Clinical profile and management of tetanus: A scoping review of evidence in the 21st century

INTRODUCTION

Tetanus is a vaccine-preventable neurological infection caused by an anaerobic Gram-positive bacillus, Clostridium tetani.¹ It is commonly found in soil and the gastrointestinal tracts of mammals.² Infection occurs when its spores enter damaged human tissue, where they transform into vegetative forms and produce the tetanospasmin toxin³ (Fig. 1). Tetanospasmin, a potent metalloprotease, travels retrograde along the motor neurons to the spinal cord and brainstem, disrupting neurotransmission in inhibitory interneurons. This results in disinhibition of anterior horn cells and autonomic neurons, leading to increased muscle tone and autonomic dysfunction.³ Recovery is slow, requiring the regeneration of affected nerve terminals, which often necessitates prolonged intensive care.¹

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FIG 1. Summary of the pathophysiology and clinical features of tetanus

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Between 1990 and 2015, global tetanus-related mortality declined significantly, with neonatal deaths decreasing by 90% and non-neonatal deaths by 81%, primarily due to expanded immunization programmes and improved healthcare access.⁴ Despite these advancements, tetanus remains a major concern in low-resource settings. In 2015, tetanus was still responsible for more than 50 000 deaths.⁴ The burden remains particularly high in South Asia and Sub-Saharan Africa, where inadequate vaccination coverage and limited healthcare infrastructure contribute to persistently high mortality rates.⁴ Research continues to explore the potential benefits of emerging therapeutic approaches, such as intrathecal immunoglobulin administration and alternative sedation strategies.

Although widespread immunization has significantly reduced the incidence of tetanus, it remains a serious health concern, particularly in under-resourced regions. Advances in critical care have improved outcomes, but mortality remains variable. Given the breadth of evidence across clinical, therapeutic, and epidemiological domains and the need to identify knowledge gaps, a scoping review approach was deemed appropriate. This scoping review examines the clinical features, treatment strategies, and outcomes of tetanus in the 21st century. It focuses on human populations, across all age groups and clinical forms, to identify gaps and guide future research and policy in both high- and low-resource settings.

METHODS

Framework. This scoping review aimed to synthesize evidence on the clinical profile and management of tetanus in the 21st century. The study followed the framework outlined by Arksey and O’Malley and the PRISMA-ScR guidelines.⁵

Search strategy. A comprehensive search was performed in PubMed and Embase databases to identify relevant studies published between 1 January 2000 and 31 December 2024. We restricted our review to studies published since 2000 to ensure relevance to current clinical practice and contemporary advances in immunization coverage, intensive care management, and antimicrobial therapy. The following search string was used: (tetanus OR tetani) AND (Clinical) AND (Human), and it was limited to the title and abstract.

Eligibility criteria. Articles in all languages, focusing on clinical profiles, treatments, and outcomes were included. The reviewing team included authors fluent in English, Dutch, and German, enabling direct review of articles in these languages. We consulted multilingual colleagues in clinical medicine and public health and used online artificial intelligence translators to obtain translations for articles in other languages. Studies on non-human subjects or in vitro studies were excluded. Case reports, case series (<10 cases), narrative reviews, and letters were excluded. The search process used Rayyan.ai, a systematic review software that facilitates study selection and screening.

Screening. After retrieving the initial search results, duplicate records were removed. Title and abstract screening were conducted to identify studies that provided clinical data on tetanus in human subjects and discussed management strategies. Studies on animal models, vaccine development, or experimental treatments without clinical application were excluded. Full-text screening was performed on the selected articles, and studies that met the inclusion criteria were considered for final review.

Data charting. We used a structured data charting form to capture relevant information from each included study systematically. Key variables charted included study design, country, publication year, sample size, population characteristics, vaccination status, clinical presentation, diagnostic approach, treatment strategies, and patient outcomes. The charting process was conducted independently by two reviewers. Any discrepancies were discussed and resolved by consensus, with arbitration by a third reviewer when necessary. The charted data were iteratively updated as new themes emerged during the review process, consistent with the flexible and exploratory nature of scoping reviews. Finalized data were cross-checked by a senior reviewer for completeness and accuracy.

Synthesis of data. A narrative synthesis approach was employed to integrate findings across different studies. This method facilitated a thematic organization of key results under epidemiology, clinical features, diagnosis, treatment, outcomes, and prevention.

RESULTS

The database search yielded 284 articles from PubMed and 447 from Embase, resulting in 731 records (Fig. 2). After removing 283 duplicate articles, 448 studies remained for title and abstract screening (Fig. 2). Following this initial review, 35 studies were selected for full-text assessment. No additional articles were found when citation search was done. One study was excluded during full-text review as it was a narrative review and did not present original clinical data, thereby not fulfilling the eligibility criteria, leading to the final inclusion of 34 studies. Of these 34 studies, 17 focused on clinical profile and outcome, 9 focused on the effect of treatment interventions, and the rest focused on vaccination and assessing vaccination response. The scoping review results have been arranged under the following heads: epidemiology, clinical features, diagnosis, treatment, outcomes, and prevention.

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FIG 2. PRISMA flow chart showing final inclusion of the studies

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DISCUSSION

Epidemiology. Tetanus develops when Clostridium tetani spores enter damaged tissue and encounter conditions favourable for bacterial growth, particularly in unimmunized individuals (Fig. 1). The incubation period reported in the studies included in this review ranged from 6 to 11.5 days.^6,7 While a shorter incubation period (<7 days) was linked to higher mortality rates, the association showed a trend toward significance (p=0.07).⁸ Vaccination coverage for primary immunization and post-exposure prophylaxis among patients was inadequate across studies. The proportion of patients who had not received primary immunization was 40.2% to 100%,^8,9 while those not receiving post-trauma immunization were 32%–96% (Table 1).^8,10

After excluding studies focusing on neonatal tetanus, the median age reported across the studies was 40–80 years, depending on the population studied and regional epidemiology (Table 1). In high-income countries, most cases were observed in older adults due to declining immunity and insufficient booster vaccinations.^6–8,11 Serological surveys from the USA and Italy revealed adequate antibody levels in young and middle-aged populations but inadequate protective immunity among older adults.^12,13 This suggests that while primary immunization coverage is adequate in these regions, waning immunity highlights the need for regular booster doses. In contrast, in low-resource settings, tetanus primarily affected middle-aged and younger individuals, indicating inadequate immunization coverage.¹⁴

Across studies, most tetanus cases were linked to minor wounds, such as punctures and lacerations, particularly on the lower limbs.^8,9,13,15,16 Many reports highlighted that these injuries frequently occurred during agricultural^17,18 or gardening activities.¹¹ In low and middle-income countries (LMICs), road traffic accidents and septic abortions were also common sources of infection.¹⁸ Additionally, male circumcision in sub-Saharan Africa has been associated with tetanus.¹⁸ Natural disasters can also contribute to tetanus outbreaks, as seen in Indonesia following the 2004 tsunami, where a cluster of cases was reported.¹⁹ Studies from Spain and the USA identified intravenous drug use, diabetes, and HIV as significant risk factors.^7,10 In England, a 2004 outbreak involving 22 tetanus cases was detected among people who injected drugs,⁶ likely due to contaminated heroin.²⁰ The majority of cases in this outbreak occurred among older drug users and women, possibly due to waning immunity with age and poor venous access, leading to a higher prevalence of intramuscular and subcutaneous injections.²⁰

Clinical presentation. Tetanus presents in 4 clinical forms: generalized, localized, cephalic, and neonatal. In our review, over three-quarters of the cases were classified as generalized tetanus.^7,9 Generalized tetanus is the most severe form of the disease, typically beginning with lockjaw (trismus) and progressing to widespread muscle rigidity and painful spasms.⁷ The characteristic opisthotonus, a state of severe hyperextension, was reported in 24.1% of tetanus cases in Spain.⁷ Respiratory distress and autonomic dysfunction were frequently observed in over half the patients across multiple studies.^8,9,11 Other commonly reported symptoms included body aches, back pain, abdominal pain, and localized pain at the wound site.^15,21 It is important to note that generalized tetanus can be mistaken for other conditions, such as drug-induced dystonia (characterized by eye deviation, intermittent spasms, and response to anticholinergics), neuroleptic malignant syndrome (marked by fever and altered sensorium), strychnine poisoning, or stiff person syndrome (which typically lacks trismus).

Localized tetanus presents with muscle spasms confined to a specific region, sometimes mimicking acute surgical conditions, while cephalic tetanus primarily involves cranial nerves following head or neck injuries. Across studies, localized tetanus was reported in 7.7%–24.1% of cases, whereas cephalic tetanus was relatively rare.^7,9 Localized tetanus may be confused with dental infections, which may cause trismus but lack progressive spasms and are usually linked to a visible abscess.

Neonatal tetanus was examined in two studies from Vietnam and China, both of which reported cases predominantly among infants born to unvaccinated mothers with a history of umbilical cord contamination due to unhygienic birth practices.^9,22 In the Vietnam study, the median age at admission was 8 days.²² Common symptoms included severe muscle spasms, respiratory distress, and autonomic instability.²²

Diagnosis of tetanus. Understanding the clinical presentation of tetanus is crucial, as the diagnosis is often based solely on clinical findings. Only 2 studies in this review reported microbiological confirmation of tetanus. In the Italian study, culture confirmation was achieved in just 3.7% of cases.¹³ In contrast, the Vietnamese study found that 54% of samples tested positive for Clostridium tetani. All isolates in this study were susceptible to penicillin and metronidazole but resistant to co-trimoxazole.¹⁶

Treatment. Our review identified 8 key studies evaluating therapeutic strategies for tetanus, including 4 randomized controlled trials (Table 2). These trials discussed below in relevant sections compared human versus equine antitoxin, intramuscular versus intrathecal administration of tetanus immunoglobulin, various antibiotic regimens (benzyl-penicillin, benzathine penicillin, and metronidazole), and siltartoxatug versus human tetanus immunoglobulin (HTIG). We also examined adjunctive therapies, such as magnesium sulphate and intrathecal baclofen.

Most patients in the reviewed studies required intensive care unit (ICU) admission, with an average hospital stay of 21–42 days.^6,15,21 Once tetanus is diagnosed, management primarily depends on whether the patient requires invasive mechanical ventilation due to airway compromise or risk of respiratory failure. The need for mechanical ventilation varied across studies, 13.2%–86.4%, depending on disease severity.^8,15 Recovery from tetanus is typically prolonged, often taking 3–4 weeks. While extended mechanical ventilation is sometimes necessary, it carries significant risks, including hospital-acquired infections, critical illness neuromyopathy, pressure ulcers, and deep vein thrombosis, all of which contribute to increased morbidity and longer hospital stays. Tracheostomy was commonly performed in patients requiring prolonged ventilation.^7,9,15,23

In resource-limited settings, simple interventions such as nursing patients in dark, quiet rooms may help reduce spasms and improve survival rates.¹⁴ The management of generalized tetanus focuses on symptom control and supportive care (Table 2).^24–34 Diazepam is commonly used to control muscle spasms for patients who do not require mechanical ventilation.^7,8 In contrast, those needing invasive ventilation may receive continuous infusions of sedatives such as midazolam or propofol. A Cochrane systematic review found that diazepam alone significantly reduced mortality compared to the phenobarbitone-chlorpromazine regimen.²⁶

Patients with increased baseline muscle tone benefit from magnesium sulphate, which helps minimize rigidity and autonomic dysfunction (Table 2).²⁵ Mechanically ventilated patients often require muscle relaxants like vecuronium or atracurium. Studies have shown that magnesium sulphate effectively controls spasms, reduces the need for ventilation, mitigates sympathetic overactivity, and lowers mortality risk.²⁴ Unlike benzodiazepines, magnesium sulphate reduces the requirement for deep sedation by acting as a presynaptic neuromuscular blocker, inhibiting calcium-mediated neurotransmitter release, thereby decreasing spasticity and sympathetic overactivity.²⁴ One study suggested magnesium sulphate alone was beneficial in mild cases but not severe tetanus.²⁵ Intrathecal baclofen, a gamma-aminobutyric acid (GABA)-B agonist, has been reported to improve symptom control in a case series of 22 patients.²⁷ However, continuous intrathecal infusion carries a risk of nosocomial meningitis.²⁷ Autonomic dysfunction, a frequent and severe complication of tetanus, requires targeted therapy. Sympathetic hyper-activity is managed with beta-blockers and central α₂ agonists like clonidine or dexmedetomidine, while bradycardia may require atropine.

Weaning a tetanus patient from prolonged mechanical ventilation is a complex, multidisciplinary process that requires addressing multiple interrelated challenges. Neuromuscular weakness often results from prolonged neuromuscular blockade and critical illness, necessitating a gradual tapering of medications, early physiotherapy, and adequate nutritional support. Sedation withdrawal is carefully managed through a stepwise reduction, with adjunctive agents like dexmedetomidine used to minimize autonomic instability. Additionally, the high risk of delirium is mitigated using non-pharmacological interventions and, when necessary, short-term antipsychotics. The potential for glottic oedema is addressed through preextubation assessments and corticosteroid administration, and with an individualized, stepwise approach, helps reduce complications, prevent reintubation, and shorten ICU stays.

Antibiotics play a crucial role in tetanus treatment by targeting Clostridium tetani to prevent further toxin production. Penicillin and metronidazole were the most commonly used antibiotics across the included studies.^7,15,21 Observational studies found no significant difference in survival outcomes.^8,11 Similarly, a randomized controlled trial comparing benzathine penicillin (single intramuscular dose), benzyl-penicillin (intravenous for 10 days), and metronidazole (oral for 10 days) showed no significant difference in patient outcomes.²⁸ However, one study reported that 2 patients remained microbiologically positive for C. tetani even after 16 days of antimicrobial therapy, underscoring the limitations of antibiotics in eliminating the infection.¹⁶ Since tetanus spores in the wound may not always respond to antimicrobial treatment, thorough wound debridement is essential in most cases to remove the bacterial source.¹⁵

Neutralizing tetanus toxin is crucial for patient survival, and both HTIG and equine tetanus antiserum (TAT) have been used in treatment. Most studies favoured HTIG over equine antitoxin.^7,21 While some studies reported higher mortality associated with equine immunoglobulin²¹ others found no significant difference in survival outcomes between human and equine preparations.^8,29 A randomized controlled trial comparing intramuscular human and equine antitoxin found no significant difference in mechanical ventilation requirements or mortality rates, suggesting that equine antitoxin remains a viable alternative in resource-limited settings.²⁹ Several studies have explored the efficacy of intrathecal versus intramuscular administration of HTIG. A meta-analysis and randomized controlled trials demonstrated significantly lower mortality and faster recovery in patients receiving intrathecal HTIG compared to the standard intramuscular route.^30,31 Intrathecal HTIG was associated with shorter duration of spasms, reduced need for mechanical ventilation, and decreased hospital stays.³⁰ Additionally, it was found to be cost-effective, making it a promising option for improving tetanus management.³²

The practical details of the management of a case of tetanus have been summarized in Supplementary Tables 1 and 2 based on our experience of this scoping review.

Outcomes and prognosis. Mortality rates across studies varied widely, 5.26%–52.8%.^8,9 These differences were influenced by disease severity, access to intensive care, and the time-liness of intervention. A systematic review from Africa reported that mechanical ventilation was unavailable in 26% of studies, and even where it was available, financial constraints often limited its use.¹⁴ Many patients were unable to access ICU care due to cost barriers.¹⁴ In an Ethiopian study, 80% of deaths occurred within the first week of hospitalization, highlighting inadequate ICU support. Additionally, mortality was significantly higher among patients from rural areas in that study.¹⁷

Key predictors of death included older age, tachycardia, respiratory complications, and nosocomial infections.^6,8,10,21,23 In the study by Tosun et al., factors such as a short incubation period, severe autonomic dysfunction, and laboratory markers, including leukocytosis, elevated C-reactive protein, and increased aspartate transaminase (AST) levels, were associated with higher mortality risk.²¹ Lanuza et al. found that chronic hypertension increased the risk of death by 4.5 times.²⁴ Prognostic tools, such as the Wood prognostic score and Ablett’s grading system, helped predict mortality.⁸

Prevention. Effective prevention of tetanus relies on timely vaccination or post-exposure prophylaxis, active immunization, passive immunization, antibody monitoring, and addressing maternal and immunocompromized populations. Tetanus prevention is primarily achieved through routine immunization with tetanus toxoid vaccines. Generally, primary immunization for tetanus is done along with diphtheria and pertussis at 2, 4, and 6 months of life, with boosters at 15–18 months and 4–6 years. A booster with tetanus toxoid and reduced diphtheria toxoid is recommended for adolescents, and regular tetanus toxoid every 10 years is recommended for all adults. Routine vaccination with at least one dose of tetanus toxoid is recommended for all pregnancies. Active immunization is also helpful immediately after exposure in those not fully immunized. Tocotrienol-rich fraction supple-mentation enhanced vaccine-induced immune responses by increasing tetanus antibody levels and reducing pro-inflammatory cytokines in a study.³⁵

Assessing immunity status is crucial for targeted booster immunization and epidemiological surveillance. However, choosing the right diagnostic assay is essential, as comparative studies on commercial enzyme-linked immunosorbent assays (ELISAs) have shown variable diagnostic accuracies.³⁶ Rapid dipstick tests have emerged as reliable and field-friendly tools for assessing vaccine-induced immunity, particularly for determining the need for tetanus prophylaxis.³⁷

Immunocompromised individuals, including those with HIV, often have weakened responses to routine immunizations. Regular monitoring of their immune status may be necessary, along with additional booster doses. A study on HIV patients revealed poor immune response to prior vaccination, but booster immunization after initiating antiretroviral therapy significantly improved immunity.³⁸ Ensuring appropriate perinatal care practices is critical for preventing neonatal tetanus. Maternal vaccination has been identified as the strongest predictor of neonatal immunity, significantly reducing the risk of seronegativity in newborns.³⁹

Passive immunization with HTIG is recommended for unprotected individuals with tetanus-prone wounds to provide immediate protection. In a recent randomized controlled trial, siltartoxatug, a recombinant monoclonal antibody, achieved faster seroprotection and maintained higher antibody levels than HTIG.³⁴

Gaps in knowledge and future directions. Despite covering a broad range of clinical and epidemiological aspects, several important knowledge gaps remain in the current literature on tetanus, as highlighted by our scoping review. First, there is a lack of prospective or longitudinal studies examining tetanus survivors’ long-term outcomes and rehabilitation needs. Most existing studies focus on acute management and hospital mortality, with limited attention to neuromuscular sequelae, psychological impact, or functional recovery post-discharge. Second, specific high-risk populations such as individuals with diabetes, HIV, or those who have undergone organ transplantation are under-represented in the literature. Third, only a limited number of studies originated from high-incidence, and resource-limited countries, which represent a significant knowledge gap, as they limit the generalizability of findings to settings where the tetanus burden is highest and where resources to implement complex interventions may be lacking. Finally, although some interventions, such as intrathecal HTIG, magnesium sulphate, and the novel monoclonal antibody siltartoxatug, have shown promise in individual studies or controlled trials, there is a clear absence of large, multicentric implementation studies assessing their cost-effectiveness, especially in resource-limited environments.