https://doi.org/10.5812/compreped.67098

Complications of Bacillus Calmette-Guérin Vaccination at a University Hospital in Iranian Neonates

authors:

avatar Soheila Siroosbakht ORCID 1 , avatar Bijan Rezakhaniha ORCID 2 , *

Department of Pediatrics, Military University of Medical Sciences, Tehran, Iran
Faculty of Medicine, Military University of Medical Sciences, Tehran, Iran
Journal of Comprehensive Pediatrics: Vol.10, issue 1; e67098
published online: November 27, 2018
article type: Research Article
received: February 4, 2018
revised: June 13, 2018
accepted: August 2, 2018

how to cite: Siroosbakht S, Rezakhaniha B. Complications of Bacillus Calmette-Guérin Vaccination at a University Hospital in Iranian Neonates. J Compr Ped. 2019;10(1):e67098. https://doi.org/10.5812/compreped.67098.

Abstract

Background:

The most common complications of Bacillus Calmette-Guérin (BCG) vaccine are lymphadenopathy, lymphadenitis, abscess, and fistula. These occur in less than one percent of vaccinated individuals. The aim of this study was to determine the frequency of these side-effects in Iranian neonates at a university hospital.

Objectives:

The researchers decided to study the new results of BCG vaccine complications at the university center and compare them with previous results from Iran and other countries until the relative position of Iran was identified.

Methods:

In a prospective, descriptive-analytical study with the census method, 214 neonates at Golestan Hospital of Tehran, Iran from May 2015 to Jan 2018 were studied. Bacillus Calmette-Guérin vaccination was performed for all these neonates at the hospital. The neonates were examined on a monthly basis by a physician and the questionnaires were completed.

Results:

In this study, the rate of lymphadenopathy, lymphadenitis, and fistulization of the abscess after BCG vaccination were 2.5%, 0.5%, and 0%, respectively. No significant difference was observed between gender and age of the infants and the occurrence of the complications (P > 0.05).

Conclusions:

This study showed a higher rate of lymphadenopathy and lymphadenitis after BCG vaccination compared with other studied countries. Various factors are involved in making this difference, such as inaccuracy in the injection site and injection method, improper dilution and type of vaccine manufacturer, and a more immunogenic vaccine (Pasteur Company, Tehran). Therefore, health authorities should help reduce the incidence of complications of BCG vaccination with continuous education of the vaccination unit personnel, monitoring the preservation and method of vaccine preparation and change of the vaccine strain.

1. Background

Tuberculosis (TB) is one of the most prevalent infectious diseases, and is the second cause of death due to infection. The most important ways to prevent tuberculosis are improving the socio-economic conditions, early diagnosis and treatment, chemical preventive measures for more susceptible groups and Bacillus Calmette-Guérin (BCG) vaccination (1). The vaccine stimulates the immune system of cells and thereby creates protection against TB infection. Furthermore, BCG is recommended for neonates in countries where there is a high occurrence rate of TB. Vaccination at birth is up to 80% effective against disseminated and meningeal TB and protection against pulmonary forms of TB in children is 50% (2).

According to the vaccination program of the World Health Organization (WHO), one dose of BCG should be administered to neonates in developing countries. A second dose is prescribed for some more inflicted countries. Children under one year of age should be given half a dose. In Iran, BCG is used in children at birth with a concentration of 0.05 mL (half dose) and in over one-year-olds with a concentration of 0.1 mL (full dose). The vaccine itself should be kept at 2 to 8°C and away from light. An opened vial should be only used in only one day. Currently, the only proposed route for BCG vaccination is intradermal, which provides a better immune response than the percutaneous route (3).

Teo et al. reported that incidence of complications was 31/10000 vaccinated infants from many countries (2). Common side-effects include topical rash and regional lymphadenitis. Fever, convulsion, loss of appetite, and irritability are rare side effects. Other side effects are rather rare, such as BCG osteomyelitis and adenitis with oral candidiasis, which suggests an underlying immunodeficiency (4). Also, there is disseminated BCG infection, a rare condition, which may affect those with impaired immune systems and occurs in one of 10 million vaccinated individuals. Supportive lymphadenitis on the other hand is one of the severe complications after BCG vaccination (5). Most BCG complications are a local disease (6). In Iran, all children are vaccinated at birth yet limited data exists on the occurrence of side-effects. Considering the fact that physician’s skills and their observance of dosage and vaccination method may influence the rate of occurrence of the above mentioned side-effects, the current study aimed at investigating the frequency of these side-effects in Iranian neonates at a university hospital. Therefore, it was decided to study the new results of BCG vaccine complications at a university center and compare them with previous results from Iran and other countries, until the relative position of Iran was identified.

2. Methods

2.1. Study Population

In a prospective descriptive-analytical study with the census method, 235 age and gender matched neonates at outpatient clinics of the General Hospital of Golestan, Tehran, Iran from May 2015 to Jan 2018 were studied. Exclusion criteria were congenital abnormalities, structural deformities, neurologic disease, immunologic, allergic, and atopic skin diseases. Neonates born at hospitals were included in the study. The used vaccine belonged to the Pasteur Company (No.: 95bco12). The dosage was 0.05 mL and intradermal injection was done for vaccination. All these neonates were vaccinated by one person. A questionnaire and checklist was added to each of the neonate’s medical file. The neonates were examined monthly by a physician and the questionnaires were filled.

From a total of 235 neonates, 21 were later excluded because they did not refer back to the hospital. Finally, 214 neonates regularly underwent medical inspection for lymphadenopathy, lymphadenitis, abscess, and fistula. Lymphadenopathy was defined as enlargement of lymph nodes in axillar or neck, and supraclavicular areas. Lymphadenitis was based on the large lymph node with redness and fluctuation on palpation (7). All vaccinated infants were followed up monthly until nine months of age and all relevant data was recorded.

2.2. Statistical Analyses

Data analysis was performed using SPSS version 16.0 (SPSS Inc, Chicago, IL, USA) and the Chi-square statistical test was used to establish whether any meaningful relationship exists between occurrence rates and each one of the two variables “age at vaccination” and “gender”. The P value of < 0.05 was considered significant.

3. Results

In this study, 214 neonate, 110 males (51%) and 104 females (49%), were studied (P = 0.81). Side-effects were observed in six neonates (3%) and the remaining 208 (97%) showed no signs of side-effects. Among the complications, five neonates had lymphadenopathy (three males and two females) (2.5%); four axillaries, one supraclavicular, and one neonate (female) (0.5%) with axillary lymphadenitis were observed and there was no statistical significant difference between genders (P = 0.68) (Table 1). Also, no abscess and fistula were seen in any of the neonates.

Table 1.

The Frequency of Complication in Neonates in Each Gendera

Total, %Boy, %Girl, %P Value
Lymphadenopathy5 (2.5)3 (1.5)2 (1)0.68
Lymphadenitis1 (0.5)0 (0)1 (0.5)
Absess and Fistula0 (0)0 (0)0 (0)

a No statistical significant between the both sex (P = 0.68).

The time of occurrence of complications from vaccination were studied in all of neonates and there was no statistical significant difference between the time of occurrence of complications and age (P = 0.87) (Table 2).

Table 2.

Time of Occurrence of Side Effects of BCG Vaccination in Neonatesa

Total, %Lymphadenopathy, %Lymphadenitis, %Abscess and Fistula, %P Value
Under 1 month1 (16.6)1 (20)0 (0)0 (0)0.87
1 month old age1 (16.6)1 (20)0 (0)0 (0)
2 months old age3 (50.2)3 (60)0 (0)0 (0)
3 months old age1 (16.6)0 (0)1 (100)0 (0)
4 months old age0 (0)0 (0)0 (0)0 (0)
5 months old age0 (0)0 (0)0 (0)0 (0)
6 months or older0 (0)0 (0)0 (0)0 (0)

a No statistical significant between the time of occurrence of complication was seen (P = 0.87).

4. Discussion

This study showed the frequency of different side-effects of BCG vaccination. In the current study, greater incidence of complications was observed compared with other countries. The cause of this was not known. This may be related to the strain of the vaccine or vaccination methods. In others studies, topical lymphadenopathy and supportive lymphadenopathy were seen among BCG vaccination in a few children. Usually, lymphadenopathy appears in the axillar or on the neck at the side where an injection has been done. These lymphadenopathies sometimes change to lymphadenitis and a few of these may change to abscess and eventually become fistula that is relatively rare (8).

In the current study, 3% occurrence of side-effects was observed, of which 2.5% were lymphadenopathies and 0.5% were lymphadenitis. These are higher than usual occurrence rates. Several studies have been carried out on the incidence of BCG vaccine complications. Some examples for occurrence rates of lymphadenopathy are: 2.2% in Semnan province in Iran (9), 0.7% in Chile (10), 5% in Zimbabwe (11), 0.7% in Turkey (12), 1% in Canada (13), 1.9% in Jamaica (14), and 0.5% in South Africa (15).

Also, some occurrence rates of lymphadenitis have been reported as: 0.54% for Semnan province in Iran (9), 0.3% in Turkey (12), 0.018% in South Africa (15), 0.03% in Brazil (16), 0.02% in Japan (17), and 0.03% in Europe (18). Several factors are involved in causing these complications, including dosage, age of vaccination, place of vaccination, method of injection, method of preparation of vaccine, brand, characteristics of the subjects studied and skills of the individuals, who inject the vaccine (13). In the study of Fretzayas et al., although the dose was divided to 0.025 ML in both arms, the incidence of lymphadenitis did not decrease and in some cases bilateral lymphadenitis occurred (19).

Another study confirmed that the type and strain of vaccine was considered to be effective in the incidence of lymphadenitis, and they believed that a change in the strain of vaccine would be effective (20).

In the present study, lymphadenitis was observed in a three-month-old infant and lymphadenopathy was found up to two months of age. There was no significant difference between BCG vaccine complications and gender, which is consistent with previous studies (9, 17, 18).

Meanwhile, there were no complications after three months old in this study, which is consistent with WHO and Jamaica studies (12-14). On the other hand, no fistula and abscess were observed in this study. On the contrary, several studies reported rare cases of fistula and abscess formation after BCG vaccination (21, 22).

This study showed that lymphadenopathy and lymphadenitis due to BCG vaccination is higher than that of other countries. However, the complications of abscess and fistula, which were rarely seen in other countries, were never seen in this study.

Various factors are involved in making this difference, such as inaccuracy at the injection site and injection method, improper dilution and type of vaccine manufacturer, and probably a more immunogenic vaccine (Pasteur Company, Tehran). Therefore, health authorities can help reduce the incidence of complications of BCG vaccination with continuing education of the vaccination unit personnel, monitoring the preservation and method of vaccine preparation and a change of vaccine strain. It is strongly recommended that the process of vaccination is closely monitored in regards to such factors.

Acknowledgements

References

  • 1.

    Chacon-Cruz E, Arellano-Estrada JL, Lopatynsky-Reyes E, Alvelais-Palacios J, Becka C. Children with lymphadenitis associated with Bacillus Calmette-Guerin (BCG) vaccination do not experience more infections when compared with BCG-vaccinated children without lymphadenitis: A three years paired-cohort in Mexico. Ther Adv Vaccines. 2017;5(4-5):103-7. [PubMed ID: 29201375]. [PubMed Central ID: PMC5697593]. https://doi.org/10.1177/2051013617741585.

  • 2.

    Teo SS, Smeulders N, Shingadia DV. BCG vaccine-associated suppurative lymphadenitis. Vaccine. 2005;23(20):2676-9. [PubMed ID: 15780451]. https://doi.org/10.1016/j.vaccine.2004.07.052.

  • 3.

    Hawkridge A, Hatherill M, Little F, Goetz MA, Barker L, Mahomed H, et al. Efficacy of percutaneous versus intradermal BCG in the prevention of tuberculosis in South African infants: Randomised trial. BMJ. 2008;337. a2052. [PubMed ID: 19008268]. [PubMed Central ID: PMC2583390]. https://doi.org/10.1136/bmj.a2052.

  • 4.

    Hatipoglu N, Guvenc BH, Deswarte C, Koksalan K, Boisson-Dupuis S, Casanova JL, et al. Inherited IL-12Rbeta1 deficiency in a child with BCG adenitis and oral candidiasis: A case report. Pediatrics. 2017;140(5). [PubMed ID: 29025965]. [PubMed Central ID: PMC5654388 conflicts of interest to disclose]. https://doi.org/10.1542/peds.2016-1668.

  • 5.

    Baek SO, Ko HS, Han HH. BCG vaccination-induced suppurative lymphadenitis: Four signs to pay attention to. Int Wound J. 2017;14(6):1385-7. [PubMed ID: 28425207]. https://doi.org/10.1111/iwj.12755.

  • 6.

    Bolursaz MR, Lotfian F, Velayati AA. Bacillus Calmette-Guerin vaccine complications in Iranian children at a university hospital. Allergol Immunopathol (Madr). 2017;45(4):356-61. [PubMed ID: 28161281]. https://doi.org/10.1016/j.aller.2016.10.006.

  • 7.

    Lotte A, Wasz-Hockert O, Poisson N, Dumitrescu N, Verron M, Couvet E. BCG complications. Estimates of the risks among vaccinated subjects and statistical analysis of their main characteristics. Adv Tuberc Res. 1984;21:107-93. [PubMed ID: 6475644].

  • 8.

    Behjati M, Ayatollahi J. Post BCG lymphadenitis in vaccinated infants in Yazd, Iran. Iran J Pediatr. 2008;18(4):351-6.

  • 9.

    Seyfhashemi M, Hamedi A, Mazaheri M, Azarbarin A, Hamedi P. Complication of BCG vaccination in children. Iran J Pediatr. 2005;15(3):209-14.

  • 10.

    Tidajani O, Amedome A. The protective effect of BCG vaccination of the newborn against childhood tuberculosis in Chile. Tubercle J. 1985;67:269-81.

  • 11.

    Ray CS, Pringle D, Legg W, Mbengeranwa OL. Lymphadenitis associated with BCG vaccination: A report of an outbreak in Harare, Zimbabwe. Cent Afr J Med. 1988;34(12):281-6. [PubMed ID: 3252979].

  • 12.

    Sirinavin S, Chotpitayasunondh T, Suwanjutha S, Sunakorn P, Chantarojanasiri T. Protective efficacy of neonatal Bacillus Calmette-Guerin vaccination against tuberculosis. Pediatr Infect Dis J. 1991;10(5):359-65. [PubMed ID: 2067885].

  • 13.

    Milstien JB, Gibson JJ. Quality control of BCG vaccine by WHO: A review of factors that may influence vaccine effectiveness and safety. Bull World Health Organ. 1990;68(1):93-108. [PubMed ID: 2189588]. [PubMed Central ID: PMC2393003].

  • 14.

    Praveen KN, Smikle MF, Prabhakar P, Pande D, Johnson B, Ashley D. Outbreak of Bacillus Calmette-Guerin-associated lymphadenitis and abscesses in Jamaican children. Pediatr Infect Dis J. 1990;9(12):890-3. [PubMed ID: 2277745].

  • 15.

    Jeena PM, Chhagan MK, Topley J, Coovadia HM. Safety of the intradermal Copenhagen 1331 BCG vaccine in neonates in Durban, South Africa. Bull World Health Organ. 2001;79(4):337-43. [PubMed ID: 11357213]. [PubMed Central ID: PMC2566397].

  • 16.

    de Souza GRM, Sant'Anna CC, e Silva JRL, Mano DB, Bethlem NM. Intradermal BCG vaccination complications—analysis of 51 cases. Tuberculosis. 1983;64(1):23-7.

  • 17.

    Jou R, Huang WL, Su WJ. Tokyo-172 BCG vaccination complications, Taiwan. Emerg Infect Dis. 2009;15(9):1525-6. [PubMed ID: 19788832]. [PubMed Central ID: PMC2819856]. https://doi.org/10.3201/eid1509.081336.

  • 18.

    Casanova JL, Blanche S, Emile JF, Jouanguy E, Lamhamedi S, Altare F, et al. Idiopathic disseminated bacillus Calmette-Guerin infection: A French national retrospective study. Pediatrics. 1996;98(4 Pt 1):774-8. [PubMed ID: 8885960].

  • 19.

    Fretzayas A, Moustaki M, Stefos E, Nicolaidou P. Splitting the dose of neonatal BCG vaccination: A naive practice. Ann Trop Paediatr. 2009;29(3):243-5. [PubMed ID: 19689870]. https://doi.org/10.1179/027249309X12467994694210.

  • 20.

    Alrabiaah AA, Alsubaie SS, Bukhari EI, Gad A, Alzamel FA. Outbreak of Bacille Calmette-Guerin-related lymphadenitis in Saudi children at a university hospital after a change in the strain of vaccine. Ann Saudi Med. 2012;32(1):4-8. [PubMed ID: 22156633]. [PubMed Central ID: PMC6087637].

  • 21.

    Middelburg TA, Snels DG, van Praag MC, Rudolphus A, Arend SM, Verhard EM, et al. A rare complication of BCG vaccination. Int J Dermatol. 2009;48(5):546-8. [PubMed ID: 19416395]. https://doi.org/10.1111/j.1365-4632.2009.03644.x.

  • 22.

    Brantsaeter AB, Romanus V, Andersen PH, Heldal E. Evidence of protective effect of BCG vaccination in persons at low risk of tuberculosis in Nordic countries. Int J Tuberc Lung Dis. 2009;13(4):440-5. [PubMed ID: 19335948].