Two cases of disseminated BCG disease following vaccination in the same family: case reports and review of the literature in China

ABSTRACT

Disseminated bacillus Calmette-Guérin (BCG) disease is a rare and serious adverse event following immunization (AEFI) with BCG. Here, we reported two cases of disseminated BCG disease in the same family and reviewed the literature to identify another 35 cases in China. The average age at onset was 3.7 ± 2.1 months among the 37 cases and only 21 cases (56.8%) were laboratory confirmed. Of the 37 cases, 22 were evaluated for immunodeficiency; definite immunodeficiency was observed in 16 cases (72.7%) and could not be excluded in the other six cases (27.3%). Following treatment, 20 of the 37 cases died (54.1%), one case developed sequelae (2.7%), four cases had progressive disease (10.8%), nine cases had stable disease (24.3%), and only three cases were cured (8.1%). Vaccination of infants with BCG is cost-effective and should not be stopped because of the possibility of rare disseminated BCG disease, especially in countries with high tuberculosis burdens such as China. However, infants with a family history of immunodeficiency should be vaccinated after excluding immunodeficiency-related diseases to minimize the risk of disseminated BCG disease. Furthermore, government should strengthen proactive surveillance programs to detect and treat rare AEFIs early and improve disease outcomes.

KEYWORDS:

• BCG
• disseminated BCG disease
• AEFI
• immunodeficiency

Introduction

The World Health Organization recommends that all healthy newborns in regions with high tuberculosis incidence should receive one dose of bacillus Calmette-Guérin vaccine (BCG), the only available vaccine against tuberculosis, at birth.¹ Although BCG is generally safe, disseminated BCG disease, a rare and serious adverse reaction, can occur following BCG vaccination. The reported incidence of disseminated BCG disease ranged from 1.56 to 4.29 cases per million doses, with a mortality rate of more than 70%.² China, a country with a high incidence of tuberculosis, has included BCG in its national immunization program since 1978 and approximately 15–20 million infants are vaccinated with BCG each year.³ Therefore, although the incidence of disseminated BCG disease is extremely low, cases are relatively common in China given the large number of vaccine doses administered.^4-8 These adverse reactions have greatly affected public confidence in the safety of the BCG.

To our knowledge, disseminated BCG disease in China has mainly been reported in individual cases, with few systematic reviews conducted. Here, we report two cases of disseminated BCG disease from the same family and conducted a systematic review of disseminated BCG in China. Our aim was to understand the distribution and characteristics of cases and to provide a scientific basis for health administration to formulate a new BCG vaccination strategy.

Methods

Data collection

Two cases of disseminated BCG disease were reported in 2014 and 2017 in the Huangpu District of Shanghai, China. The patients were sisters from the same family. Information regarding these two cases of disseminated BCG disease was collected including on the vaccination process, clinical course, and outcome of the disease.

Systematic review

We searched for reports published between 1978 (the year BCG was included in China’s national immunization program) and 2019 in the Pubmed, China National Knowledge Infrastructure, and WanFang databases. We used the following search terms: (“BCG”) and (“disseminated BCG” or “disseminated mycobacterial infection”). Publications were limited to case reports of disseminated BCG disease in China.

Two authors (JW and QSW) identified and screened potentially eligible studies by reviewing the titles and abstracts of the articles. Relevant publications were then selected for full-text review. Studies were excluded if they were not case reports (e.g., literature reviews). Duplicate reports of the same cases or reports containing incomplete data were also excluded. The case inclusion criteria were based on Talbot et al.’s definition of disseminated BCG.⁹ We divided the included cases into laboratory-confirmed cases or clinically diagnosed cases from whom BCG was not cultured or identified using molecular methods.

A total of 594 articles were retrieved from database searching (23 in English and 571 in Chinese). After review, 32 reports of 35 cases were included. Two authors (JW and QSW) independently extracted the following information: authors' name, publication date, case onset date, vaccination history, age at onset, diagnosis type, and outcome indicators.

Results

Case reports

Case A, a female, was born on 12 November 2013 and received the BCG vaccine 3 days later. She was admitted to Shanghai Public Health Clinical Center for treatment of fever and axillary lymph node enlargement on 4 March 2014. She was diagnosed with pulmonary tuberculosis and lymphatic tuberculosis and admitted to hospital on the same day. A chest computed tomography (CT) scan showed inflammatory lesions in the left upper lobe of the lung, enlarged lymph nodes above the hilum, and bilateral axillary lymph node enlargement (1.3 cm), especially on the left side. Anti-tuberculosis therapy with isoniazid, rifampicin, and ethambutol (HRE) was started on 4 March 2014. Case A was discharged from the hospital with an unmodified diagnosis on 10 March 2014. Genetic testing at Children’s Hospital of Fudan University in 2015 showed no mutations in IFNGR1 and IFNGR2 for Case A or her parents. No other immunodeficiency-related genes were detected. Case A recovered after receiving anti-tuberculosis therapy for 2 years in the outpatient clinic of Shanghai Public Health Clinical Center.

Case B, also a female, was born on 17 October 2017 and received the BCG vaccine 2 days later. She developed left axillary lymph node enlargement and pulmonary infection around 1 month following BCG vaccination. On 11 December 2017, case B was hospitalized at the Shanghai Public Health Clinical Center. On 19 December 2017, a CT scan showed inflammatory lesions in her chest on the posterior segment of the right upper lobe, the dorsal segment of the lower lobe, and the left lower lobe. Enlarged lymph nodes were observed in the right left axilla. Case B was given anti-tuberculosis therapy (isoniazid, rifampicin and pyrazinamide or isoniazid, rifampicin, pyrazinamide, ethambutol, and levofloxacin) following admission. She was discharged on 25 December 2017 and diagnosed with pulmonary infection and pulmonary tuberculosis. Case B was diagnosed with immunodeficiency disease (IL-12 receptor deficiency) and tuberculosis infection on 8 April 2018 while hospitalized at Xinhua Hospital. On 15 April 2018, Case B was transferred to the Shanghai Public Health Clinical Center, where she received gamma interferon and further anti-tuberculosis (HRE) therapy. No mycobacteria were detected by PCR. Case B was discharged from hospital on 21 April 2018 with a diagnosis of pulmonary tuberculosis, immunodeficiency, and intracranial infection. She died at home on 5 May 2018.

Cases of disseminated BCG disease in China

A total of 594 records were retrieved from database searching. After detailed analysis, 35 cases of disseminated BCG were determined to be eligible. These 35 cases, along with the two cases we reported here, are listed in Table 1 (37 cases in total). Thirty-three cases (89.2%) were reported after 2005, the year China’s Adverse Events Following Immunization (AEFI) monitoring system was launched. Of these 37 cases, 19 were male (51.4%), 17 were female (45.9%) and one case was of unknown gender (2.7%). The average age at onset was 3.7 ± 2.1 months (range: 0.6–9 months). Twenty-one cases were laboratory confirmed (56.8%) and the remaining 16 cases were clinically diagnosed (43.2%). Immunodeficiency was described in 22 (59.5%) of the 37 cases, including 16 cases with immunodeficiency (72.7%) and another six cases with suspected immunodeficiency (27.3%). Of the 37 cases, 30 received anti-TB treatment (81.1%). After treatment, 20 of the 37 cases died (54.1%), one case developed sequelae (2.7%), four cases had progressive disease (10.8%), nine cases had stable disease (24.3%), and only three cases were cured (8.1%). The average duration from onset to death was 133.7 ± 86.62 days (range: 18–300 days).

Table 1. Cases of disseminated BCG disease reported in China

Case No. (reference)	Year	Gender	Age/Month	Diagnose classification	Immune deficiency	Antituberculosis therapy	Outcome	Days from onset to death
1^Citation4	2018	M	2	Laboratory	NR	Yes	Death	106
2^Citation10	2017	NR	7	Laboratory	Yes	Yes	Death	268
3*	2017	F	1	Clinical	Yes	Yes	Death	167
4^Citation11	2016	M	0.6	Laboratory	CGD	Yes	Disability
5^Citation12	2016	M	2	Clinical	NR	Yes	Death	150
6^Citation13	2015	M	2	Clinical	NR	Yes	Death	NR
7^Citation5	2015	F	3	Laboratory	Suspected	Yes	Stable
8^Citation14	2014	F	3	Laboratory	Suspected	No	Death	72
9^Citation6	2014	M	4	Laboratory	NR	Yes	Improving
10*	2014	F	4	Clinical	Suspected	Yes	Recovery
11^Citation15	2013	M	7	Clinical	CGD	No	Death	193
12^Citation16	2013	M	9	Laboratory	CGD	Yes	Death	263
13^Citation17	2012	M	0.7	Laboratory	CGD	Yes	Death	NR
14^Citation18	2012	M	4	Laboratory	NR	Yes	Stable
15^Citation19	2012	M	2	Laboratory	Suspected	Yes	Stable
16^Citation20	2012	F	5	Clinical	Yes	No	Death	198
17^Citation21	2012	F	3	Clinical	NR	Yes	Stable
18^Citation22	2012	M	4	Clinical	NR	Yes	Improving
19^Citation23	2012	F	5	Laboratory	Yes	Yes	Death	77
20^Citation24	2011	F	3	Laboratory	Yes	No	Death	77
21^Citation24	2011	F	3	Laboratory	Yes	Yes	Recovery
22^Citation17	2011	F	2	Laboratory	Yes	Yes	Stable
23^Citation25	2011	M	3	Laboratory	NR	Yes	Improving
24^Citation26	2011	M	5	Laboratory	Yes	Yes	Death	88
25^Citation27	2011	F	2	Clinical	NR	Yes	Stable
26^Citation6	2010	M	6	Clinical	NR	Yes	Death	25
27^Citation28	2009	M	6	Clinical	CGD	No	Stable
28^Citation7	2008	F	8	Laboratory	NR	Yes	Death	32
29^Citation29	2008	M	4	Clinical	Yes	Yes	Death	300
30^Citation30	2007	F	2	Laboratory	Suspected	Yes	Death	179
31^Citation31	2007	M	3	Laboratory	NR	Yes	Improving
32^Citation8	2006	F	7	Clinical	NR	Yes	Stable
33^Citation32	2005	F	5	Clinical	Suspected	Yes	Stable
34^Citation32	2001	M	4	Clinical	NR	Yes	Death	NR
35^Citation33	2001	F	3	Clinical	NR	Yes	Recovery
36^Citation34	1994	M	0.7	Laboratory	Yes	No	Death	18
37^Citation35	1984	F	3	Laboratory	Yes	No	Death	60

NR, not reported; GCD, Chronic granulomatous disease. *:Cases reported in this study.

Discussion

In addition to the two cases of disseminated BCG reported here for the first time, we identified another 35 cases in China through a literature review. Surveillance data show that the incidence of disseminated BCG disease in China in 2009–2010 was 0.15 per 1 million doses,³⁶ much lower than the results of a study by Lotte et al. (1.56–4.29 cases per 1 million doses).² Nearly 90% of the 37 cases were reported after the introduction of China’s AEFI surveillance system, indicating a significant increase in the sensitivity of AEFI reporting in China. However, the system works as a passive monitoring mechanism and may underestimate adverse reactions following vaccination, especially for rare AEFIs such as disseminated BCG disease. Therefore, efforts to monitor these rare adverse reactions by government departments need to be further strengthened.

Disseminated BCG disease is most common in people with immunodeficiency or human immunodeficiency virus (HIV) infection.¹ The disease also occurs occasionally in patients with unspecified immunodeficiency diseases or in children without significant immunodeficiency.³⁷ The types of immunodeficiency present in disseminated BCG cases include severe combined immunodeficiency, chronic granulomatous disease, and deficiency of the interleukin-12/interferon R pathway. A literature review found that 85.7% (24) of 28 disseminated BCG cases (including nine cases with HIV) were immunodeficient.² Of the 23 cases of disseminated BCG treated in a hospital in China, immunodeficiency occurred in only 65.2%,³⁷similar to the rate of immunodeficiency observed in our literature review (72.7%). The low prevalence of immunodeficiency in disseminated BCG cases reported in China may be related to the exclusion of HIV patients from these studies. Disseminated BCG disease is generally severe. In this study, we found that the cure rate of 37 cases reported in China was only 8.1% and the mortality rate was as high as 54.1%. This mortality rate was lower than figures reported in two early studies conducted in developed countries (71% and 80%, respectively).³⁷ There are two possible explanations for the low mortality rate of disseminated BCG cases in China. First, cases in China have been reported mostly during the last 15 years, and were thus treated using advanced medical technology. Second, updates to PCR and other technologies have enabled the early detection and treatment of cases. Therefore, parents of newborns should be educated about disseminated BCG so that they can see a doctor immediately when symptoms are suspected, avoiding treatment delays and reducing mortality rates.

The two cases of disseminated BCG disease reported in our study occurred in a single family. There have been several publications documenting multiple cases of disseminated BCG disease within the same family.^38-40 Because primary immunodeficiency disorder is a recessive hereditary disease,³⁹ a familial distribution of disseminated BCG disease may occur when all siblings are vaccinated with BCG. Therefore, it is recommended that newborns with a family history of immunodeficiency should undergo genetic screening to rule out immunodeficiency prior to BCG vaccination. Furthermore, proactive surveillance of AEFIs should be strengthened to enable early detection of rare cases.

Monajemzadeh et al. showed that of 21 cases of mycobacterial infection in children following BCG vaccination, 80% were caused by BCG, 13% by Mycobacterium tuberculosis and 7% by other mycobacteria.⁴¹ Of the 37 cases of disseminated BCG reported in China, only 56.8% were laboratory confirmed as BCG. However, China has a high incidence of TB, and in the absence of laboratory evidence, it remains possible that a subset of these cases may have been caused by infection by Mycobacterium tuberculosis or other mycobacteria. Therefore, laboratory tests for disseminated BCG cases should be improved to identify the underlying pathogen of disease. This is necessary to improve public confidence in the safety of the BCG vaccine and to maintain the high coverage of BCG vaccination in China.

This study had two limitations. First, we reported the distribution and characteristics of disseminated BCG cases occurring in China, and extrapolation to other regions is complicated by the different vaccination strategies of other countries. Second, most of the cases in our study were identified through a literature review, which may have influenced the results because unreported cases of disseminated BCG diseases were not included. However, we reviewed the literature over a period of 32 years, starting from the year that BCG was included in the Chinese immunization program until 2019. Thus, our study included as many cases as possible.

For countries with a high incidence of tuberculosis, BCG vaccination of newborns is cost-effective and should not be stopped because of the possibility of rare disseminated BCG disease.^1,16 However, nurses administering vaccinations in neonatal units should understand the contraindications to BCG vaccination and strengthen pre-vaccination work before inoculation. A family history of immunodeficiency or immunodeficiency related diseases should be excluded before vaccination of newborns to avoid the risk of severe AEFIs such as disseminated BCG disease. Furthermore, government should strengthen proactive surveillance programs to detect rare AEFIs early so they can be treated, improving disease outcomes.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Additional information

Funding

This research received no external funding.