Tetanus in individuals with previous tetanus toxoid immunization

Tetanus is rare in Canada with an average of four cases per year (range 1-10 per year) between 1990 and 2010 ^{Footnote 3}. Since the 1920s there has been a significant decrease in the number of deaths from tetanus due to the availability of vaccine and improvements in critical care ^{Footnote 1,Footnote 2}. The case fatality rate due to tetanus in unvaccinated persons varies significantly from 10% to over 80% with the very young and elderly being at greatest risk ^{Footnote 1,Footnote 3,Footnote 4}.

In Canada, the routine immunization schedule consists of four doses of tetanus toxoid-containing vaccine, given at 2, 4, 6 and 12 to 23 months of age (typically at 18 months of age), with a booster dose at age 4-6 years Footnote 3. After the completion of the first three doses of tetanus toxoid, more than 99% of individuals will have evidence of a protective antibody titre Footnote 3. Although traditionally a tetanus antibody titre of >0. 01 IU/mL by mouse neutralization assay has been considered protective; some studies have suggested a higher correlate of protection, such as 0.1 IU/mL. is required Footnote 5-7. Observational studies have demonstrated the efficacy of pre- and post-wound exposure immunization regimens Footnote 3. Subsequent booster doses are recommended at 10-year intervals, although the most recent edition of the Canadian Immunization Guide indicates that new evidence on the optimal timing of booster doses is currently under review Footnote 3. Depending on the nature of the wound and prior immunization history, post-exposure immunization (active and passive) may also be indicated Footnote 3.

Nevertheless, tetanus may still occur post immunization. Given the above case of tetanus with a history of a complete and documented primary series of tetanus toxoid, along with a "booster" nine years prior to presentation, a systematic review was conducted to assess the characteristics of tetanus in previously immunized individuals.

Methods

A systematic literature search was undertaken using Ovid MEDLINE(R) and EMBASE databases for articles published between 1946 and September 3, 2013. The search strategy was developed in MEDLINE using the following MESH terms: tetanus/, tetanus toxoid/, diagnosis/, diagnosis, differential/, immunization/, vaccination/. The controlled vocabulary was supplemented by the use of related keywords to increase the specificity of the search: "fully", "preexisting", "previous* ", "prior", "presen*", "protective", "active", "antibodies", immune*", "vaccine*". The search terms were combined using Boolean operators. No limits were applied to search in MEDLINE. The search in EMBASE, after the controlled vocabulary was translated to Emtree terms, was limited to non-MEDLINE content.

Abstracts were screened for the article being written in either English or French and a diagnosis of tetanus in one or more individuals. Abstracts meeting both screening criteria were obtained for full text review. Two authors (JPH, SEW) reviewed the articles for inclusion in the review.

In order to be included in the review, the article had to describe at least one case of tetanus, the immunization history of a fully or partially immunized case and/or present the results of anti-tetanus antibodies and be written in either English or French. The formal search was supplemented by PubMed snowball searches performed on articles meeting pre-specified inclusion criteria. In addition, a review of references from each relevant article was undertaken.

Relevant data, including number of tetanus cases, age, sex, antibody titre, clinical outcome, historic tetanus toxoid immunization, including number of doses and timing were abstracted and collated (Microsoft Excel 2010, Redmond, WA). One author (JPH) abstracted the data which was reviewed for accuracy by a second author (SEW). Discrepancies (which were rare) were resolved through consensus.

A formal quality assessment of individual articles was not undertaken. The retrieved articles included case reports, case series or surveillance reports. To the authors' knowledge, there is no validated tool for quality appraisal of these study designs. However, studies that were missing relevant data were excluded as per a priori inclusion and exclusion criteria. As this was a narrative synthesis of the literature, funnel plots and statistical assessments of heterogeneity were not appropriate measures of publication bias.

Results

Over 4000 articles were initially identified. Fifty-one unique articles were included in the review. Figure 1 summarizes the literature search results.

Figure 1: Literature search results

Text equivalent - Figure 1

This Figure is an Algorithm on the literature search results. There are four blue boxes along the left side identifying the Four steps. The first step is identification and the two top boxes identifies that through database searching 4110 records were identified and through additional sources 9 records were identified. The second step is screening. In a single box at the level below identification it notes duplicate records were removed leaving 1492 records. The box points to the next level that notes the records were screened. A horizontal arrow points to a box that notes 1385 recods were excluded. The third step is Eligibility and at this level a box notes 107 articles were assessed for eligibility. A horizontal arrow points to a box that notes 56 full text articles were excluded, not relevant, not in English or French, unimmunized against tetanus, no immunization history or anti-tetanus antibodies reported, diagnosis not tetanus, duplicate. The fourth step is Included and the box at this level notes that there were 51 studies included in the qualitative synthesis.

In the 51 studies that were included there were 359 cases of clinical tetanus in individuals with prior receipt of one or more doses of tetanus toxoid vaccine and/or levels of tetanus antibody titres generally considered protective (8-9). The majority of studies (n=25) were based on data from the United States. Of 47 cases where age and sex were described, 26 (39.4%) were male with a median age of 26 years (range 1-79 years). Fourteen cases had tetanus antibody titres drawn prior to administration of antitoxin, while the remaining 345 cases had immunization confirmed on record review. All cases of tetanus were diagnosed based on clinically compatible symptoms and signs. The isolation of Clostridium tetani was not reported in any case.

Vaccination histories of cases were reviewed within the case reports. While inclusion criteria required all cases to have received one or more doses, only 175 (48.7%) reported the exact number of doses. Ninety-four cases (26.2% of total cases) received three or more doses suggesting the primary series may have been completed, although it was not possible to assess the interval between doses. With respect to doses which occurred beyond early childhood and were described as "boosters" but which may or may not have been preceded by a complete primary vaccine series, 57 cases (15.9%) received a booster dose of tetanus toxoid within the last 10 years, 54 cases (15.0%) received a booster dose 10 or more years in the past and 248 cases (69.1%) last received a booster at an unknown interval (or no booster was given), or the case was not eligible for a booster (e.g. based on a historic policy or age) (data not shown). As more than half of the cases did not report the number of doses of tetanus toxoid received and there were a small number of deaths (n=30), it was not possible to analyze survival data by number of doses.

The high survival in published case reports suggest milder disease that is associated with better prognosis in individuals with a history of tetanus immunization ^{Footnote 3,Footnote 4,Footnote 20-23}

Of the 180 of 210 (85.7%) cases that reported on clinical outcome survived to discharge and in cases that were followed beyond discharge, all except three ^{Footnote 17,Footnote 27,Footnote 28} had complete resolution of symptoms. While survival generally appeared to improve over time, 42% of studies (n=149) did not report the clinical outcome so it was not possible to study survival trends as they related to other factors (e.g. systematic improvements in critical care over time and increased implementation of a 3-dose primary immunization series). The studies are summarized in Tables 1 and 2.

Table 1: Case reports of tetanus in individuals with complete data (detailed information on tetanus immunization history or tetanus antibody and clinical outcome)

Author / country	Study design/ number of cases (n)	Age (years) and sexTable 1 - Footnote 1	Risk factors for tetanusTable 1 - Footnote 2	Vaccination historyTable 1 - Footnote 3	Tetanus antibody titre at diagnosisTable 1 - Footnote 4	Patient outcomeTable 1 - Footnote 5
AbrahamianNote de bas de page 8 / United States	Case report/ n = 1	45 M	IDU	?	++	-
Atabek Note de bas de page 9 / Turkey	Case report/ n = 1	7 F	Laceration	++	?	+
Aydin-Teke Note de bas de page 29 / Turkey	Case report/ n = 1	15 M	Injury	++	?	+
Bardenheier Note de bas de page 22 / United States	Surveillance / n = 31	?	?	+ Note de bas de page 15 ++ Note de bas de page 16	?	+ Note de bas de page 30 - Note de bas de page 1
Berger Note de bas de page 16/ United States	Case report/ n = 1	25 F	IDU	?	+	+
Boyd Note de bas de page 30/ Europe and Africa	Retrospective surveillance / n = 16	?	?	+ / ++	?	+ Note de bas de page 11 - (5)
Boyer Note de bas de page 31/ France	Case review / n = 10	?	?	+ / ++	?	+ (2) - (8)
Coniglione Note de bas de page 32/ United States	Case report/ n = 1	29 M	Injury	++	++	+
Crone Note de bas de page 17/ United States	Case report/ n = 3	29 M 42 F 57 F	? IDU Reused syringe	++ + +	++ Note de bas de page 3	+ - + (deficits)
de la Chapelle Note de bas de page 33/ France	Case report/ n = 1	52 M	Injury, IS	?	++	+
Dyce Note de bas de page 27 / United States	Case report/ n = 1	24 F	Piercing	++	?	+ (deficits)
Faust Note de bas de page 34 / United States	Hospital surveillance / n = 1	5 M	?	+	?	+
Fiorillo Note de bas de page 35/ Canada	Case report/ n = 1	10 M	Injury	++	++	+
Hall Note de bas de page 36/ United States	Case report/ n = 2	?	?	+ (2)	? (2)	+ (1) - (1)
Hedrick Note de bas de page 37 / United States	Case report/ n = 2	10 M 45 M	Injury ?	++ +	? (2)	+ (2)
Hopkins (this report) / Canada	Case report/ n = 1	22 M	Injury, IS	++	?	+
König Note de bas de page 10/ Germany	Case report/ n = 1	14 M	Injury	++	?	+
Livorsi Note de bas de page 11 / United States	Case report/ n = 1	44 M	Injury	?	++	+
Lodha Note de bas de page 38 / Inde	Case report/ n = 2	3 F 4,5 M	? (2)	? ++	? (2)	+ (2)
Long Note de bas de page 39/ United States	Surveillance / n = 6	?	Injury	++ (6)	?	+ (3) - (3)
Loscalzo Note de bas de page 40 / United States	Case report/ n = 1	23 F	Piercing	++	?	+
Luisto Note de bas de page 12/ Finland	Retrospective case series / n = 5	5 M 10 F 12 M 13 F 15 F	Animal bite Infection Injury Injury Burn	++ ++ ++ ++ ?	? Note de bas de page 5	+ Note de bas de page 5
Newton-John Note de bas de page 23/ Australie	Case series / n = 19	?	?	++ Note de bas de page 13 + Note de bas de page 6	?	+ Note de bas de page 17 - Note de bas de page 2
Otero-Maldonado Note de bas de page 28/ Puerto Rico	Case report and surveillance / n = 7	67 M ? Note de bas de page 6	Injury ? Note de bas de page 6	+ ? Note de bas de page 6	? Note de bas de page 7	+ (deficits) + Note de bas de page 5, - Note de bas de page 1
Pascual Note de bas de page 21 / United States	Surveillance / n = 30	?	?	+ Note de bas de page 10 ++ Note de bas de page 20	? Note de bas de page 30	+ Note de bas de page 10 + (19), - Note de bas de page 1
Passen Note de bas de page 14/ United States	Case report/ n = 1	35 M	Injury	++	++	+
Peterson Note de bas de page 18/ Suède	Case report/ n = 1	12 M	Injury	++	++	+
Spittle Note de bas de page 41/ Nouvelle-Zélande	Case report/ n = 1	25 F	Injury	++	?	+
Tiwari Note de bas de page 4/ United States	Surveillance / n = 55	?	?	+ Note de bas de page 26 ++ Note de bas de page 29	? Note de bas de page 55	+ Note de bas de page 17, - Note de bas de page 3, ? Note de bas de page 6 + Note de bas de page 24, - Note de bas de page 1, ? Note de bas de page 4
Vieria Note de bas de page 19 / Australia	Case report/ n = 1	18 M	Injury	++	?	+
Footnote 1 1M (male), F (female),? (unknown/not reported) Footnote 2 2? (unknown/not reported) Footnote 3 3++ (3 or more doses), + (1 or 2 doses),? (exact number of doses not reported) Footnote 4 4++ (>0. 1 IU/ml), + (0. 01-0. 09 IU/ml),?=not measured Footnote 5 5+ (alive at discharge), - (deceased),? (unknown/not reported) Footnote 6 6+ (en vie au moment de quitter l'hôpital), - (décédé), ? (inconnu / non indiqué) IDU = injection drug use IS = immunosuppression

Table 2: Case reports of tetanus in individuals lacking complete data (detailed) information on tetanus immunization history and/or clinical outcome)

Author/ country	Study design/ number of cases (n)	Age (years) and sexTable 1 - Footnote 1	Risk factors for tetanusTable 1 - Footnote 2	Vaccination historyTable 1 - Footnote 3	Tetanus antibody titre at diagnosisTable 1 - Footnote 4	Patient outcomeTable 1 - Footnote 5
Bankole Note de bas de page 42/ Nigeria	Case series / n = 11	?	?	?	?	?
Beltran Note de bas de page 43/ United States	Case report / n = 1	58 M	Morsure d'animal	?	++	?
Bunch Note de bas de page 4/ United States	Case series / n = 5	53 F 59 F 62 F 65 F 75 F	? Injury Infection Laceration Laceration	? Note de bas de page 5	? Note de bas de page 5	+ Note de bas de page 5
Christensen Note de bas de page 45 / United States	Case report / n = 1	10 M	Injury	+	?	?
Culbertson Note de bas de page 46 / United States	Case report / n = 1	41 M	Burn, lacerations	?	?	+
deSouza Note de bas de page 47 / India	Case control / n = 1	?	?	+	?	?
Earis Note de bas de page 48 / Royaume-Uni	Case report / n = 1	66 F	Tumeur fongique	?	?	+
Edsall Note de bas de page 49 / multiple	Review of previously published cases6/ n = 4	?	?	? Note de bas de page 4	?	+ Note de bas de page 3 - Note de bas de page 1
Ferris Note de bas de page 50 / United Kingdom	Case report / n = 1	17 M	Trauma	?	?	+
Geeta Note de bas de page 51 / India	Case series / n = 12	1 M ? Note de bas de page 11	?	++ + Note de bas de page 11	?	?
Hahn Note de bas de page 52 / United States	Case report / n = 1	58 M	?	?	?	+
Henderson Note de bas de page 53 / United States	Case series / n = 5	?	Various injuries; IDU	?	?	?
Iqbal Note de bas de page 54 / Pakistan	Case series / n = 10	?	?	?	?	?
LeeNote de bas de page 55 / Taiwan	Case series / n = 2	3 ? 5 ?	? Note de bas de page 2	? Note de bas de page 2	? Note de bas de page 2	? Note de bas de page 2
Masthi Note de bas de page 56 / India	Case series / n = 2	?	?	?	?	?
O'Malley Note de bas de page 13 / United States	Case report / n = 1	27 F	Piercing	?	++	?
Orwitz Note de bas de page 57 / United States	Case report / n = 1	79 M	Infection	?	?	?
Percy Note de bas de page 58 / United States	Case series / n = 1	?	?	+	?	?
Quackenbush Note de bas de page 59 / United States	Case report / n = 1	44 F	Injury	?	?	+
Rushdy Note de bas de page 20 / Royaume-Uni	Surveillance report / n = 5	?	?	?	?	?
Shimoni Note de bas de page 15 / Israel	Case report / n = 1	34 M	?	?	?	+
Srigley Note de bas de page 60 / Canada	Case report / n = 1	78 F	Injury	?	?	-
Footnote 1 1M (male), F (female),? (unknown/not reported) Footnote 2 2? (unknown/not reported) Footnote 3 3++ (3 doses ou plus), + (1 ou 2 doses), ? (nombre exact de doses non indiqué) Footnote 4 4++ (>0. 1 IU/ml), + (0. 01-0. 09 IU/ml),?=not measured Footnote 5 5+ (alive at discharge), - (deceased),? (unknown/not reported) Footnote 6 6Studies described in table (p. 127). Original studies were obtained where possible (Long, Hall, Boyd, Boyer, Christensen). Remaining studies were not indexed in PubMed, MEDLINE or EMBASE. The Journal of the American Medical Association (JAMA) was contacted for the original reference list which was excluded from the published manuscript due to length, but no copy was archived. Cases summarized here are from Moss and Hedrick. IDU = injection drug use IS = immunosuppression

Discussion

To the authors' knowledge, this is the first systematic review which assesses the occurrence of tetanus in previously immunized individuals. Since 1946, at least 359 cases of tetanus have been described in previously immunized individuals and of those whose outcomes were reported, there was a survival rate of 85.7% with few cases reporting residual deficits at discharge. In cases that reported the number of doses of tetanus toxoid previously received by individuals, the clinical severity of disease appeared to be less compared to those who received fewer previous doses (although this could not be studied systematically due to the small number of deaths and cases symptomatic at discharge).

A previous review found a similar relationship between the number of doses and clinical severity. A review of 175 tetanus cases reported through routine surveillance between 1984 and 2000 in England and Wales found that clinical severity was greater in those with no previous history of immunization (although this did not reach statistical significance (p=0. 068))^{Footnote 20}.

Potential explanations for the occurrence of clinical tetanus in the setting of past immunization could include: waning of vaccine-derived immunity; vaccine failure; the presence of an unrecognized immunodeficiency resulting in sub-optimal immune response to active vaccination; or compromised vaccine storage and handling resulting in reduced immunogenicity of the vaccine product. Alternatively, the burden of tetanus exotoxin may exceed an individual's immune response which may be additionally influenced by factors that cause immune suppression, such as chronic diseases or medications.

Limitations of this review include: the inability to assess how frequent this phenomenon is due to the lack of a denominator; potential publication bias; and incomplete data (e.g. survival). In addition, the inherent limitations of case studies and surveillance reports include: collection of source information (e.g. recall bias if self-reported, data quality and consistency if taken from databases; under-reporting or ability to capture all cases in a surveillance system); and a lack of a consistent clinical definition for tetanus in case reports created challenges in interpretation of the data.

Nonetheless, this study contributes significantly as it is possibly the first systematic review which summarizes the characteristics of tetanus in cases previously immunized with tetanus toxoid. Other strengths of this study include: the systematic methodology used to identify relevant studies; and the inclusion of articles from multiple countries, studies from 1946 through 2013 and studies in two languages.

Attenuation of disease severity in immunized hosts suggests the potential for under-reporting if the person does not present for medical care as well as the possibility of delayed diagnosis, although this was not consistently described in the included articles. This has important implications for the surveillance of vaccine-preventable diseases and clinical practice.

Future research directions might focus on understanding the incidence of tetanus in those with previous vaccination with tetanus toxoid and whether this is due to waning immunity or vaccine failure, the optimum timing of tetanus toxoid boosters and further research into the cut-off and role of anti-tetanus antibodies in determining immunity to tetanus.

Conclusions

Tetanus is a rare, but potentially lethal disease and Clostridium tetani are ubiquitous in the environment. A completed primary vaccine series and appropriate boosters clearly do not confer protective immunity in all recipients; however the survival rate is high in those with previously documented doses of tetanus toxoid. Clinicians should maintain a high index of clinical suspicion for tetanus when the clinical symptoms suggest it, regardless of vaccination history.

Acknowledgements

The authors express their sincere thanks to Public Health Ontario Library Services, in particular Beata Pach, for assistance with the systematic search and retrieval of literature and to Dr. Shelley Deeks for her helpful comments on an earlier draft of the manuscript.

Conflict of interest

There are no conflicts of interests to declare.

Funding

No funds were received for this study