- Case Report
- Open Access
Disseminated Bacillus Calmette-Guérin (BCG) infections in infants with immunodeficiency
BMC Research Notes volume 10, Article number: 177 (2017)
The Bacillus Calmette-Guérin (BCG) preparations are live-attenuated derivatives of Mycobacterium bovis. These products are used to vaccinate infants at birth, a practice that may result in a disseminated infection in those patients who have an unidentified immunodeficiency.
Patients who were immunized at birth with BCG and who developed a disseminated infection are reported here to emphasize the importance of taking an extensive medical history before giving the BCG vaccine. Patient 1 has a sibling who had familial hemophagocytic lymphohistiocytosis. Patient 2 has a severe immunodeficiency with profound lymphopenia. Patient 3 has a sibling who had a disseminated BCG infection. Patient 4 has two siblings with an immunodeficiency disorder; one sibling passed away in infancy and one is receiving regular immunoglobulin infusions. Patient 5 has profound lymphopenia and his brother had cytomegalovirus (CMV) pneumonitis and passed away in infancy.
These unfortunate events could have been avoided by compiling the relevant clinical and laboratory information. These cases also underscore the importance of a strict adherence to the BCG vaccine policies. Local and international registries that estimate the birth prevalence of primary immune deficiencies are needed prior to implementing universal BCG vaccination administration.
BCG preparations were first derived in 1921 by attenuating several Mycobacterium bovis (M. bovis) cultures. From these cultures, live vaccines were produced and distributed worldwide. However, marked genetic changes in the commercial strains have evolved over time causing the well-documented “BCG diversity” [1, 2]. In addition, strain-dependent variations in T cell activation have also been demonstrated [3, 4].
The United Arab Emirates (UAE) started to utilize the Staten Serum Institute (SSI) Copenhagen (Danish-SSI 1331) strain in 2005, which is administered to infants at birth. The vaccine must have acquired significant mutations, which may be contributing to the frequently observed adverse events in vaccinated infants. Therefore, reporting clinical experience with this vaccine is very important [5,6,7,8,9].
Development of firm health policies that would prevent BCG vaccine administration to vulnerable neonates is required. Five patients are described here to emphasize the importance of taking essential precautions prior to any use of this live vaccine.
This patient received the BCG vaccine (Danish-SSI 1331) at birth. Her older brother passed away in infancy of presumed familial hemophagocytic lymphohistiocytosis (FHL). Another sibling had meningitis and died at 20 days of age. She presented at 4 months of age with persistent fever and erythematous skin nodules (Fig. 1a). Biopsies of a skin lesion (Fig. 1b, c) and bone marrow (Fig. 1d, e) revealed infiltrations by histiocytes ingesting acid-fast bacilli (AFB), Fig. 1f. Subsequently, she developed central nervous system and bone infections with mycobacterium avium-intracellulare. She was treated with rifampin, clarithromycin, ethionamide, and ethambutol.
This patient received the BCG vaccine (Danish-SSI 1331) at birth. She presented at 9 months of age with bilateral pneumonia (Fig. 2a) and lymphopenia (lymphocyte count, 1620/µL). Subsequently, her lymphocyte counts ranged from 480 to 1060/µL, averaging 816/µL (5th percentile reference count for age = 3000/µL). At about 18 months of age, she developed skin lesions (Fig. 2b) and seizures. The brain MRI showed multiple abscesses (Fig. 2c–e). FAB smear of a drained abscess in the right parieto-occipital region revealed 3+ acid-fast bacilli; Mycobacterium tuberculosis complex was detected by polymerase chain reaction. The isolate was sensitive to ethambutol, rifampin, and streptomycin and resistant to pyrazinamide and isoniazid, suggestive of the M. bovis/BCG strain. Biopsy of a skin lesion revealed perivascular and periadnexal dermatitis; Gram stain, periodic acid–Schiff–diastase (PAS), Gomori methenamine silver (GMS), AFB, and FITE’S acid fast stains were negative. She was treated with high-dose isoniazid, ethambutol, and rifampin, and responded favorably to the treatment.
At the age of 42 months, her CD3 T-cell count was 29/µL (reference, 2110–3950/µL), CD4 T-cell count was 13/µL (920–2100/µL), CD8 T-cell count was 14/µL (810–1650/µL), CD19 B-cell count was 256/µL (420–1200/µL), and NK cell count was 1/µL. Screening for RAG1 (recombination activating gene 1), RAG2 (recombination activating gene 2), and adenosine deaminase mutations was negative. Her serum immunoglobulin levels were below the 5th percentile reference count for age. She was started on regular immunoglobulin infusions while awaiting bone marrow transplantation.
This patient received the BCG vaccine (Danish-SSI 1331) at birth. His older sister passed away at 6 months of age of disseminated BCG infection. He presented at 2 months of age with BCG purulent (suppurative) axillary adenitis (Fig. 3, left panel). The culture grew Mycobacterium TB complex. The isolate was sensitive to ethambutol, rifampin, and streptomycin and resistant to pyrazinamide and isoniazid. This susceptibility profile was suggestive of the M. bovis/BCG strain. He was treated with rifampin and high-dose isoniazid. At 6 months of age, he presented with enlarged cervical and inguinal lymph nodes. Ciprofloxacin and clarithromycin were added, and he responded favorably to this treatment. At 7 years of age, he continued to have chronic (recurrent) cervical adenitis (Fig. 3, right panel). His younger brother and sister were advised not to receive the BCG vaccine and they remained healthy.
This patient received the BCG vaccine (Danish-SSI 1331) at birth. His older brother passed away in early infancy of overwhelming sepsis. Another 12-year-old brother is on regular immunoglobulin infusions since he was 2 years of age. The patient presented at 4 months of age with disseminated BCG infection involving axillary and cervical lymphadenitis and splenomegaly. He was treated with isoniazid and started on regular immunoglobulin infusions. At 5 months of age, his IgA and IgG levels were undetectable, and his IgM level and CD19 B-cell count were normal. These findings were suggestive of hyper-IgM syndrome, but genetic confirmation was not done. He responded favorably to the treatment.
This patient received the BCG vaccine (Danish-SSI 1331) at birth. His older brother had profound lymphopenia (lymphocyte count of 220/µL at 4 months of age) and passed away in infancy of cytomegalovirus (CMV) pneumonitis. Similar to his brother, this infant had a lymphocyte count of 1100/µL at 6 days of age. Lymphocyte immunophenotyping showed: CD3 T-cell count = 703/µL (10th percentile for age = 2500/µL), CD4 T-cell count = 38/µL (10th percentile for age = 1600/µL), CD8 T-cell count = 601/µL (10th percentile for age = 560/µL), CD19 B-cell count = 59/µL (10th percentile for age = 300/µL), and NK cell count = 102/µL (normal for age). He was asymptomatic. He was treated with isoniazid and responded favorably to the treatment. He had bone marrow transplantation to treat his immunodeficiency.
BCG vaccination should be avoided if any family history, clinical or laboratory evidence suggests concerns about the immune competency status of the neonate. Thus, it is essential to attain a detailed history addressing family members with probable immune deficiency or adverse effects of the vaccine prior to administering BCG; a short list of these conditions is shown in Table 1. In addition, disseminated BCG infection should be suspected in any vaccinated infants with a persistent fever or compatible illness of undetermined etiology.
Local and international registries are necessary for estimating the birth prevalence of primary immune deficiency in the population prior to implementing universal BCG administration policies. The Canadian national surveillance program revealed a relatively high prevalence of severe combined immune deficiency among the Canadian First Nations Métis and Inuit newborns, endorsing the health authority’s policy on discontinuing the use of BCG vaccine and replacing it with enhanced TB screening and control measures . Similarly, a delay in BCG administration has been suggested in order to avoid vaccinating the highly vulnerable neonates .
Several BCG vaccines are available worldwide. These products are prepared from M. bovis strains that contain diverse mutations, which create phenotypic properties that are likely to affect the adverse events of the vaccine . In a randomized study involving human neonates, immune responses (Mycobacterium-specific polyfunctional and CD107-expressing CD4 T-cells associated with Th1 cytokines) were documented following the vaccination with various strains including the BCG-Denmark (Danish-SSI 1331) preparation . It is unclear, however, whether these mounted immune responses can protect against M. bovis infection . In one study involving white-tailed deer, the BCG Danish-SSI 1331 strain ameliorated the lymphadenopathy severity scores that followed the intratonsillar inoculation of virulent M. bovis .
General information on the BCG vaccine (indications, contraindications, monitoring, proper method of administration, and potential adverse events) are found in the product inserts. Briefly, guidelines for administering the vaccine include ensuring the correct dose (0.05 mL of the reconstituted vaccine), appropriate site of administration (deltoid region of the arm, one-third down the upper arm over the insertion of the deltoid muscle), appropriate method of injection (intradermal), and routine post-BCG assessments for early detection of adverse reactions . These guidelines should be followed.
Despite high trafficking of tuberculosis (TB) in UAE , the prevalence of latent TB infection (LTBI) in the Emirate of Abu Dhabi among pediatric patients presenting for routine care is relatively low (0.45%) . BCG vaccine may have contributed to this low prevalence in the country, especially since the prevalence of LTBI among Emirati medical students is much higher (8–10%) .
Prevalence of BCG adenitis varies from 0.5 to 5.8%. Medical records of 5900 neonates who received the BCG vaccine at Tawam Hospital (Al Ain City, UAE) from June 2009 to September 2010 were reviewed (unpublished observations). Thirty-five (0.6%) neonates had BCG adenitis. The median age at presentation was 3 months (range, 1.5–7 months). Lesions were on the side of the body where the injection was administered; 31 neonates had swollen axillary nodes, three had supraclavicular nodes, and one had axillary and supraclavicular nodes. Five neonates had suppuration, manifested as discharge, fluctuation, or sinus tract infections. Increased suppurative lymphadenitis caused by M. bovis BCG has been reported in Saudi Arabia, and the majority of the cases are related to the Danish 1331 strain . The authors concluded that: “lack of nationwide data on real magnitude of BCG related adverse events warrants population centric, long term future studies” . In another recent report, injection site reactions and non-suppurative adenitis were managed conservatively . The outcome of suppurative adenitis was variable . Therefore, suppurative adenitis should be considered a serious adverse event of the vaccine [19, 20].
In summary, health authorities should regulate BCG vaccination and enforce well-founded guidelines to avoid its administration to neonates with an immunodeficiency disorder or with a family medical history compatible with immunodeficiency. The BCG vaccine should be totally avoided if any concerns related to the immune competency status of the neonate exist. Published reports related to the clinical experience with different strains (lots) should be encouraged.
- M. bovis :
latent TB infection
Staten Serum Institute
familial hemophagocytic lymphohistiocytosis
Behr MA, Small PM. A historical and molecular phylogeny of BCG strains. Vaccine. 1999;17:915–22.
Behr MA. BCG—different strains, different vaccines? Lancet Infect Dis. 2002;2:86–92.
Aguirre-Blanco AM, Lukey PT, Cliff JM, Dockrell HM. Strain-dependent variation in Mycobacterium bovis BCG-induced human T-cell activation and gamma interferon production in vitro. Infect Immun. 2007;75:3197–201.
Ritz N, Hanekom WA, Robins-Browne R, Britton WJ, Curtis N. Influence of BCG vaccine strain on the immune response and protection against tuberculosis. FEMS Microbiol Rev. 2008;32:821–41.
Bolger T, O’Connell M, Menon A, Butler K. Complications associated with the bacille Calmette-Gue´rin vaccination in Ireland. Arch Dis Child. 2006;91:594–7.
Bernatowska EA, Wolska-Kusnierz B, Pac M, Kurenko-Deptuch M, Zwolska Z, Casanova J-L, et al. Disseminated Bacillus Calmette-Guérin infection and immunodeficiency. Emerg Infect Dis. 2007. http://wwwnc.cdc.gov/eid/article/13/5/06-0865. doi:10.3201/eid1305.060865.
Hesselberg I. Drug resistance in the Swedish/Norwegian BCG strain. Bull World Health Org. 1972;46:503–7.
Al-Salem AH, Kothari MR, AlHani HM, Oquaish MM, Khogeer SS, Desouky MS. Safety of intradermal Bacillus Calmette-Guerin vaccine for neonates in Eastern Saudi Arabia. Saudi Med J. 2012;33:172–6.
Azzopardi P, Bennett CM, Graham SM, Duke T. Bacille Calmette-Guérin vaccine-related disease in HIV-infected children: a systematic review. Int J Tuberc Lung Dis. 2009;13:1331–44.
Rozmus J, Junker A, Thibodeau ML, Grenier D, Turvey SE, Yacoub W, Embree J, Haddad E, Langley JM, Ramsingh RM, Singh VA, Long R, Schultz KR. Severe combined immunodeficiency (SCID) in Canadian children: a national surveillance study. J Clin Immunol. 2013;33:1310–6.
Marciano BE, Huang CY, Joshi G, Rezaei N, et al. BCG vaccination in patients with severe combined immunodeficiency: complications, risks, and vaccination policies. J Allergy Clin Immunol. 2014;133:1134–41.
Ritz N, Dutta B, Donath S, Casalaz D, Connell TG, Tebruegge M, Robins-Browne R, Hanekom WA, Britton WJ, Curtis N. The influence of bacille Calmette-Guerin vaccine strain on the immune response against tuberculosis: a randomized trial. Am J Respir Crit Care Med. 2012;185:213–22.
Parthasarathy A, Sharma H. BCG vaccination: is there light at end of the tunnel? J Pediatr Sci. 2010;5:e48.
Palmer MV, Thacker TC, Waters WR. Vaccination with Mycobacterium bovis BCG strains Danish and Pasteur in white-tailed deer (Odocoileus virginianus) experimentally challenged with Mycobacterium bovis. Zoo Public Health. 2009;56:243–51.
http://www.fda.gov/downloads/biologicsbloodvaccines/vaccines/approvedproducts/ucm202934.pdf. Accessed 16 Sept 2014.
Al Hosani FI, Yahia GA. Prevalence of pulmonary tuberculosis among expatriates subjected to medical visa screening in Abu Dhabi, United Arab Emirates. J Epidemiol Global Health. 2013;3:23–30.
Al Mekaini LA, Al Jabri ON, Narchi H, Kamal SM, Mabrook A, Al Kuwaiti MM, Sheek-Hussein MM, Souid AK, Alsuwaidi AR. The use of an interferon-gamma release assay to screen for pediatric latent tuberculosis infection in the eastern region of the Emirate of Abu Dhabi. Int J Infect Dis. 2014;23:4–7.
Sheek-Hussein M, Hashmey R, Alsuwaidi AR, Al Maskari F, Amiri L, Souid AK. Seroprevalence of measles, mumps, rubella, varicella-zoster and hepatitis A-C in Emirati medical students. BMC Public Health. 2012;12:1047.
Al-Hajoj S, Memish Z, Abuljadayel N, AlHakeem R, AlRabiah F, Varghese B. Molecular confirmation of Bacillus Calmette Guerin vaccine related adverse events among Saudi Arabian children. PLoS ONE. 2014;9:e113472.
Venkataraman A, Yusuff M, Liebeschuetz S, Riddell A, Prendergast AJ. Management and outcome of Bacille Calmette-Guérin vaccine adverse reactions. Vaccine. 2015;33:5470–4.
AAH, ARA, ETA, and GAG identified the patients and wrote the manuscript. AKS edited the manuscript. All authors read and approved the final manuscript.
We are grateful to the patients and their families for their support. The contribution of Ms. Bonnie R. Mcghee in editing the final draft is greatly appreciated.
The authors declare that they have no competing interests.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Consent to publish
Written consents were obtained for all patients for publication of these Case Reports and accompanying images as follows:
Patient 1: father
Patient 2: father
Patient 3: maternal grandfather
Patient 4: father
Patient 5: mother.
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