Reports of lymphadenitis following administration of BCG Vaccine SSI®

HSA would like to update healthcare professionals on the suspected reports of lymphadenitis following the administration of the Bacillus Calmette-Guérin (BCG) Vaccine Staten Serum Institute (SSI)®. This observation arose from the active surveillance and monitoring of vaccine adverse events (VAEs) at the sentinel site at KK Women's and Children's Hospital (KKH).

In 2009, HSA collaborated with KKH to initiate active surveillance for VAEs related to H1N1 vaccines in pregnant women and children. This was subsequently expanded to include all VAEs following childhood immunisation. This active surveillance system is different from the spontaneous adverse drug reaction reporting system in that potential VAEs are identified from patients' medical record and vaccination history when patients are first admitted into the hospital.

In Singapore, BCG vaccine is routinely given to newborns as part of the National Childhood Immunisation Schedule. Since June 2003, the BCG vaccine manufactured by SSI is the sole BCG vaccine registered in Singapore. BCG Vaccine SSI® contains an attenuated strain of Mycobacterium bovis (BCG), Danish strain 1331.

Reports of lymphadenitis

Local reports (January 2009 to October 2011)

In 2009, there were 26 reports of BCG-associated lymphadenitis of which 23 cases (88%) presented as suppurative lymphadenitis*. Of these, 22 cases required surgical intervention such as excision or incision and drainage; one case was lost to follow-up. In 2010, there were 25 reports of lymphadenitis. Sixteen cases (64%) presented as suppurative lymphadenitis which required surgical intervention. From January 2011 to October 2011, the reports of lymphadenitis increased to 53. Twenty-seven (51%) of these cases presented as suppurative lymphadenitis, of which 25 cases required surgical excision or drainage. The other two cases resolved without requiring surgical intervention. The remaining 26 cases were non-suppurative cases**. The increase in number of non-suppurative cases captured could be partially due to the opening of a new specialist outpatient clinic at KKH in mid-2011 to specifically review paediatric referrals with mycobacterial infections including those with BCG-related complications through active case-finding.

Chart A provides a breakdown of the reports received from January 2009 to October 2011.

Chart A: Reports of lymphadenitis from January 2009 to October [PDF, 30 KB] ↗ (opens in new tab)

_{*BCG vaccine-associated suppurative lymphadenitis has been defined as the presence of fluctuation on palpation or pus on aspiration, the presence of a sinus, or large lymph nodes adherent to skin with caseous lesions on excision.¹}

_{** The figures for 2011 have yet to be finalised as many non-suppurative cases are currently under further observation to determine if the lymph nodes may eventually suppurate or resolve without surgery}

B) Overseas reports

An increase in the number of suspected reports of BCG-associated suppurative lymphadenitis has also been identified in some countries such as Ireland and Latvia in recent years. However, the overall rate and pattern of VAEs remain consistent with the expected frequency of occurrence listed in the package insert of BCG Vaccine SSI®. HSA has been in contact with regulatory agencies overseas to better understand the trend of BCG-associated lymphadenitis over the past few years observed in their countries and the possible factors that could have contributed to the increase in numbers. The interim finding was that the observed rate of lymphadenitis was likely to be multi-factorial.

Possible factors influencing BCG-associated lymphadenitis

Studies have revealed that the incidence of suppurative lymphadenitis is dependent on a number of factors including the strain of BCG vaccine and its constituents, host-related factors as well as the administration techniques.²

Clustering of lymphadenitis in vaccination programmes are commonly associated with a change in vaccine strain, almost invariably to the Pasteur strain 1173P2 or Danish strain 1331. These strains are considered to be more reactogenic than others such as Tokyo strain 172 and Glaxo strain 1077 and more likely to produce large ulcers at the inoculation site and suppurative lymphadenitis.^3-5 It has also been reported that for BCG vaccines in general, the risk of lymphadenitis after vaccination increases with the number of colony forming units (CFUs) in the vaccine.³ Host-related factors such as serious immunodeficiency states like severe combined immunodeficiency (SCID) and AIDS are also associated with increased incidence of local as well as systemic disseminated BCG infection after vaccination.²

Intradermal administration technique³ is also one of the determinants of the risk of lymphadenitis, and is most pronounced in infants aged under six months.⁶ This is attributed to an increased risk of inadvertent subcutaneous injection for neonatal vaccination. It has been reported that the frequency of BCG-associated VAEs was lower when a papule was visible during the injection, reflecting that the injection was given intradermally.⁷ Overdosing during intradermal BCG injection has also been found to increase the risk of VAEs including lymphadenitis, as some neonates receiving larger doses are more likely to overreact to the injection.⁷

Discussion

Based on the number of local reports received at KKH, the estimated local incidence rates for BCG-associated suppurative lymphadenitis with BCG Vaccine SSI® are 0.58/1,000, 0.43/1,000 and 0.96/1,000^# for 2009, 2010 and 2011 respectively. From these figures, the cases of suppurative lymphadenitis appear to have doubled this year, possibly attributed to the additional review of paediatric referrals with mycobacterial infections at the new specialist outpatient clinic at KKH.

_{^# incidence based on figures to date and not extrapolated to end of 2011.}

The incidence of suppurative lymphadenitis observed locally this year is comparable to background incidences reported in literature. The European summary of product characteristics of BCG Vaccine SSI® states that regional lymph nodes larger than 1cm is infrequent (between 1/100 and 1/1000) and that suppurative lymphadenitis is rare (<1/1000). However, the reported incidence of these VAEs varies widely (from 1.9/1000 to 31/1000) in various studies.⁷

In view of the observed trend in the local incidences of suppurative lymphadenitis related to BCG vaccination, the Vigilance Branch will continue to monitor the reports of lymphadenitis closely and review the data when the outcomes and doses administered for the year are finalised.

HSA's advisory

Intradermal administrative technique plays an important role in minimising BCG-associated complications such as suppurative lymphadentitis. This consideration is important when administering reactogenic vaccines such as the BCG Vaccine SSI®. More details on the administration of the BCG Vaccine SSI® are available on the package insert of the product.

It is also advisable for healthcare professionals to inform parents of possible suppurative lymphadenitis following vaccination so that early treatment can be sought. The median duration of symptoms prior to patient's presentation at the clinic is two months. Healthcare professionals are strongly encouraged to report all suspected VAEs with BCG Vaccine SSI® to the Vigilance Branch of has.

References

1. Adv Tuberc Res 1984; 21: 107–93

2. Postgrad Med J 2002; 78: 327–329

3. Bull World Health Organ 1990; 68(1):93-108

4. Arch Dis Child 2006; 91: 594-597

5. Vaccine 2005; 23: 2676-2679

6. Clin Infect Dis 2002; 34: 447-53

7. Vaccine 2009; 27: 6967-6973

The editorial team would like to thank Dr Thoon Koh Cheng, Head and Consultant (Infectious Diseases Services) from the Department of Paediatrics, KKH for his contribution to the above article.