Does OM-85 BV prophylaxis trigger autoimmunity in IgA deficient children?

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Abstract

Background

IgA deficiency (IgAD) is the most common primary antibody deficiency. Although two-third of the cases are reported to be asymptomatic, some IgAD children may have frequent infections that urge the clinicians to search for prophylactic measures. OM-85 BV is one of these agents that is known to stimulate mucosa associated lymphoid tissue, and upregulate Th-1 response. This study was performed to determine a possible role of OM-85 BV in triggering autoimmunity in IgAD children within a four-year-follow up period.

Methods

Sixty-three children (34 males (54%), 29 females (46%)) with sporadic IgAD and recurrent febrile infections were included. Patients were carefully screened for autoimmunity both on admission and in follow-up: Those with autoimmune features or under immunosuppressant treatment were excluded. Patients were randomly divided into two groups: Group I received bacterial lysate propylaxis (OM-85 BV) (n:37), and Group 2 received no prophylactic regimen (n:26). Development of clinical autoimmune findings or autoantibodies (anti-nuclear antibody (ANA), ANA profile (14 antigens), anti-cytoplasmic antibodies (ANCA), anti-cardiolipin antibodies IgG and IgM (aCL), rheumatoid factor (RF), direct Coombs test, anti-thyroglobulin (anti-T) and anti-thyroid microsomal antigen (anti-M)) were evaluated.

Results

Mean age of the study group, age at the onset of infectious symptoms and at admission were 102.9 ± 42.2, 27.1 ± 24.9, and 55.2 ± 25.1 months, respectively. Follow-up duration of the whole study group was 48.3 ± 23.1 months. Number of infections was 6.2 ± 2.7 per year in the whole study group. Sixteen patients (25.4%) of the whole study group showed ANA positivity in different patterns and titers. Frequency of ANA, ANCA and RF positivity was 24.3%, 5.4%, 2.7% in Group 1, and 26.9%, 11.5%, 3.8% in Group 2, respectively. Statistical comparisons revealed no significant difference between the two groups.

Conclusion

Significant clinical or laboratory markers for autoimmunity in follow-up were not observed between receivers or non-receivers of OM-85 BV. Frequency of ANA positivity was comparable to the previously reported values in IgAD children which was not affected by OM-85 BV usage. Possible effect of triggering autoimmunity with repeated cures of bacterial lysates needs to be further clarified. Side effects requiring the cessation of treatment were not recorded.

Highlights

► OM-85 BV is an immunoactive lyophilized bacterial extract that can reduce the number of respiratory tract infections. ► No serious adverse effects due to OM-85 BV have been reported up to date. ► Significant clinical or laboratory markers for autoimmunity in IgA deficiency were not observed in receivers of OM-85 BV.

Introduction

IgA deficiency (IgAD) is the most common primary antibody deficiency. It is defined by serum levels of IgA less than 5 mg/dl in the presence of normal IgG and IgM in a patient older than 4 years [1]. Although the fundamental defect is elusive, an impaired terminal differentiation of B cells and defect in switching to IgA-producing plasma cells are presumed to be responsible [2].

Most affected individuals are asymptomatic, whereas approximately one third of patients suffer from recurrent sinopulmonary infections, allergies and autoimmune diseases. Both systemic and organ-specific autoimmune diseases have been described as associated to IgAD. Autoimmune diseases associated with IgAD include immune thrombocytopenic purpura, autoimmune hemolytic anemia, rheumatoid arthritis, celiac disease, systemic lupus erythematosus (SLE), thyroiditis and vitiligo [3], [4].

Management of patients with IgA deficiency is still being discussed. The causative bacteria in the majority of mild to moderate respiratory tract infections are Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. Bacterial infections of the respiratory tract are often treated empirically. Prophylactic treatment should be considered for patients whose clinical symptoms recur. In these patients, first-line treatment includes antibiotic therapy early in the course of the infection and supportive symptomatic therapy. Vaccination with conjugate vaccines, and prophylactic therapy with either antibiotics and OM-85 BV have been shown to decrease the number of infections per year [5].

OM-85 BV (Broncho-Vaxom; OM Pharma, Meyrin/Geneva, Switzerland) is an immunoactive lyophilized extract from eight pathogenic bacteria (H. influenzae, Diploccocus pneumoniae, Klebsiella pneumoniae, Klebsiella ozeanae, Staphylococcus aureus, Streptococcus pyogenes, Streptococcus viridans, and Neisseria catarrhalis). OM-85 BV provokes a local immune response via activation of the mucosa-associated lymphoid tissue and stimulates the production of salivary and bronchoalveolar serum IgA as well as serum IgA and IgG [6].

Several randomized clinical trials have shown that OM-85 BV can reduce the number of respiratory tract infections by 25% to 50% compared with placebo in adults and children [7], [8], [9], [10], [11]. No serious adverse effects due to OM-85 BV have been reported up to date.

Several mechanisms of developing autoimmunity have been reported. It has long been accepted that one of the possible mechanisms of induction of autoimmunity might be immunization with an antigen that cross-reacts with a self antigen. In addition to cross-reactivity, in which the antigenic determinants are similar but not identical, recent studies have demonstrated areas of identity between bacteria and self antigens (molecular mimicry) [12].

The fact that OM-85 BV stimulates mucosa associated lymphoid tissue may cause a molecular mimicry with its high antigenic load of 8 different bacteria, and it has been suggested that it may have an effect to induce autoimmunity. In this four year duration prospective trial, we aimed to investigate if there is developing clinical and laboratory autoimmune findings in patients with IgA deficiency who received OM-85 BV as prophylaxis.

Section snippets

Patients and methods

This 50-month-prospective study was conducted at Ege University, Faculty of Medicine, Department of Pediatric Immunology (Izmir, Turkey) from July 2006 to August 2010. The Ethics Committee of Ege University Faculty of Medicine approved this study. Parents provided written informed consent prior to the study.

Sixty-three patients with IgA deficiency and with recurrent febrile infections were recruited into the study. Children with severe combined immunodeficiencies, common variable

Results

Sixty-three children [34 males (54%), 29 females (46%)] with IgAD were enrolled in the study. Mean age of the study group, age at the onset of infectious symptoms and mean age at admission to our department were 102.9 ± 42.2 (range 39–210 months), 27.1 ± 24.9 (10–120 months) and 55.2 ± 25.1 months (range 12–156 months), respectively. Follow-up duration of the whole study group was 48.3 ± 23.1 months. All cases were sporadic with no family history. None of the patients were born to a consanguineous family.

Discussion

IgA deficiency is the most common form of primary immunodeficiency in the world. Most people with IgAD are asymptomatic, whereas one third of these patients present with recurrent infections, particularly respiratory and gastrointestinal infections. In our study group, most prevalent clinical presentation was recurrent upper respiratory tract infections.

The prevalence of autoimmune disorders in IgAD patients varies from 7 to 36%, with more than 40% of patients having abnormal serum antibodies

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      IgA-deficient patients have an increased baseline risk of developing autoimmunity and therefore clinical or laboratory markers of autoimmunity were recorded at the beginning of the study. The application of bacterial lysates in this group did not result in an increase in incidence of autoimmune disease nor the synthesis of antinuclear antibodies when compared to the placebo group [74]. In summary, the results of the presented studies provide evidence that bacterial lysates are an interesting and safe therapeutic option for children with recurrent respiratory infections, but their clinical effect, despite being visible, is moderate.

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    The authors declare that they have no competing interests.

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