Clinical profile and outcomes of tetanus patients in a tertiary hospital in the Philippines: a ten-year retrospective study

As of 2022, the global incidence of tetanus was at 0.9 per 1 million total population, representing a steady decline since 2012 when the incidence was at 2 per 1 million total population. The Western Pacific region ranks second with an incidence of 0.6 per 1 million total population, of which the Philippines has the highest incidence rate of approximately 7 per 1 million total population [4, 6]. This study found an incidence rate of 0.03% or 269 per 1 million inpatient admissions in a tertiary hospital. The significantly higher incidence noted in this study is likely due to referral bias since UP-PGH serves as the national referral center for tertiary care in the country. Similar to Philippine data, this study showed a gradual decrease in tetanus cases over the past decade [8].

A systematic analysis on the global epidemiology and burden of tetanus over the past 30 years found that the incidence of tetanus was significantly correlated with economic level, and has also been termed as a “disease of the underdeveloped world [3, 9].” Agricultural lifestyles, humid environments, poor wound care, low vaccination rates, and poor awareness of tetanus are some factors which could explain the regional burden of tetanus [10]. Despite the inclusion of free tetanus vaccination for children under the Expanded Program on Immunization [11], there are still low tetanus immunization rates locally, with fluctuating immunization coverage ranging from 55 to 81% over the past ten years [12]. Data on catch-up immunization rates in both the pediatric and adult population are also lacking. This is likely due to the devolved healthcare service delivery and out-of-pocket expenditure for adult tetanus immunization.

Similar to the findings of two earlier retrospective studies done on adult tetanus patients from 1997 to 2003 and from 2008 to 2013 in the same institution, the majority of tetanus patients are males regardless of age group, with unknown immunization status [13, 14]. The presence of comorbidities which was not explored in these previous studies revealed that more 1 in 5 adult tetanus patients had concomitant malignancy, and that interestingly, chronic hypertension significantly increased the hazard of death by 4.5 times compared to those who are non-hypertensives. This may be due to the interaction between an already compromised cardiovascular status and autonomic dysfunction. Dysautonomia, a feature that is usually associated with severe tetanus, has been noted in 32-62.1% of patients with tetanus [15, 16]. In a 10-year retrospective cross-sectional study done in two tertiary level centers in Pakistan involving 96 tetanus patients, those presenting with autonomic disturbance were found to have a higher mortality rate (47%) compared to those without autonomic dysfunction (15%; p = 0.002) [16]. The link between the propensity towards poor outcomes and the interaction between hypertension and autonomic dysfunction has been emerging in the literature. In a systematic review involving 17 studies, it has been proposed that patients with chronic hypertension have increased arterial stiffness and consequently a reduced baroreflex sensitivity [17]. This implies that any form of autonomic dysfunction, as in the case of tetanus, could be more deleterious among hypertensives compared to those without chronic hypertension. It is interesting to note however that no significant relationship has been found between dysautonomia and survival in the results of this study; this may be attributed to poor detection and documentation.

While tetanus is known to arise from post-traumatic wound contamination [2, 3], this study noted differences in terms of the likely source of infection between adults and children. Tetanus was mostly acquired through puncture wounds on the lower extremities for adults, while head and neck infections were the more common presumed source in children. Two retrospective studies on pediatric tetanus found trauma to still be the most common cause of tetanus among children, but noted otogenic and dental infections to be the next likely etiology (52% vs. 44% and 42% vs. 38% in these studies respectively) [18, 19]. Such differences may be explained by their usual activities, as adults are more exposed to external injuries from occupational hazards, whereas children are more prone to develop otitis media and dental infection due to differences in ear anatomy, poorer hygiene, and the lack of a fully mature immune system [20].

Trismus was still the most common presenting symptom, followed by dysphagia and truncal spasms, consistent with existing literature [2, 13, 14]. On chart review, it was observed that patients often opted to observe their symptoms for a few days prior to seeking consult, while some consulted with a dentist, an otorhinolaryngologist, or the local health center who failed to recognize tetanus and sent these patients home. Educating the public as well as encouraging these professionals to have a higher index of suspicion for tetanus can potentially minimize delays in management, and consequently decrease the risk of further morbidity and mortality in these patients.

Metronidazole was the antibiotic of choice for all patients, consistent with existing guidelines [1]. Diazepam was given in most patients for control of spasms, but midazolam and rocuronium were used more in the pediatric subgroup. A recent review on the pharmacological management of tetanus noted that although midazolam is theoretically better than diazepam due to its potency and faster onset of action, substantial evidence showing the efficacy of midazolam or its superiority over diazepam in tetanus is still limited [21]. The use of rocuronium in tetanus patients has been documented in a few case reports in adults, but data on its efficacy in the pediatric population is still lacking [20].

In terms of factors associated with survival, this study found that treatment with magnesium sulfate significantly decreased the hazard of death by 35 times (p = 0.005). The role of magnesium sulfate in the treatment of tetanus is based on its mechanism of action as a presynaptic neuromuscular blocker via calcium ion antagonism thereby reducing muscle spasms, and as an inhibitor of catecholamine release thereby reducing the tendency for hypertensive spikes and dysautonomia [23]. It is logical to consider that its role in reducing mortality could be due to its role in reducing autonomic dysfunction in patients with tetanus. This relationship is also reflected in a prospective study done in a tertiary institution in Kolkata, India involving 86 patients which showed a lower rate of dysautonomia among those treated with intravenous magnesium sulfate (10%) compared to those who did not receive the drug (24%) [24]. Although there is significant benefit in terms of spasm control, no mortality benefit has been demonstrated. A randomized controlled trial involving 42 patients demonstrated that patients who received magnesium encountered significant reductions in spasm frequency (4.1 ± 1.6 spasms per hour at the onset to 0.13 ± 0.05 spasms per hour in the second week of trial) compared to those who received diazepam-only treatment (from 3.4 ± 1.5 spasms per hour to 0.33 ± 0.2 spasms per hour, p = 0.010) [25]. These findings are also congruent with the results of a randomized trial in a tertiary center in Pakistan involving 36 patients [26]. The non-demonstration of significant survival benefit of magnesium sulfate in the cited trials could be due to a dose-response issue or a type 2 error due to low sample size. In a retrospective study done in Nepal comparing small and large doses of magnesium sulfate among patients with tetanus, those who received larger doses had lower mortality rates compared to the lower dose group [27].> Further studies involving larger sample sizes and various dosing regimens are needed to demonstrate the potential efficacy of magnesium sulfate in reducing mortality among patients with tetanus.

The Philippines reported a case fatality rate of 22% for non-neonatal tetanus as of 2021. Earlier reviews done in UP-PGH reported a case fatality rate of 22.2% from 1997 to 2023, and 19% from 2008 to 2013 [13, 14]. This study noted a higher overall case-fatality rate of 29%, 24% in adults and 36% in the pediatric subgroup. Age greater than 60 years, incubation period, higher severity staging, and presence of tachycardia on admission have been previously identified to be associated with increased mortality in tetanus [13, 14, 28]. Although not found to be statistically significant, the higher proportion of patients with stage III tetanus (58% vs. 56% and 28%) and the shorter incubation periods (7 days vs. 16 days) may explain the higher mortality rates noted in this study [13, 14]. The shorter incubation period among children (median: 3.5 days) compared to adults (median: 8 days) may also be associated with their higher mortality rate. Septic shock was the leading cause of death among tetanus patients, mostly secondary to nosocomial pneumonia and bacteremia which were the leading complications encountered during hospitalization.

This study has several limitations. Given its retrospective nature, data collection was primarily limited by the availability and completeness of existing records; hence, pertinent information such as vaccination status which were not documented in patient charts could no longer be retrieved. However, despite this limitation, the total number of available charts and the number of years covered (i.e. minimum of 82 samples per category over 12.5 years) are still greater than those of previous retrospective studies from the same institution, as well as other cited studies from different institutions and countries, with sample sizes ranging from 24 to 54 over 1 to 6 years [13, 14, 18, 19]. Possible reporting bias was avoided by disclosing the number of unavailable data per category, and computing proportions based on what was available. The risk of measurement bias was also minimized by having two reviewers extract data independently into a pre-made detailed abstraction form. Another limitation is that this study was confined to a single center with cases mainly coming from its nearby regions. Nevertheless, being the largest tertiary referral hospital in the country with a large sample size, these results are still likely reflective of tetanus cases in the Philippines.