Knowledge on rare diseases and orphan drugs

Although the prevalence is not really known, >100 cases have been reported in the literature. The frequency ranges from 11-60% in selected patients with unexplained bacterial infections.

This condition can affect children > 2 years-old or adults, although most of the published cases are adults. Patients suffer from recurrent bacterial infections, mostly of the respiratory tract, such as bronchopulmonary infections (with or without bronchiectasis), recurrent bacterial sinusitis, or chronic rhinosinusitis. Sepsis and meningitis occur less frequently. Offending bacteria possess a polysaccharide capsule, such as pneumococci, Haemophilus influenzae (serotype b), meningococci and group B streptococci. Allergic manifestations are observed in half of the patients.

This immunodeficiency is likely heterogeneous with multiple causes. Higher prevalence in certain ethnic populations and familial cases suggest genetic factors are involved. Several hypotheses have been proposed concerning the cause of the disease, but the most likely is a defect in splenic marginal zone B cells (MZB), which is supported by the observed impaired polysaccharide antibody response in splenectomized patients.

The diagnosis is established by identifying deficient antibody response to polysaccharide antigens (usually unconjugated Streptococcus pneumoniae vaccine) contrasting with normal immunoglobulin (including the IgG subclasses) levels and unaffected antibody production to protein antigens (tetanus toxoid, diphtheria) and conjugate polysaccharides. The response to pneumococcal capsular polysaccharide is tested using the third-generation enzyme-linked immunosorbent assay adopted by the WHO. The results must be interpreted according to the guidelines issued in 2012 by the American Academy of Allergy, Asthma & Immunology (AAAAI) Working Group. A single serotype is considered to have normal response if the post-immunization antibody titer is > 1.3 μg/mL (considered to be protective) and/or achieves a 4-fold increase (relative to the preimmunization value). A 2-fold increase is considered acceptable if the initial titer was already > 1.3 μg/mL. A good immunization is defined if a normal response is observed for at least 50% (for children) to 70% (for adults) of the evaluated serotypes. As most children < 2 years old have a physiological defect in response to polysaccharide antigens, the diagnosis cannot be made before this age. Additionally, some patients also appear to be poor responders to conjugate polysaccharides. Anti-polysaccharide response cannot be evaluated in patients treated with steroids or immunosuppressants.

Practicians should exclude other primary immunodeficiencies also characterized by a defective response to polysaccharide antigens, mostly common variable immunodeficiency (CVID), the IgG2 and IgG3 deficiencies. A defect in antibody production to polysaccharides may also be associated with Wiskott-Aldrich syndrome.

Antibiotics should be given to both control and prevent infections as a prophylactic treatment when they are too frequent. Immunoglobulin substitution could also be of benefit whenever prophylactic antibiotherapy fails. Vaccinations with the conjugate antipneumococcal, antimeningococcal and anti-Haemophilus serotype b vaccines are also required.

Under treatment, infections are generally well controlled. However, patients should be carefully followed-up since this condition could evolve into a more severe immunodeficiency (IgG subclass deficiency or CVID), particularly if the diagnosis is made during childhood.

Last update: July 2023 - Expert reviewer(s): Dr Guillaume LEFEVRE