Bacillus Calmette-Guérin (BCG) complications associated with primary immunodeficiency diseases

Summary

Primary immunodeficiency diseases (PIDs) are a group of inherited disorders, characterized by defects of the immune system predisposing individuals to variety of manifestations, including recurrent infections and unusual vaccine complications. There are a number of PIDs prone to Bacillus Calmette-Guérin (BCG) complications. This review presents an update on our understanding about the BCGosis-susceptible PIDs, including severe combined immunodeficiency, chronic granulomatous disease, and Mendelian susceptibility to mycobacterial diseases.

Introduction

Tuberculosis (TB) is a common deadly infectious disease, caused by various strains of mycobacteria, including Mycobacterium tuberculosis (M. Tuberculosis).1, 2 Emergence of multiple-drug resistant M. Tuberculosis strains and notable increase in the rate of non-tuberculous mycobacteria are features mandates paying more attention to identify the potential conditions, which can predispose individuals to acquire such infections.3, 4, 5 Bacillus Calmette-Guérin (BCG) vaccination aims to prevent early-life infections with M. Tuberculosis.3, 4 The BCG vaccine was developed by Albert Calmette and Camille Guerin in France between 1908 and 1921. The original BCG strain (Mycobacterium bovis BCG) was an attenuated form of M. bovis, resulting from 231 3-week-subcultures in a media aimed to preserve the microorganism's immunogenicity minimizing its virulence. Nowadays, several substrains derived from the original preparation are used in the manufacturing of the currently used different BCG vaccines.⁶ World Health Organization (WHO)-recommended vaccination of newborns with BCG takes place in several countries, especially those with high burden of TB or neighboring such regions, to prevent from miliary and meningeal forms of TB.

The BCG vaccination itself is believed to be merely safe for a competent immune system. However, a potentially lethal infection could be expected in immunocompromised hosts. In fact immunocompromised patients are vulnerable not only to mycobacterial diseases, but also to adverse complications of BCG vaccine.6, 7, 8 Hence, a close scrutiny for primary immunodeficiency diseases (PIDs) is required at the time of detecting an overwhelming infection following the vaccination, a condition ranging from regional disease (BCGitis) to disseminated disease (BCGosis).⁹

Primary immunodeficiency diseases (PIDs) are inherited immune system disorders that lead to a variety of manifestations, including recurrent infections, autoimmunity, and malignancies; more than 150 types of PIDs with distinct underlying gene defects have been identified so far.¹⁰ It has been shown that some PIDs tend to remain undiagnosed until the appearance of the presumed complications, including BCGosis.6, 11 Meanwhile a number of PIDs are susceptible to severe mycobacterial disease following vaccination with BCG, including severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), and Mendelian susceptibility to mycobacterial diseases.¹² There are a number of reports that investigated underlying PIDs in those with disseminated BCG (Table 1). This review is to present PIDs that prone to BCG complications, whilst vulnerability to other mycobacterial infections in any of these BCGosis-susceptible PIDs is discussed as well.

We searched PubMed and ISI Web of Science, and EMBASE for articles published in English with no time and language limitations on date up to January 2012. We used free text and MESH terms to search the Medline electronic bibliographical Database (accessing via PubMed) combining terms for study patients/population, problem and intervention. We did not include terms for the comparison groups (more sensitive, less specific search) and did not put “Methodological filter” (study type filter) for our search strategy, as our preliminary search revealed that there were no randomized controlled trial identifiable for the review question. In our preliminary search, we made use of built-in search filters of PubMed “clinical queries” and did a rapid search on PubMed and the ISI Web of Science. We also used free texts to search EMBSE (accessing via Ovid). BCG complications, including BCGitis and BCGosis (disseminated disease) were searched through the literature and articles were selected for their relevance to the analysis of underlying disorders. Indeed, cohort and case reports/series of patients with severe combined immunodeficiency, chronic granulomatous disease, and Mendelian susceptibility to mycobacterial diseases, including their subtypes (IFN-γR1, IFN-γR2, IL-12Rβ1, IL12p40, STAT1, and IKBKG deficiencies) were enrolled and BCG complications were investigated in the selected articles. Each article was then assessed for its methodological quality and the relevance of its results. Preference was given, but not restricted to, clinical studies with large number of cases and definite diagnosis. Additional references were identified from citations in retrieved articles.

Severe combined immunodeficiency (SCID) is the most severe forms of PIDs, which are genetically deficient in development and function of T-lymphocytes and could also be associated with decreased numbers of B-lymphocytes and NK-cells.¹³ SCID is considered as an emergency of pediatric practice, whilst early detection of SCID and appropriate treatment is life-saving and could prevent further complications, such as BCGosis following BCG vaccination.14, 15, 16 Severe combined immunodeficiency is a lethal disease, if timely diagnosis and appropriate treatment, e.g. bone marrow transplantation, is not made.17, 18 Therefore, screening for SCID has been started as a routine program for newborns in some countries (e.g., United States since 2008), and is under evaluation in some others. In the US project, T-cell receptor excision circles (TRECs) are detected by polymerase chain reaction (PCR) from Guthrie cards, as a marker of thymic activity and thymic output.¹⁹

Several gene defects responsible for SCID phenotype have been identified so far; therefore SCID could be sub-classified to four groups based on lymphocyte subpopulation (Table 2). Indeed, without a normally functional specific arm of the immune system such as CD4 T helper (Th) lymphocytes (e.g., Th1, Th2, Treg, Th17), innate arm of the immune system like macrophages, even with an abundant quantity, could not play its proper role.19, 20, 21 In addition to above-mentioned classification, SCID could also be divided into four groups regarding to the defective mechanism involved in pathogenesis, including purine metabolism defect which lead to premature lymphocyte precursor cell death, defective signaling through the common gamma chain dependent cytokine receptor, defective pre T-cell receptor (TCR)/TCR signaling, and defective V(D)J recombination.22, 23

BCG complications including BCGosis, as the adverse reaction to BCG vaccination, could be seen in all underlying genetic types of SCID. So far, there are no identifiable differences described between rates of infections among the various types of SCID; however, large multicenter international studies would be necessary to confirm or refute this and other concepts related to BCG complications in SCID patients. Several reports described BCGosis in patients with SCID (Table 3). Numerous reports on this group of patients were related to adverse complication of early BCG vaccination,²⁴ whilst in the majority of cases, BCGosis is the preliminary sign of the underlying disease.

In contrary to high incidence rate of BCGosis in patients with SCID, reports investigating vulnerability of SCID to NTM are rare. Although there are few reports of disseminated infection with Mycobacterium avium or Mycobacterium marinum,25, 26 infection with M. tuberculosis in SCID is not noteworthy²⁷ and probably due to lack of exposure.

Based on these findings, the susceptibility of SCID patients to overwhelming BCG infection is of substantial importance, particularly in countries with national wide vaccination programs. Although this relationship is not surprisingly, given the impact of SCID on cell-mediated immunity which is required for immunity against BCG, the topic is surprisingly underestimated on the SCID literature. It should be emphasized that BCG vaccination is more frequent in developing countries where other comorbidity factors have a strong influence on child mortality, while SCID could be under-diagnosed frequently in these regions. How age at BCG vaccination, the administration rout, the type of vaccination strain or which variant of SCID is more susceptible to BCG complications, are still unanswered questions.

Altogether, precise control and measures aiming in order to avoid administration of BCG at birth in those with family history of recurrent infections and immunodeficiency is highly recommended. BCG vaccination could be done later once screening tests rule out underlying immunodeficiencies.

Chronic granulomatous disease (CGD) is a heterogeneous genetic disorder in which the phagocytes (neutrophils, monocytes and macrophage) are not capable to kill microorganisms as a result of a defect in production of reactive oxygen spicies (ROS) due to impaired nicotinamide adenine dinucleotide phosohate oxidase (NADPH) activity.²⁸ Therefore patients with CGD usually suffer from recurrent bacterial and fungal infections.28, 29 This increased infectious susceptibility results of the impairment of at least three reactive oxygen spices (ROS)-dependent antimicrobial mechanisms ²⁹: i) decreased phox-generated ROS with intrinsic antimicrobial activity; ii) decreased phox-mediated activation of microbicidial granule proteases; and iii) decreased phox-mediated release of neutrophil extracellular traps.29, 30, 31 Besides, these patients are also characterized for presenting dysregulated inflammation and increased granuloma formation.

Constitutional inactivating mutations in CYBB [Cytochrome b(-245), beta subunit, OMIM*300481] gene leads to X-linked (XL) form of CGD, where as mutations in the CYBA [Cytochrome b(-245), beta subunit, OMIM+608508], NCF1 [Neutrophil cytosolic factor 1, OMIM*608512] and NCF2 [Neutrophil cytosolic factor 2, OMIM*608515] genes that encode subunits of phagocyte NADPH oxidase result in autosomal recessive (AR) forms of CGD.32, 33 More recently, mutations in NCF4 (Neutrophil cytosolic factor 4, p40^phox, OMIM*601448) were also described to be associated to AR forms of CGD.³⁴

The patients with CGD are vulnerable to infections caused by Staphylococci, Burkholderia, Serratia, Salmonella, and Aspergillus; although an increased predisposition to infections with M. tuberculosis has been documented in some CGD patients, it is still a debate. It has been shown that the oxidative burst plays an important role in host defense against mycobacterium infections ³⁵; however, phagocytes in CGD patients are not capable to destroy intracellular BCG in vitro.³⁶

Also in practice, vaccination with attenuated M. bovis BCG vaccine could result in BCGosis in these patients.35, 37 These patients are sacrifice to the BCG vaccination to show up their underlying disease.⁹ Review of literature reveals several reports on complications of BCG in CGD patients (Table 4), while no BCG complication was reported in few studies.³⁸ CGD patients are more likely to show BCG lymphadenitis.³⁹ However, they are more prone to cure with anti-TB regimen in contrast to the SCID patients.37, 40, 41

BCG vaccination is contraindicated in infants with CGD, but due to its administration at birth in some countries, most patients are diagnosed with CGD after being vaccinated and developing BCG complications.⁴⁰

Nowadays, CGD patients are showing increased survival rates compared to a few decades ago. This is probably the natural consequence of aggressive prophylactic and diagnostic measures, better antifungal medications and the very promising results of hematopoietic stem cell transplantation. As diagnosis of underlying immunodeficiencies before BCG vaccination could be beneficial and life-saving, postponing BCG vaccination could be suggested as a short-term solution for those suspicious to immunodeficiency with positive family history of recurrent infections and immunodeficiencies. Indeed usage of safer anti-tuberculosis vaccines could be advised in order to prevent BCG complications in immunodeficient patients.

Mendelian susceptibility to mycobacterial diseases (MSMD) describes a group of PIDs highly vulnerable to weakly virulent species of mycobacterium.⁴² Not a particular ethnic group or geographic region is specific for MSMD patients. These individuals are usually presented with supreme disseminated mycobacterial infections,9, 43 especially BCG9, 44, 45 (Table 5).

Although most of MSMD are likely prone to disseminated BCG infection or NTMs,⁴³ infection with M. tuberculosis yet comprises a considerable number of case presentations. Different clinical features of this disease may arise from the variable existing gene mutations.⁴⁶

All genetic types of MSMD seem to have defects in IFN-γ mediated immunity. It seems that IFN-γ is mandatory for efficient immune response to Mycobacterial species. Moreover, it has been shown that IL12/23 axis is necessary for promotion of a competent IFN-γ secretion. Therefore, any mutation which leads to a defect in IFN-γ or IL12/23 receptors or signal transduction pathways would lead to incomplete response to Mycobacterial infections.47, 48

Mutations in several gene loci have been detected for MSMD: IFN-γR1, IFN-γR2, IL-12Rβ1, IL12B, STAT1, and IKBKG (Table 6). However, it is worthy to declare that in numerous cases of MSMD, no genetic defect has been discovered.

IFN-γ receptor is composed of two chains; IFN-γR1 and IFN-γR2. Mutations in the genes encoding these receptors would result in a defect in the action of IFN-γ.48, 49, 50, 51 STAT1 mutations lead to diminished Gamma Activating Factor (GAF, STAT1 homodimers) -mediated response to IFN-γ. IL12RB1 mutations bring about β1 chain deficiency in IL12/23 receptor complex. NK and T cells activity are dependable on the above-mentioned pathways. IKBKG mutations, as an XL form of MSMD, cause NF-kB essential modulator (NEMO) deficiency.46, 50, 51, 52 NEMO deficiency clinically presents with a hypohydrosis, hypotricosis, peg-shaped teeth and immunodeficiency syndrome called ectodermal dysplasia anhydrotic with immunodeficiency (EDA-ID). Some patients show a more severe phenotype of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID), while others present with immunodeficiency with no (or very minimal) ectodermal manifestations. Moreover, high serum levels of IgM, and low levels of IgG, IgA resembling Hyper IgM syndromes have also described found in a subset of these cases. IKBKG-hypomorphic mutated patients are highly susceptible to of BCG complications and NTMs infections.53, 54, 55

Interferon Regulatory Factor 8 (IRF8, OMIM*601565) gene controls the development of dendritic cells, as well as differentiation of granulocytes and macrophages IRF8 also plays a fundamental role in regulation of function of hematopoitic cells. One of the reported mutations of the IRF8, K108E, is inherited as an AR pattern leading to a syndrome manifested by early onset disseminated BCG. Lack of monocytes and dendritic cells in this patient was associated with opportunistic infections. A distinct mutation, T80A, has also been reported with AD pattern of inheritance resulting in a less severe immunodeficiency picture. These patients also show susceptibility to BCG infection.56, 57

Recently, macrophage gp91^phox deficiency, which is due to mutation in CYBB gene, has been classified under category of MSMD,⁵⁸ in addition to CGD,⁸ while a group of these patients are identified who has isolated susceptibility to mycobacteria.⁵⁸

Under certain cultural or religious precepts, cousin to cousin marriage is still an ongoing ritual. In countries with high rates of consanguineous marriage, AR forms of MSMD (as other AR diseases) are significantly more prevalent than autosomal dominant (AD) or XL forms of the diseases. Besides, most of these countries are also the ones encouraging strong neonatal BCG vaccination policies. In such cases the BCG complications are manifested in the child of otherwise clinically healthy parents.

In addition to SCID, CGD, and MSMD, other PIDs have increased vulnerability to BCG infection; however BCG vaccination complications are usually less prevalent and severe than in the diseases mentioned above.

Patients with hyper-immunoglobulin E syndrome (HIES or Job's syndrome), as an autosomal dominant syndrome due to mutations in the Signal Transducer and Activator of Transcription 3 (STAT3, OMIM*102582) gene, develop skeletal abnormalities, abnormal faces and delay in shedding of primary teeth. These patients could show early (even neonatal) eczema and respiratory infections. There are few reports of BCG infection in HIES; however, the patients have shown more vulnerability to BCG or NTM infections than M. tuberculosis.59, 60, 61, 62

One of the rare hereditary disorders in T-cells activity is X-linked hyper IgM syndrome (XL-HIGM) due to mutations in the CD40 Ligand (CD40L, OMIM*300386) gene. There are few reports of regional or disseminated BCG in these patients. It is noteworthy that the AR forms of hyper IgM syndrome affecting B-cell intrinsic function are not more susceptible to mycobacterial disease.13, 63, 64, 65