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Three Part Question

In [adults with acute sore throat] who [have recently travelled to a high risk area and have not had a diphtheria vaccination within 10 years] is [diphtheria vaccination recommended]?

Clinical Scenario

A 35 year old man came into A&E complaining of a sore throat. He had a fever, anterior cervical lymphadenopathy and tonsillar exudates. He had returned from Russia 1 week ago and was unsure of his vaccination status.

Search Strategy

Medline 1966 to June Week 1 2005
Embase 1980 to 2005 Week 24
Cinahl Cumulative Index to Nursing & Allied Health Literature 1982 to June Week 1 2005
The Cochrane Library Issue 2 2005
Only studies since 1995 were included
{{diphtheria.mp. OR exp Diphtheria/} AND {vaccination$.mp. or exp VACCINATION/}} OR exp Diphtheria Toxoid/ AND {protect$.mp. OR protection.mp.} AND {effective$.mp. OR efficac$ OR effectiveness.mp.} limit to (humans and english language)

Search Outcome

Medline-447 papers found, 9 relevant papers found including one review of 7 trials.
Embase 762 papers found-no extra relevant papers
Cinahl-41 papers found-no extra relevant papers
Cochrane-no relevant papers found

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Bottiger M, Gustavsson O, Svensson A Feb 1998 Sweden	A random sample of 4800 people stratefied to age group and sex were selected. 3390 (70.6%) of these gave a blood sample, from which diphtheria antitoxin levels were determined and so adequacy of protection against diphtheria was assessed.	survey Level 3 evidence	estimated proportion immune to diphtheria of those born after 1956	75% irrespective of sex	The response rate was 70.6% and the details of non participants are not given. They are assumed to be uninformative. The raw data was not given, only % therefore it was not possible to see if the figures added up. In sweden only 3 vaccines were offered whereas in england 5 are given so the results may not be generalized?
			estimated proportion of women vs men immune to diphtheria	all age groups men 61.5% vs women 48.8%(p<0.001)
			% not fully protected against diphtheria of those born after 1956	25%
Garcia-Corbeira P, Dal-Re R, Garcia-de-lomas J 1999 Spain	4787 healthy subjects were randomly selected for another study. They were cluster sampled by age, sex and randomly selected primary care centres. Due to the volume of serum available only 3944 of these subjects were used.	Survey, level 3 evidence	Full protection against diphtheria	1033, 26%;95% CI 25-28%	Loss of 843 sujects from original random selection. In spain unlike the UK, routine revaccination has been recommended for adults every 10 years. This may affect the ability to generalise the study to UK patients.
			Not protected against diphtheria	2911, 74% 95% CI 72-75%
			Age groups?
Edmunds WJ, Pebody RG, Aggerback H et al 2000 UK. Data from 7 countries in W Europe.	7 Western European countries (Italy, Germany, Finland, France, The Netherlands, England and Wales, and Sweden) undertook collection of several thousand sera specimens, representative of age. Prospective, population based random sampling was performed in The Netherlands and Sweden. The other countries used residual sera collected during routine laboratory testing. Finland, France and Germany used the Vero cell neutralization test. UK and Germany used double antigen delayed time resolvedfluorescence immunoassay (DELFIA) The Netherlands used a toxin-binding inhibition test, Sweden used a single-antigen enzyme-linked immunosorbant assay (ELISA) The results of diphtheria toxin testing were standardized. Country specific data was gathered on diphtheria vaccine programme structure.	Survey, level 3 evidence.	% of adults >30 yrs not protected against diphtheria.(titre<0.01 IU/ml) The Netherlands	33% females, 21% males (p=<0.0001)	Results data was provided in bar charts but the figures were not given although they could be requested from the authors. Statistical standardizing of the different laboratoy tests is unlikely to give as comparable results as testing in the same laboratory. Response rates not given for Sweden, Netherlands approximately half of those particpants invited to participate did. Different vaccination programmes.
			France	27%, 14%
			Sweden	37%, 28%
			Finland	29%, 16%
			Germany	45%,42% (p=0.19)
			Italy	28%, 29% (p=0.68)
			UK	50%, 50% (p=0.55)
Aue A, Hennig H, Kruger S et al 2003 Germany	321 blood donors (192 male and 129 female) who regularly donated blood between 1994 to 1998. Donors were between 18 and 65 yrs. Samples collected from 2 to 4 consecutive and from one donation at the end of 1997 or beginning of 1998. Antitoxin levels were determined by ELISA A questionnaire was sent to all subjects to find out whether and when they had been immunized against diphtheria	Survey, Level 3 evidence	Level of protective immunity from diphtheria in 1994	4/277 (1.5%)	This study may have a high level of bias due to its participants all being blood donors. There is no mention of how the donors were selected to take part although they are representative of age groups. The internal data in the study does not add up, this reduces the credability of the study.
			Level of protective immunity from diphtheria 1997/8	10/282 (3.5%)
			% of general population not fully protected 98.5%	98.5% 1994, 96.5% 1997/8
Walory J, Grzesiowski P, Hryniewicz W 2001 Poland	Between 1996 and 1998, 4829 serum samples were collected from healthy individuals. Neutralization of toxin in Vero cells and ELISA were perfomed.	Survey, level 3 evidence.	No diphtheria protection (IgG-DTAb<0.1 IU/ml	23% of all participants, 32% of adults	The study does not state how the participants were selected so i therefore assume it was not by random selection, they are not representative of age groups. It is not clear how many participants invited to participate gave samples. Poland has a 4 dose primary schedule followed by 3 boosters. This differs from the UK policy therefore the ability to generalise this study must be considered.
			Basic diphtheria protection(0.1-1.0 IU/ml)	64% of all participants, 63% of adults
			Effective seroprotection	13% of all participants, 5% adults
			Adults not vaccinated in the previous 10 years not protected against diphtheria	43%
			% of all adults not fully protected against diphtheria	87%
Deanna M, Kruszon-Moran MS, McQuillan GM et al 2004 USA	9411 females stratefied representative sample of age and ethnic origin was attempted, through household interviews and mobile examination centres. Samples obtained were assessed for diphtheria antitoxin by neutralization assay in VERO monkey kidney cells.	Survey, Level 3 evidence	% of all women over 20 years immune to diphtheria	50.7%	Oversampling of some groups occurred but was compensated for by weighting of the statistics. This survey was more concerned with comparing data between adifferent ethnic origins.
			% not fully protected	49.3%
Pachon I, Amela C, De Ory F 2002 Spain	3932 healthy participants aged 2-39 years, attending phlebotomy centres were sampled. Vaccination cover was assessed. The level of diphtheria antitoxin was assessed by passive haemagglutination.	Survey, Level 3 evidence.	% of population with immunity to diphtheria by age. 2-15 years	96%	Only those with public health care included, although this is 95% of the population. Between 8 and 12% of participants were excluded from the study due to small serum samples. 1% refused to participate. This study only includes 2 to 39 year olds so does not represent the whole population.
			15-19 years	67%
			20-24 years	58.7%
			25-29 years	59.5%
			30-39 years	32.3
von Hunolstein C, Rota MC, Alfarone G et al 2000 Italy	3111 serum samples obtained from healthy patients aged 0-84 years for other diagnostic purposes were used. They were representative of geographic area and age. The diphtheria antitoxin levels of the sera were analysed using DELFIA.	Survey, Level 3 evidence.	% of population susceptible to diphtheria	9.9%, 21.1% of children, 15% over 14 yrs	As subjects were already having blood tests, this may introduce more bias.
			% of population with basic protection against diphtheria	30.2%,21.1%,37%
			Protected against diphtheria	59.9%, 75.8%, 48%
			% of population not fully protected against diphtheria	40.1%
de Melker HE, van de Hof S, Berbers GAM et al 2003 The Netherlands	9948 'population-based' sample of sera, representative of age and geographical area. A Toxin-Binding Inhibition Assay for diphtheria antibodies was performed.	Survey, Level 3 evidence	% of general population not fully protected against diphtheria	11.9%	The Netherlands has a group of orthodox reformed individuals who refuse vaccination, the study stated that this group had a lower level of immunity but did not provide results separately therefore the ability to generalise the results to the UK should be condidered. The participation rates were only 55 and 52.5%. This paper was more concerned with assessing all of the national immunisation programme, not specifically diphtheria, and not many relevant statistics were performed
			% of population fully protected against diphtheria	88.1%

Comment(s)

Assessing the susceptibility of a population to diphtheria by its seroprevalence is not ideal. I have included countries in Western Europe and the USA however due to different vaccine policies implemented at different times it is very difficult to compare results. Also the cumulative paper of Western Europe which includes the surveys with the least risk of bias splits the groups into men and women. As the other papers it is more accurate to split the data into men and women. The best data may be to just use evidence from UK.

Clinical Bottom Line

50% of people in the UK are susceptible to diphtheria. Therefore although it is very rare in the UK if a patient has travelled to a high risk area and has not had a diphtheria vaccination in the last 10 years a diphtheria vaccination is recommended.

References

1. Bottiger M, Gustavsson O, Svensson A Immunity to tetanus, diphtheria and poliomyelitis in the adult population of Sweden in 1991 International Journal of Epidemiology 1998;27: 916-925
2. Garcia-Corbeira P, Dal-Re R, Garcia-de-lomas J Low prevalence of diphtheria immunity in the spanish population: results of a cross sectional study. Vaccine Apr 1999 17 pg 1978-1982
3. Edmunds WJ, Pebody RG, Aggerback H et al The sero-epidemiology of diphtheria in Western Europe Epidemiol. Infect. 2000 125 113-125
4. Aue A, Hennig H, Kruger S et al Immunity against diphtheria and tetanus in German blood donors Med Microbiol Immunol 2003 192:93-97
5. Walory J, Grzesiowski P, Hryniewicz W The prevalence of diphtheria immunity in healthy population in Poland Epidemiol. Infect 2001 126 225-230
6. Deanna M, Kruszon-Moran MS, McQuillan GM et al Tetanus and diphtheria immunity among females in the United States:Are recommendations being followed? American Journal of Obstetrics and Gynaecology 2004 190 1070-6
7. Pachon I, Amela C, De Ory F Age specific seroprevalence of poliomyelitis, diphtheria and tetanus antibodies in Spain. Epidemiol. Infect 2002 129 535-541
8. von Hunolstein C, Rota MC, Alfarone G et al Diphtheria Antibody Levels in the Italian Population Eur J Clin Microbiol Infect Dis 2000 19 433-37
9. de Melker HE, van de Hof S, Berbers GAM et al Evaluation of the national immunisation programme in the Netherlands: immunity to diphtheria, tetanus, poliomyelitis, measles, mumps, rubella and Haemophilus influenzae type b. Vaccine 2003, vol 21 716-720