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The Effect of BCG Vaccination on Tuberculin Reactivity and the Booster Effect Among Hospital Employees
Santiago Moreno, MD;
Rosa Blázquez, MD;
Abel Novoa, MD;
Isabel Carpena, MD;
Ana Menasalvas, MD;
Cristóbal Ramírez, PharmD;
Carmen Guerrero, MD
Arch Intern Med. 2001;161:1760-1765.
ABSTRACT
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Background We estimated the effect of remote BCG vaccination on tuberculin reactivity
and the booster effect among hospital employees.
Methods Cross-sectional survey at a university hospital. All personnel employed
during a 24-month period were included in the study. Employees were administered
2-step tuberculin testing, and BCG vaccination scars were verified.
Results Of 665 hospital employees studied, 239 (36%) had been vaccinated with
BCG in childhood. Significant tuberculin reactions ( 5 mm) were more frequent
among BCG-vaccinated (60%) than among nonvaccinated (29%) employees (odds
ratio [OR], 3.6; 95% confidence interval [CI], 2.6-5.2). The predictive value
of tuberculosis infection increased with increasing reaction size and greater
age (from 37% in subjects 30 years or younger with indurations 5 mm to
100% in subjects 50 years or older with indurations 15 mm). Among 374
employees with a negative tuberculin test reaction who underwent a second
test, 39 (43%) of 91 vaccinated subjects had a positive booster reaction in
contrast to 51 (22%) of 232 nonvaccinated subjects (OR, 3.4; 95% CI, 2-5.7).
Neither different size criteria nor different definitions of the booster effect
had an impact on the predictive value of tuberculosis infection.
Conclusions Remote BCG vaccination largely influences the tuberculin reaction and
the boosting phenomenon among hospital employees. The interpretation of the
results of 2-step tuberculin testing in a BCG-vaccinated subject must take
into account age, size of the reaction, and local prevalence of tuberculosis
infection. No single criterion, however, can accurately separate reactions
caused by true infection from those caused by BCG vaccination.
INTRODUCTION
ALTHOUGH tuberculosis has long been recognized as an occupational hazard
for health care workers,1-2 concern
about the risk of acquisition of the infection has increased recently after
reports of occupationally acquired tuberculous infection and disease among
hospital employees.3-6
This concern led the Centers for Disease Control and Prevention to revise
previous recommendations and to publish more stringent and comprehensive guidelines
for reducing the risk of transmitting Mycobacterium tuberculosis in the hospital environment.7 Central
in the Centers for Disease Control and Prevention recommendations is the monitoring
of tuberculous infection of hospital personnel who are likely to be exposed
to tuberculous patients, through periodic tuberculin testing. Two-step testing
(ie, administration of a second tuberculin test after 1 to 3 weeks when there
has not been a significant reaction to a first test) is the procedure recommended
in the initial examination of hospital employees, so that a boosted response
can be elicited in those with remote tuberculosis infection. The reaction
to the boosted (second) test is considered to indicate the infection status
of the person tested.
Vaccination with BCG has been used, and is still being used, for its
potential to prevent the development of tuberculosis in persons who are at
risk of acquiring the infection. The capability to protect against drug-sensitive
and drug-resistant M tuberculosis has led to the
proposal of administering the vaccine to health care workers who are at high
risk of contracting the infection, especially when they are immunosuppressed
and multidrug-resistant tuberculosis is a possibility.8-9
The potential for complications of the use of BCG vaccine in immunocompromised
persons has not been determined. The effect that BCG vaccination may have
on tuberculin reactivity, however, could preclude adequate surveillance programs
in the hospital.10 In fact, the interpretation
of tuberculin reactions and the booster effect among hospital employees who
have received BCG vaccination is a practical problem frequently faced by health
care professionals involved in tuberculosis treatment and control. Some studies
have evaluated tuberculin reactivity in different populations who are BCG
vaccinated, and BCG vaccination has been identified as one of the factors
associated with a positive tuberculin test in health care workers.11-12 However, no studies have evaluated
the interpretation of the tuberculin test and the booster effect among BCG-vaccinated
hospital personnel.
We performed this study to estimate the effect of remote BCG vaccination
on tuberculin reactivity and on the booster effect among employees in a Spanish
hospital located in an area where routine BCG vaccination was given from 1965
to mid-1980. We also sought to determine the value of different reaction size
criteria in predicting tuberculosis infection in BCG-vaccinated hospital employees.
SUBJECTS AND METHODS
STUDY POPULATION AND DATA COLLECTION
The study population was recruited from the employees at Hospital Morales
Meseguer, a 400-bed institution in Murcia, Spain, in a 24-month period. In
Murcia, BCG immunization was routinely given to newborns from October 1965
to May 1980, and to schoolchildren aged 6 to 14 years from 1965 to 1976. Vaccination
was done by intradermal administration in the shoulder area of 0.1 mL of a
lyophilized Göteborg strain from the Seruminstitut, Copenhagen, Denmark.
Hospital employees were excluded from this study if they had a documented
history of a positive tuberculin skin test, a previous diagnosis of tuberculosis,
or an identifiable cause of immunosuppression, including the administration
of corticosteroids or other immunosuppressive therapy. No person was undergoing
treatment for suspected or confirmed tuberculosis. Before skin testing and
reading, all participants had the following data collected: sex, age, departmental
group (physicians, nursing, other clinical, and administrative), degree of
direct contact with patients (categorized as frequent, infrequent, or rare
or no contact), previous tuberculin skin tests, and BCG vaccination status.
The BCG vaccination status of each person was determined by recording the
presence of the vaccine scar. The BCG vaccination scars were identified on
the upper third of the upper arm, usually no more than 4 cm below the shoulder
vertex. No data could be collected regarding the age of the subjects when
vaccinated (whether in infancy or later) or the number of subjects with repeated
vaccinations.
TUBERCULIN TESTING
To evaluate the response to tuberculin, intradermal injection of 2 U
of the RT-23 strain, equivalent to 5 TU of purified protein derivative (PPD),
was administered into the volar surface of the forearm with disposable syringes
and 27-gauge needles.13 Responses were read
by the ballpoint method14 at 48 to 72 hours
after administration, and the maximum induration in millimeters was recorded.
The PPD test was administered and the results were interpreted by a single
trained nurse. At the time of reading, the nurse was unaware of the person's
BCG vaccination status. A positive response to the PPD test was defined as
an induration of 5 mm or more in diameter at 48 to 72 hours after administration
of the antigen.
Employees with a reaction to the first test of less than 5 mm had a
second PPD test applied 1 to 3 weeks later on the other forearm. The techniques
for testing and reading were the same as for the initial tuberculin test.
A positive booster effect was defined as a reaction
to the second PPD test of 5 mm or more. All employees with a positive initial
or second tuberculin test were referred for further medical evaluation and
appropriate therapy.
ANALYSIS
For purposes of analysis, hospital employees were divided into 2 groups
according to whether they had received BCG vaccination. The groups were compared
by means of the t test or Mann-Whitney test for continuous
data, and  2 or Fisher exact test for categorical data. To
evaluate the effect of BCG vaccination on tuberculin reactivity, odds ratios
with 95% confidence intervals were calculated. Multiple logistic regression
analysis was used to determine the risk factor associated with a positive
initial or second tuberculin test.
To determine the value of different tuberculin reactions in predicting
tuberculosis infection in BCG-vaccinated hospital employees, the sensitivity,
specificity, and positive predictive values of different reaction sizes (5, 10,
and 15 mm) were calculated. In these calculations, according to a national
consensus in Spain,15 we assumed that a tuberculin
reaction of 5 mm or more had a sensitivity of 100% in our area, ie, all those
with tuberculous infection would manifest at least this reaction, and that
those with a tuberculin reaction of 5 mm or more, and not BCG vaccinated,
were actually infected with tuberculosis (ie, nontuberculous mycobacterial
infections as a cause of false-positive reaction are extremely rare). These
assumptions are based on studies that evaluated the prevalence of nontuberculous
mycobacterial infection in Spain.16-18
Given the strong association observed between tuberculin reactivity and age,
all calculations were made for different age groups (<30, 30-49, and 50
years). To make the calculations, the disease status for BCG-vaccinated persons
was considered to be the same as that for persons not BCG vaccinated.
All statistical associations were assessed with 2-tailed tests. A P value of less than .05 was considered to indicate statistical
significance.
RESULTS
STUDY POPULATION
The rate of tuberculosis in our area is approximately 35 cases per 100 000
population. From 1995 to 1997, 32 to 35 new cases of culture-proved tuberculosis
were diagnosed annually at Hospital Morales Meseguer, and case rates ranged
from 244.4 to 281.5 per 100 000 hospital discharges. Between January
1, 1995, and December 31, 1996, 813 persons were employed at the hospital.
Of them, 665 (82%) were eligible to participate in the study. The remaining
148 hospital employees were excluded because of a previous positive tuberculin
test (80 employees), an antecedent of tuberculosis (2 employees), the use
of immunosuppressive therapy (4 employees treated with corticosteroids), or
absence from the hospital at the moment of the study (44 patients). Eighteen
employees refused to participate. Employees who participated and those who
did not participate in the study did not differ in their baseline characteristics.
Overall, 239 participants (36%) had received BCG vaccination. The characteristics
of the employees and the univariate statistics for the BCG-vaccinated and
non–BCG-vaccinated groups are shown in Table 1. When compared with the nonvaccinated group, BCG-vaccinated
subjects were significantly older (P = .007). There
were no significant differences in the departmental group to which employees
belonged, the degree of contact with patients, or the proportion of subjects
who had previously been tuberculin tested.
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Table 1. Characteristics of Hospital Employees According to BCG Vaccination
Status*
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In total, 356 (56%) of 640 hospital employees who underwent 2-step tuberculin
testing had a positive reaction, including those who reacted to the first
and to the second tuberculin tests. The rate of tuberculin reactivity was
significantly influenced by BCG vaccination. Of 234 BCG-vaccinated employees,
182 (78%) had significant reactions, compared with 174 (43%) of 406 nonvaccinated
subjects (P<.001).
INITIAL TUBERCULIN TESTING
Of the 665 participants, 266 (40%) had significant reactions (5
mm) to the first tuberculin skin test. The antecedent of BCG vaccination was
highly predictive of a positive result. Of the 239 employees who had received
BCG vaccination, 143 (60%) had significant tuberculin reactions, compared
with 123 (29%) of the 426 nonvaccinated subjects (odds ratio, 3.6; 95% confidence
interval, 2.6-5.2). These differences were also present for tuberculin reactions
measuring 10 mm or more or 15 mm or more, but disappeared for reactions measuring
20 mm or more (Table 2). Overall,
the distribution of the size of reactions among employees who were vaccinated
with BCG was not different from that of nonvaccinated employees. No size criterion
(5, 10, 15, or 20 mm) could accurately separate reactions
caused by true infection from those caused by BCG vaccination.
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Table 2. Size of Initial Tuberculin Skin Test Reaction by BCG Vaccination
Status*
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Multivariate analysis of characteristics presented in Table 1 showed that, in addition to BCG vaccination, only age was
associated with a significant tuberculin reaction (P<.001).
The association between greater age and tuberculin reactivity was seen in
both vaccinated and nonvaccinated subjects. Among employees who were not BCG
vaccinated, a positive reaction was found in 18% of those younger than 30
years and in 64% of those older than 50 years. Similarly, among BCG-vaccinated
employees, a positive reaction was found in 52% and 71% of subjects younger
than 30 years and older than 50 years, respectively. The differences in tuberculin
reactivity among vaccinated and nonvaccinated employees were present in all
age categories considered, except in those older than 50 years. Other factors,
such as the sex of patients, the departmental group, the degree of contact
with patients, or previous administration of the tuberculin test, were not
found to be predictive of a positive tuberculin reaction.
THE BOOSTER EFFECT
Of the 399 employees who had a negative tuberculin test, 374 (94%) underwent
a second test 1 to 3 weeks later. For different reasons, 5 BCG-vaccinated
and 20 non–BCG-vaccinated employees did not receive a second test. A
positive booster reaction (a difference of 5 mm between the first and
the second tests) was observed in 90 subjects (23%); a difference of 10 mm
or more was observed in 78 subjects (20%) (P = .3).
As for the first tuberculin test, BCG vaccination had a significant effect
on the boosting phenomenon (Table 3).
Of the 91 hospital employees vaccinated with BCG who had a second tuberculin
test, 39 (43%) had a positive booster reaction, compared with 51 (18%) of
283 employees who were not vaccinated (odds ratio, 3.4; 95% confidence interval,
2.0-5.7). As seen in Table 3,
BCG vaccination affected the booster reaction no matter what definition of
the booster effect (10 or 15 mm) was considered.
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Table 3. Booster Effect Among Hospital Employees According to BCG Vaccination
Status*
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In univariate analysis, greater age was significantly associated with
a positive booster reaction (P = .003), in both vaccinated
and nonvaccinated employees. The effect of BCG vaccination on the booster
reaction was found in all the age categories considered, although no conclusions
could be obtained for employees older than 50 years because of the small number
of subjects in this category who underwent a second test. In multivariate
analysis, only BCG vaccination was associated with a positive booster effect.
PREDICTIVE VALUE OF A TUBERCULIN REACTION IN BCG-VACCINATED EMPLOYEES
Table 4 shows the overall
sensitivity, specificity, and positive predictive value of different tuberculin
reactions to establish tuberculosis infection in an employee of our hospital
with remote BCG vaccination. The size of the reaction affects the positive
predictive value of a positive test, which ranges from 48% for reactions of
5 mm or more to 67% for reactions of 15 mm or more. As previously stated,
we have assumed, to make these calculations, that a tuberculin reaction of
5 mm or more has a sensitivity of 100% and a specificity of 100% in persons
not vaccinated with BCG in our area.
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Table 4. Sensitivity, Specificity, and Positive Predictive Value of
Different Tuberculin Reactions and Different Definitions of Booster Reactions
in Hospital Employees With Remote BCG Vaccination*
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Since age was found to be independently associated with a positive tuberculin
test, calculations were made that took into account the age of the employee
(Table 5). As expected, the predictive
value of a positive test increases with the size of the reaction and with
the age of the employee, ranging from 37% in subjects younger than 30 years
with reactions of 5 mm or more to 100% in subjects older than 50 years with
reactions of 15 mm or more.
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Table 5. Positive Predictive Value of Different Tuberculin Reactions
According to Age in Hospital Employees With Remote BCG Vaccination*
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With regard to the interpretation of a booster effect in a BCG-vaccinated
hospital employee, the predictive value of a positive test was low whatever
definition was considered (Table 4).
The use of more stringent criteria, ie, greater difference between the second
and the first tests, results in diminished sensitivity with no improvement
in the positive predictive value. Reactions of 15 mm or more appear to be
highly specific and, thus, not attributable to vaccination with BCG.
COMMENT
In this prospective survey of tuberculin reactivity among hospital employees
in an area with a high prevalence of tuberculosis, we found that age and BCG
vaccination, given between approximately 15 and 30 years earlier, are major
determinants of the tuberculin reaction. In this setting, the interpretation
of a tuberculin reaction in a BCG-vaccinated subject must take into account
the age, the size of the reaction, and the local prevalence of tuberculosis
infection. No single criterion, however, can accurately separate reaction
caused by true infection from that caused by BCG vaccination. The boosting
phenomenon is also largely affected by previous BCG vaccination. In 2-step
tuberculin testing, large reactions with the second tuberculin test have a
high specificity, but the predictive value of tuberculosis infection is low.
Previous reports have evaluated the effect of BCG vaccination on tuberculin
reactivity in different population groups, with results ranging from 0% to
90% of significant reactions in vaccinated subjects.19-21
This variability seems to be influenced by multiple factors, including the
type and infecting dose of the BCG vaccine used, the number of vaccinations,
the age at vaccination, the time interval from vaccination to tuberculin testing,
and the effect of repeated tuberculin testing.21-24
In a community-based survey in Quebec, the authors found that the most important
determinant of effect of BCG vaccination on tuberculin reactivity was the
age at which the subject was vaccinated (7.9% of the subjects who had been
BCG vaccinated in the first year of life had significant reactions compared
with 18.3% and 25% of those who had been vaccinated at 2-5 years and at 6
years or older, respectively).24 Unfortunately,
we have not been able to confirm these findings in our study, since the age
of BCG vaccination was lacking in the vast majority of cases. However, we
have found that the age of the hospital employee was highly predictive of
a positive reaction. In an area where tuberculosis is highly prevalent, an
increasing chance of older employees being exposed to tuberculosis sources
in the hospital setting, as well as in the community, is the most likely explanation
for this finding. This is supported by the fact that the influence of age
on the tuberculin reaction affects persons who have been vaccinated with BCG
and, even more significantly, persons who have not been vaccinated.
Despite the findings of different studies, it is unclear at present
how to interpret a significant tuberculin reaction in hospital employees who
received BCG vaccination long ago, and what recommendations are to be given.
From previous reports, it seems clear that positive tuberculin reactions in
persons vaccinated in the first year of life should be regarded as indicative
of tuberculosis infection.24 In the case of
persons who have been BCG vaccinated later in life, more than 1 factor should
be considered before a recommendation can be made. The size of the reaction
has been shown to have some predictive value in several studies, with a trend
to larger indurations in persons with true infection. Since the predictive
value of a positive test is highly affected by the expected prevalence of
the disease in the population, the local prevalence of tuberculosis infection
is of great importance in decision making. From the findings of this study,
we have calculated the positive predictive value of different tuberculin reactions
in BCG-vaccinated persons according to the expected prevalence of tuberculosis
infection in a given area (Table 6). These data highly agree with those calculated by Menzies and Vissandjee,24 based on their survey in Quebec. Both the expected
prevalence and the size of the reaction determine the probability that a person
is infected with M tuberculosis. Since the prevalence
of tuberculosis infection is expected to be higher in older people, age is
an additional factor to be considered, especially when prevalence rates are
unknown. It should be noted that the interpretation of the test results may
be different for areas with different conditions, such as a higher prevalence
of atypical mycobacteria.
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Table 6. Positive Predictive Value of Different Tuberculin Reactions
in Persons With Remote BCG Vaccination According to Expected Prevalence of
Tuberculosis Infection
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Of special importance in health care personnel and other hospital employees
is the interpretation of the booster effect after 2-step tuberculin testing.7 Booster reactions have been associated with previous
BCG vaccination or sensitization with atypical mycobacteria,22, 25-27
and a recent study from Canada found that tuberculous infection was rarely
the cause of a booster effect in young adults.27
Only 2.5% of the students who were not BCG vaccinated had a positive booster
reaction, in contrast to 10.1% of those who were BCG vaccinated. In our population
of hospital employees, with a prevalence of tuberculous infection higher than
that among young students in Quebec, tuberculous infection seems not to be
uncommon as a cause of a positive booster effect. Up to 22% of persons not
vaccinated with BCG had a significant reaction with the second tuberculin
test, with a much higher rate in persons who were BCG vaccinated (43%). It
is unlikely that factors other than tuberculous infection, such as greater
age or atypical mycobacteria, might explain this observation. Multivariate
analysis failed to show an association between a positive booster effect and
age in our study, and atypical mycobacterioses are extremely rare in our area.12, 18 Thus, it seems that a high prevalence
of tuberculous infection may result in frequent positive booster reactions,
even in young people. In these groups, routine 2-step tuberculin testing should
be considered in settings other than periodic testing of hospital personnel.
The interpretation of the test results, both initial tuberculin and the booster
reaction, may be different for areas with different conditions, such as a
higher prevalence of atypical mycobacteria. However, even in areas or countries
with a high prevalence of atypical mycobacterioses, the local prevalence of
tuberculosis continues to be the major factor to be considered for an adequate
interpretation of the tests.
The predictive value of a positive booster effect in BCG-vaccinated
persons is low, regardless of the definition considered. Large reactions (a
difference of 15 mm between the second and the first tests) have high
specificity but do not significantly increase the predictive value. Practical
decisions, such as recommendation of chemoprophylaxis to hospital employees,
must take into account other factors because of the high rate of false-positive
results. As with the initial tuberculin test, the prevalence of tuberculosis
infection is possibly the major determinant.
AUTHOR INFORMATION
Accepted for publication December 4, 2000.
Corresponding author and reprints: Santiago Moreno, MD, Servicio
de Enfermedades Infecciosas, Hospital Ramón y Cajal, Ctra de Colmenar,
Km 9,100, 28034 Madrid, Spain (e-mail: smoreno{at}hrc.insalud.es).
From the Department of Clinical Microbiology and Infectious Diseases,
Hospital General Universitario José Ma Morales Meseguer,
Murcia, Spain. Dr Moreno is now with the Department of Infectious Diseases,
Hospital Ramón Cajal, Madrid, Spain.
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