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Table of Contents
Year : 2022  |  Volume : 27  |  Issue : 2  |  Page : 114-119

Tuberculin conversion rate after BCG vaccination of apparently healthy infants in a resource-poor setting

1 Department of Paediatrics, University of Nigeria Teaching Hospital Ituku-Ozalla, Enugu, Enugu Campus, Nigeria
2 Department of Paediatrics, College of Medicine, University of Nigeria, Enugu, Enugu Campus, Nigeria

Date of Submission22-Mar-2021
Date of Decision04-Oct-2021
Date of Acceptance21-Nov-2021
Date of Web Publication3-Mar-2022

Correspondence Address:
Kenechukwu Kosisochukwu Iloh
Department of Paediatrics, University of Nigeria Teaching Hospital Ituku-Ozalla, Enugu.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijmh.IJMH_9_21

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Background: Although Bacillus Calmette Guerin (BCG) vaccine remains one of the most important public health preventive measures against tuberculosis (TB), the presence of a BCG scar may not imply an immune response. Tuberculin reactivity after BCG vaccination has been the most common measure of the effect of the BCG vaccine. Post-vaccination BCG-induced tuberculin reactivity ranges from no induration to an induration diameter of 15 mm. However, tuberculin conversion in infants is usually about 10 mm in more than 90% of infants tested at 12 weeks post-vaccination age. Objective: This study sought to assess the tuberculin conversion rate after BCG vaccination. Materials and Methods: It was a hospital-based cross-sectional study. Two hundred and eighty (280) infants aged 13 to 15 weeks who received BCG vaccination within one month of birth were enrolled. The BCG scar diameter was measured, and Mantoux test was done. Data were analyzed by using the Statistical Package for Social Sciences (SPSS), version 20 (Chicago Il). Results: Among the 280 BCG-vaccinated infants, tuberculin conversion rate was 64%, whereas scar failure rate was 28.9%. Overall, 75.9% of infants with a BCG scar had a positive Mantoux test. The BCG-vaccinated infants with a BCG scar were about six times more likely to have a tuberculin conversion than those without a BCG scar (OR =5.641, 95% C.I = 3.227 to 9.859). Conclusion: There was a 64% conversion rate among the BCG-vaccinated infants. The presence of the BCG scar correlated well with the tuberculin conversion rate.

Keywords: BCG, Mantoux, scar failure, tuberculin conversion

How to cite this article:
Enemuo EJ, Iloh KK, Ubesie AC, Okafor HU, Ikefuna AN. Tuberculin conversion rate after BCG vaccination of apparently healthy infants in a resource-poor setting. Int J Med Health Dev 2022;27:114-9

How to cite this URL:
Enemuo EJ, Iloh KK, Ubesie AC, Okafor HU, Ikefuna AN. Tuberculin conversion rate after BCG vaccination of apparently healthy infants in a resource-poor setting. Int J Med Health Dev [serial online] 2022 [cited 2022 Dec 7];27:114-9. Available from: https://www.ijmhdev.com/text.asp?2022/27/2/114/339036

  Introduction Top

TB is a chronic inflammatory disease caused by the bacillus, Mycobacterium Tuberculosis and it affects more than 30% of the world’s population.[1] Developing countries bear the brunt of TB burden due to poverty, overcrowding, and unhygienic living conditions.[1],[2] According to the World Health Organization (WHO) 2013 TB report, 530,000 new cases of TB occurred worldwide among children in 2012.[3] In areas of sub-Saharan Africa, where human immunodeficiency virus (HIV) is the most prevalent, more than a third of HIV-infected individuals are coinfected with TB.[4] Nigeria was ranked 10th among the 22 high-burden TB countries in the world in 2010.[5]

Vaccination with the BCG remains one of the most important preventive measures and the only available vaccine against TB, offering varying degrees of protection ranging from 0 to 80%.[1],[2] However, its protective effect for disseminated TB appears to be higher (50–80%).[1],[6] Since its inception and use, several strains have been applied that differ widely in characteristics. Host immune response and hence, protection also differs after vaccination irrespective of BCG scar formation. These differences have been attributed to the age at vaccination, vaccine strain, methodological variation, nutritional status, and concurrent as well as chronic infections.[2] Tuberculin skin testing (TST) is a procedure resulting in the development of a delayed hypersensitivity reaction to tuberculin protein.[1],[7] This reaction typically follows infection with the tubercle bacilli but may also follow previous BCG vaccination. Post-vaccination BCG-induced tuberculin reactivity ranges from no induration to an induration diameter of 15 mm.[7] However, tuberculin conversion in infants is usually about 10 mm in more than 90% of infants tested at 12 weeks post-vaccination age.[1],[7],[8] Hence, tuberculin reactivity after BCG vaccination has been the most common measure of the effect of the BCG vaccine.[8] Despite certain drawbacks, TST remains in widespread use due to its advantages of low cost, availability, simplicity, and interpretation.[9] This study sought to evaluate the tuberculin conversion rate after BCG vaccination in apparently healthy infants at the University of Nigeria Teaching Hospital.

  Materials and Methods Top

The study was conducted at the Institute of Child Health (ICH), University of Nigeria Teaching Hospital (UNTH) Ituku-Ozalla, Enugu. Enugu state lies about 223m above sea level, is located in the tropical rain forest zone, and has a tropical savannah climate. Its climate is humid with a mean daily temperature of 26.7°C. The average annual rainfall in Enugu is about 2000 mm. The ICH of the UNTH offers a range of child health services: immunization, growth monitoring, research, health education, training, counseling, child health clinics, school health programs, nutritional rehabilitation, and community outreach. An average of 15–25 infants and 70–100 infants are vaccinated with the BCG vaccine weekly and monthly, respectively, at the ICH and UNTH (giving about 1000 infants on an average annually).

This was a hospital-based cross-sectional study on infants aged 13–15 weeks who presented at the ICH for routine immunization Sample size was calculated by using the Cochrans formula. Healthy term infants delivered between 37 and 42 weeks gestation, aged 13–15 weeks at the time of enrollment, who had evidence of BCG vaccination within 28 days of birth, and whose parents consented to the study were included. Infants who received BCG vaccination outside the Institute or were malnourished or sick were excluded from the study. In addition, infants with a history of close contact with an adult with known pulmonary TB or who had a chronic cough for more than two weeks were excluded.

Ethical considerations

The approval to conduct this study was obtained from the Health Research and Ethics Committee (HREC) of UNTH, Ituku-Ozalla. Thumb-printed and/or signed informed consent was obtained from the parents/guardians of the children.

Administration of the questionnaire

A pretested questionnaire was administered to the parent(s)/caregiver(s) to obtain information such as postnatal age approximated in weeks, gestational age at birth approximated in weeks, birth weight, sex, place of domicile, and age at BCG vaccination. The gestational age at birth was calculated by determining/subtracting the time elapsed from the mothers’ last menstrual period to the date of birth or from the expected date of delivery (EDD) to the actual date of delivery.

During the visit, the infant’s weight, length, and occipitofrontal circumference were measured and values were documented.

BCG scar assessment

Each infant’s right and left deltoid regions were inspected for the presence of a BCG scar. The transverse diameter of each scar was measured by using a transparent calibrated rule and documented. Infants with a complete absence of scar were regarded as having scar failure.

Mantoux test procedure

Parents/caregivers received pretest counseling on the benefits and complications of the Mantoux test. The site for the test was the volar surface of the right forearm about 5 cm from the cubital fossa. An area devoid of superficial veins, rash, scars, or excess skin hair was selected, cleansed with a methylated spirit swab, and allowed to air-dry. Thereafter, 0.1ml containing 5TU of the purified protein derivative (PPD) was withdrawn into a 1.0-mL syringe with a size 27G steel needle. The PPD was manufactured under license by ARKRAY Healthcare Pvt. Ltd, India, with License number G/28/1507 and LOT/Batch code number 000015205. Each was calibrated and standardized against batch PPD RT 23 manufactured by Staten Serum Institute Copenhagen (one of the two WHO-accepted standard tuberculins) and diluted in 0.005% of tween 80 that served as a stabilizer. The PPD was stored unfrozen in a refrigerator, transported in an ice pack, and kept in a flask, away from light. Each vial was exhausted within 30 days of first use.

With the forearm slightly flexed and the skin held taut, PPD was injected intra-dermally into the volar surface of the left forearm with the beveled surface facing upward and at an angle of five to fifteen degrees from the skin.[7],[10],[11] The sites of infiltration were immediately observed for a wheal measuring 6 to 10 ml in diameter: an indication of appropriateness of the technique.[10],[11] The absence of a wheal or any wheal measuring less than 6 ml at the site of inoculation necessitated a repeat testing done on the contralateral arm.[10],[11] In circumstances where bleeding occurred at the site of inoculation, it was gently dabbed using a dry piece of cotton wool. Using an indelible marker, the area was identified circumferentially, giving a margin of about 0.5 cm around the wheal. The infants were subsequently observed for 15 min signs of allergic reaction to the tuberculin before being allowed home. None of the infants reacted adversely to the PPD. Appointments were scheduled 48 h later.

Mantoux test reading

At the time of the scheduled appointments, each infant’s proforma was retrieved and the personal information was confirmed to avoid errors. The site of Mantoux inoculation was examined by both inspection and palpation for any induration.[11],[12] The margins of the induration were marked by using the ball point pen method[11],[12],[13] and measured with a transparent calibrated rule, perpendicular to the longitudinal axis of the forearm.[7],[10] The degree of immune response to BCG was ascertained by the diameter of Mantoux induration. The largest diameters of Mantoux induration were recorded and classified as negative (<10 mm) and positive (≥10 mm).[10] Infants with indurations of ≥ 10 mm were considered as having a tuberculin conversion and hence adequate immune response after BCG.[14] Post-test counseling was offered to the parents based on the findings of the test and its interpretation. A repeat BCG vaccination was recommended for infants without a BCG scar who had a negative Mantoux response.

Data analysis

The collected data were cleaned, coded, and entered into the SPSS, version 20.0 (SPSS Inc. Chicago, Illinois, USA). Quantitative variables were summarized by using mean and standard deviation, whereas categorical variables were used for frequencies and proportions. The student’s t test was used to compare the mean age at BCG vaccination among BCG scar positive and negative infants. The association between gender, tuberculin conversion, and the presence of BCG scar was tested by using the chi-square test. Odds ratio with a 95% confidence interval (CI) was used to determine the measure of association between gender, tuberculin conversion, and BCG scar formation. The relationship between scar diameter and degree of immune response was tested by using the Pearson correlation analysis at a 95% CI. The sensitivity and specificity of the BCG scar in determining tuberculin conversion, as well as the positive predictive value (PPV) and the negative predictive value (NPV) of the BCG scar were calculated, respectively. All tests were considered significant at a p-value less than 0.05.

  Results Top

A total of 290 infants between the ages of 13 and 15 weeks were enrolled into this study over a period of six months. Of these, 280 (96.6%) infants returned after 48 h for their Mantoux reading. There were a total of 143 (51.1%) males and 137 (48.9%) females, giving a male-to-female ratio of approximately 1:1. One hundred and forty-nine (53.2%) of the infants were enrolled at 14 weeks of age, as shown in [Table 1]. Two hundred and twenty-six (80.7%) of the 280 infants received BCG vaccination within the first week of life, of whom 90 (39.8%) were vaccinated within 48 h of birth. Thirty-four (12.1%), 11 (3.9%), and nine (3.2%) infants were vaccinated at 8–14, 15–21, and 22–28 weeks, respectively.
Table 1: Postnatal age and gender distribution of the BCG-vaccinated infants

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Tuberculin conversion

One hundred and eighty (64%) infants had tuberculin conversion, as evidenced by a positive Mantoux test response (induration diameter of at least 10 mm). Conversely, 100 (36%) subjects failed to demonstrate tuberculin conversion. Of the 143 males, 104 (72.7%) had a positive Mantoux response, compared with 76 (55.5%) of the 137 females (P = 0.003, OR = 2.140, 95% C.I = 1.300 to 3.525), as shown in [Table 2].
Table 2: Association between gender and tuberculin conversion

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BCG vaccination and scar failure

Of the 280 subjects studied, 199 (71.1%) developed BCG scars, whereas 81 (28.9%) had scar failure. However, among the 199 infants who had scars, 56 (28.1%) had scars less than 3 mm, and this represents 20% of all the BCG-vaccinated infants.

BCG scar diameter and degree of tuberculin response

The mean diameter of the BCG scar was 3.9 ±1.9 mm, whereas the mean diameter of Mantoux induration was 13.4 ± 4.2 mm. Pearson correlation between BCG scar diameter and degree of tuberculin response demonstrated a significant positive correlation between the two variables [Pearson correlation (r) = 0.477, P < 0.001].

Of the 199 subjects with a BCG scar, 151 (75.9%) had a positive Mantoux, whereas 29 (35.8%) of those without a scar had tuberculin conversion (χ2 = 40.273, P < 0.001). The BCG-vaccinated infants with a BCG scar were about six times more likely to have a tuberculin conversion than those without a BCG scar (OR =5.641, 95% C.I = 3.227 to 9.859).

The sensitivity of the BCG scar in determining tuberculin response after BCG vaccination was 83.9%, whereas the specificity was 52%. Among infants with a BCG scar, the probability of tuberculin conversion (the PPV) was 75.9%. However, among infants without a BCG scar, the probability of a negative tuberculin response (the NPV) was 64.2%. The sensitivity, specificity, PPV, and NPV are observed in [Table 3].
Table 3: Association between the presence of BCG scar and Mantoux response

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As shown in [Table 4], among the 199 infants who had a BCG scar, 143 (71.9%) had scars that were at least 3 mm in diameter, whereas 56 (28.1%) had scars that were less than 3 mm in diameter. Of the 143 infants with a scar diameter of 3 mm and above, 124 (86.7%) had a positive Mantoux compared with 27 (48.2%) of the 56 infants with scar diameters less than 3 mm. Infants with scar diameters of 3 mm and above were seven times more likely to have tuberculin conversion after BCG vaccination than infants with scar diameters of less than 3 mm (P < 0.001, OR= 7.010,CI = 3.437 – 14.296).
Table 4: Association between BCG scar size and Mantoux response

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Age at BCG scar vaccination and BCG scar formation

The BCG scar was present in 58 (64.4%) of the 90 infants who received BCG vaccination within the first two days of birth but it was absent in 32 (35.6%) infants. Also, the BCG scar was also present in 141 (74.2%) infants and absent in 49 (25.8%) of the 190 infants who received BCG vaccination at or beyond the third day of life (χ2 = 2.833, P = 0.092). The mean ages at BCG vaccination among infants with and without a BCG scar were 5.9 ± 5.9 days and 4.8 ± 4.8 days, respectively (P = 0.079). Fifty-four of the 90 infants (60%) vaccinated within two days of birth, compared with 126 of the 190 infants (66.3%) vaccinated at or beyond the third day of life had a positive Mantoux response (χ2 = 1.061, P = 0.303). This is shown in [Table 5].
Table 5: Association between age at BCG vaccination and BCG scar formation

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  Discussion Top

The tuberculin conversion rate in this study was 64% irrespective of the presence or absence of a BCG scar. This shows that up to a third of the infants may not have achieved the desired immune response, hence they may still be at a risk of morbidity and mortality that is associated with severe forms of TB. The tuberculin conversion rate of 64% in this study is comparable to rates of 69.8% reported in Lagos, Nigeria,[14] 68.2% in Taiwan,[15] and 70.8% in Brazil[16] and it can be explained by a similarity in methodology. In contrast, higher conversion rates were documented in the Indian studies,.[17],[18] This disparity could be because tuberculin conversion was defined by Mantoux induration of ≤ 5 mm in the Indian studies. Although Faridi et al[19] in India documented a lower conversion rate, 2TU was administered to the study participants in contrast to 5TU used in this study. The response to Mantoux is documented to be dose dependent, with a peak induration identified by using 5TU of the PPD. Additional doses beyond 5TU have been shown not to provide any significant increase in the induration diameter.

There are conflicting reports in the literature regarding the effect of gender on tuberculin conversion. However, in this study, males were twice as likely as females to have a tuberculin conversion after BCG vaccination (OR= 2.140, P = 0.003). This finding was corroborated by Gambo et al.[20] in Northern Nigeria and Fine et al[21] in Northern Malawi. A previous study conducted in Southeast Nigeria by Ifezulike [22] reported no significant difference in tuberculin conversion rates in both genders. The reason for the male gender preference in tuberculin conversion demonstrated in this study may be due to speculations that males have a greater tendency than females to develop delayed hypersensitivity to mycobacterial antigens.

There was a high prevalence of scar failure in this study. Further, about two thirds of the infants without a BCG scar also failed to demonstrate tuberculin response, hence leaving no evidence of immunity from the BCG vaccine. Scar failure rates were lower in studies conducted in Northern Nigeria by Gambo et al,[20] (18.5%) in Peru by Santiago et al.[23] (1.4%), and in India by Aggarwal et al.[18] (0%). A possible explanation is that although this study included infants who were assessed for scar failure at about three months of age, the studies with lower scar failure rates were conducted on infants at or beyond six months of age. The earlier assessment of BCG scars in this study may have resulted in the exclusion of infants with a delayed scar process. Delays in scar formation have been documented to occur beyond six months and even after 1 year.[23] Faridi et al.[19] in India reported a higher scar failure rate of 52.8% but included preterm and low-birth-weight infants who were excluded in the current study. Preterm and low-birth-weight infants are less likely to mount adequate immune responses.

This study revealed a significant positive association between the presence of the scar and tuberculin conversion. There was also a moderate positive correlation between the diameter of the BCG scar and the diameter of Mantoux induration, with a high sensitivity (83.9%) of the BCG scar in determining immune response but a low specificity of 52%.The positive relationship between these two variables as well as the high sensitivity infers that the presence of a BCG scar is a good indicator of tuberculin conversion and is likely to determine the immune response to BCG. In addition, the larger the diameter of the BCG scar, the greater the degree of tuberculin response. However, the low specificity of the BCG scar in determining the tuberculin response infers that the absence of the BCG scar does not necessarily imply the absence of a tuberculin response.

We did not find any significant difference in the prevalence of scar formation and scar failure between infants who received BCG within 48 h of birth and those who received BCG after 48 h of birth. Similarly, the Mantoux response was not significantly different among infants whom received BCG within 48 h of birth and those whom received BCG after 48 h of birth. Hence, contrary to speculations, postnatal age at BCG vaccination did not affect the process of BCG scar formation as well as the rate of tuberculin conversion.

  Conclusion Top

We report a tuberculin conversion rate of 64% among BCG-vaccinated infants at the University of Nigeria Teaching Hospital, Enugu. The presence of a BCG scar was associated with a higher tuberculin response rate.

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Conflicts of interest

There are no conflicts of interest.

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[PUBMED]  [Full text]  
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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