sulfate in tetanus management.[6][20] It has been used alone and in combination with benzodiazepines to manage spasms and catecholamine release. The limited number of studies suggest a therapeutic benefit, particularly in less severe cases of tetanus. However, the optimal dose and duration of magnesium sulfate infusion remain to be determined.(B3)

Intrathecal baclofen has been utilized to control tetanic spasms, showing benefit in the few reports in the literature. However, the optimal dose and duration of infusion have not been established, and the potential for intrathecal baclofen to cause respiratory depression and cardiac instability necessitates administration in an ICU setting.[20](B3)

Antimicrobial therapy with either metronidazole or penicillin for the wound is typically administered for 7 to 10 days, although no randomized controlled trials have established a specific therapy duration. The aim of using these antibiotics is to eradicate C tetani from the wound, but they have no value in managing muscle spasms and autonomic nervous system dysfunction. In addition to metronidazole, broader spectrum agents may be used to treat infected wounds containing mixed flora. There is a theoretical concern regarding high-dose intravenous penicillin, as it may compete with inhibitory post-synaptic neurotransmitters.[20] (B3)

Comparative studies between metronidazole and penicillin in the management of tetanus-associated wounds are limited, and their results are inconclusive regarding the benefit of one antibiotic over the other in this setting. 

Differential Diagnosis

Teanus has a limited differential diagnosis, as noted below. However, due to the rarity of cases, most clinicians may encounter difficulty in promptly identifying or may even miss the diagnosis, which can have lethal consequences.[2][4][5][17][18] The differential diagnosis includes:

• Oropharyngeal abscess: Depending on the location and extent of the abscess, dysphagia and trismus may be observed.  

• Stroke: Ischemic or hemorrhagic strokes can lead to cranial nerve palsies. 

• Meningitis: Inflammation of the meninges may present with muscle rigidity but without the characteristic spasms of tetanus. An early symptom is neck stiffness. 

• Strychnine poisoning: Similar spasms but generally lack the autonomic dysfunction seen in tetanus. Poisoning can occur due to intentional and unintentional poisoning; the latter has occurred due to adulterated cocaine and heroin.[22][23]

• Botulism: A severe neurological condition caused by a toxin produced by Clostridium botulinum manifests with distinct clinical features, including dysphagia and cranial nerve palsies followed by flaccid paralysis. Unlike tetanus, botulism does not involve muscle spasms or hypertonia.

• Hypocalcemia: Low calcium levels may cause muscle spasms, but the autonomic features of tetanus are usually absent. 

• Neuroleptic malignant syndrome: Drug-induced condition with hyperthermia, altered mental status, and muscle rigidity. This condition is distinguished from tetanus based on clinical history.

Prognosis

The prognosis following tetanus depends on the time to symptom onset or the incubation period. Generally, a shorter incubation period often signifies a more severe disease. Adverse prognostic factors include an incubation period of fewer than 48 hours, addiction to narcotics, the presence of generalized tetanus, a high fever exceeding 104 °F, acquiring tetanus from surgical procedures, burns, intravenous drug use, or a septic abortion. Unfavorable outcomes are particularly associated with cephalic and neonatal tetanus.

Individuals with localized tetanus experience low mortality and morbidity rates. While recovery is generally slow, it may extend over months or years for a full recovery. Surviving individuals should undergo active immunization since recovery from tetanus does not confer any immunity.  

Complications

Respiratory compromise resulting from airway obstruction, aspiration, and medication-associated respiratory suppression are the primary contributors to tetanus-associated morbidity and mortality. Cardiac arrhythmias, labile blood pressure, and profuse sweating due to hypersympathetic activity are common complications. Physical exhaustion due to diffuse muscle spasms further complicates management. Iatrogenic complications associated with prolonged hospitalization frequently complicate the management of tetanus.