Primary antibody deficiency

What is primary antibody deficiency?

Primary antibody deficiencies (PADs) are the most common primary immunodeficiency diseases. They are a diverse group of disorders which are characterised by various degrees of dysfunctional antibody production because of disruption of B-cell differentiation. There is often a significant delay in reaching a diagnosis of PAD, leading to an increase in morbidity and mortality.¹

Types of primary antibody deficiency¹

Classification of primary antibody deficiency has been a matter for discussion and debate with various classifications being proposed. The following are the main types of primary antibody deficiency disorders.

• Agammaglobulinaemia.² The basic defect is the failure of B cell precursors to mature into antibody-producing cells resulting in severe antibody deficiency. It is of two types:

  • X-linked (Bruton's disease, or XLA) - accounts for 85% of cases and results from mutation in the BTK genes. It only affects boys.

  • Autosomal recessive - accounts for the remaining 15% and can result from a number of genetic mutations.

• Immunodeficiency with low IgG and normal or high IgM (hyper IgM syndromes).³ Patients with hyper IgM syndromes have inability to switch from production of antibodies of IgM type to antibodies of other types such as IgG, IgA and IgE. Consequently, these patients have low levels of IgG and IgA but normal or high level of IgM.

• Common variable immunodeficiency (CVID).⁴ This is a relatively frequent form of immunodeficiency (hence the term common), often diagnosed in adults. The degree and type of deficiency of immunoglobulins and consequently the presentation varies (hence the term variable).

• Selective IgA deficiency.⁵ This is relatively common in the Caucasian population and causes no symptoms in many of those affected, although some may develop significant clinical problems. It is characterised by undetectable levels of IgA in blood and secretions but no other immunoglobulin deficiencies.

• IgG subclass deficiency.⁶ There are four subtypes of IgG - namely, IgG1, IgG2, IgG3 and IgG4. Patients with persistently low levels of one or two IgG subclasses but normal total IgG level have selective IgG subclass deficiency.

• Specific antibody deficiency (SAD).⁷ Patients who have normal immunoglobulin levels but lack the ability to produce protective IgG molecules against the type of organisms which cause respiratory tract infections (eg, Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae type b) are said to have SAD. It is also known as impaired polysaccharide responsiveness.

• Transient hypogammaglobulinaemia of infancy (THI).⁸ All infants between the ages of 3 to 6 months have low antibody levels, as the level of transplacentally acquired IgG falls and the infants' own production of antibodies is initially slow (physiological hypogammaglobulinaemia of infancy). THI is diagnosed in infants over 6 months of age if the IgG levels are significantly lower (fewer than two standard deviations) than 97% of the infants at that age. This usually self-corrects by 2 years of age, although sometimes it last a few more years.

• Unspecified antibody deficiencies. Patients with primary hypogammaglobulinaemia and intact cellular immunity who do not fulfil diagnostic criteria of any of the PADs are said to have unspecified antibody deficiency.

Symptoms of primary antibody deficiency (presentation)^{1 9 10 11}

Clinical presentation is variable in this heterogeneous group of conditions. Patients with primary antibody deficiencies commonly develop recurrent respiratory infections which can lead to bronchiectasis, long-term morbidity and increased mortality. Recognising symptoms and making an early diagnosis is vital to enable timely treatment.¹²

All clinically significant PADs are characterised by high prevalence of chronic or recurrent infections commonly caused by pyogenic encapsulated bacteria - eg, S. pneumoniae and H. influenzae type b. In addition to common infections, intestinal giardiasis and cryptosporidiosis may be problematic. The possibility of a PAD is suggested by:

• Recurrent and severe infections of different types, including:

  • Sinopulmonary infections (pneumonia, sinusitis, otitis media).

  • Meningitis and/or sepsis.

  • Gastrointestinal infections (chronic diarrhoea or malabsorption).

  • Cutaneous infections.

• Autoimmune disorders including autoimmune haemolytic anaemia, neutropenia or thrombocytopenia as well as systemic lupus erythematosus (SLE) and rheumatoid arthritis.

• Allergic disorders with elevated serum IgE levels.

• Abnormal lymphoid tissue, such as nodular lymphoid hyperplasia in the gut or congenital absence of tonsils.

• Unexplained signs such as hepatosplenomegaly or arthropathy.

Differential diagnosis¹

• Secondary immunodeficiencies, including HIV infection.

• Other conditions which cause severe recurrent or chronic respiratory infections, such as cystic fibrosis, bronchiectasis.

• Other causes of recurrent or persistent diarrhoea - eg, Crohn's disease.

• Other causes of recurrent or persistent infections - eg, diabetes mellitus.

• Other causes of failure to thrive.

Evaluation and investigation

• Detailed clinical history including family history and thorough physical examination should be done in all patients with suspected PAD.

• Radiographic evaluation of target organ such as the lungs or sinuses may be indicated.

• A systematic and stepwise laboratory evaluation of the immune system should be undertaken. This includes:

  • FBC.

  • Quantitative serum immunoglobulin levels (IgM, IgG and IgA), including IgG subclasses.

  • Evaluation of specific antibody responses to protein and polysaccharide antigens (tetanus and diphtheria toxoid, capsular antigen of H. influenzae type b and S. pneumoniae).

Who needs to be screened for primary antibody deficiency?

• Patients with frequent or unusually severe infections or lack of response to treatment.

• Children with faltering growth and frequent infections.

• Patients with recurrent fever of unknown origin.

Management of primary antibody deficiency¹³

Recent developments in molecular studies have allowed the identification of several possible targets for specific treatments. Targeted therapies comprise monoclonal antibodies and small molecules, such as cytokines or cytokine inhibitors, employed to up- or down-regulate a particular pathway, depending on the need. They can be used instead of or in combination with traditional immunosuppressant/immunomodulating agents, also as a bridge to definitive treatment, such as haematopoietic stem cell transplantation or gene therapy. Well-known targeted therapies are:¹⁴

• Rituximab (anti-CD20) to treat autoimmune and lymphoproliferative manifestations.

• Enzyme replacement therapy with pegylated bovine adenosine deaminase (ADA) to treat ADA-severe combined immunodeficiency (SCID).

• IFN-γ to increase superoxide production in the monocytes/macrophages of patients with chronic granulomatous disease and to enhance anti-mycobacterial immunity in patients with defects of the IFN-γ/IL-12R pathway.

• Anti-tumour necrosis factor alpha (anti-TNFα) to treat defects of the immunoproteasome causing an autoinflammatory syndrome.

• IL-1 signal antagonists to treat inflammasome disorders.

• Mechanistic target of rapamycin (mTOR) inhibitors to control aberrant proliferation of effector T cells in various immune dysregulation disorders, such as in IPEX, or to downregulate increased mTOR signalling, such as in activated phosphoinositide 3-kinase δ (PI3Kδ) syndrome (APDS, or PASLI).

Management is otherwise focused on prevention and treatment of infections using immunoglobulin (antibody) replacement therapy and antimicrobial therapy.

Immunoglobulin replacement therapy (IRT)

• IRT with polyclonal human immunoglobulin is the cornerstone of management for significant PAD such as CVID and XLA.

• For most patients IRT is a lifelong requirement.

• Current formulations replace only IgG and are given by intravenous (IV) or subcutaneous infusions in the hospital or increasingly at home.

• Subcutaneous and IV preparations are therapeutically equivalent and carry the risk of adverse infusion-related reactions and transmitting infections - eg, hepatitis C. Subcutaneous immunoglobulin is preferred in those with poor veins or adverse reactions to IV products.¹³

• Department of Health guidelines recommend that IRT should be tailored to individual patient outcomes with the minimum aim of maintaining serum IgG levels within the related normal range.

• Usual starting dose of immunoglobulins is 0.4 to 0.6 g/kg per month but individual patients may need higher doses in the long term.

Prophylactic antibiotics

• Many patients with the milder types of PAD (eg, THI, selective IgA deficiency or IgG subclass deficiency) can be managed with prophylactic antibiotics alone.

• Antibiotic prophylaxis (in addition to IRT) is also recommended in the severe cases (eg, CVID or XLA) with infectious complications such as bronchiectasis or chronic sinusitis.

Treatment of infections

• Some patients need longer courses of treatment than immunocompetent individuals and it needs to be ensured that infection is completely eradicated before stopping antibiotics.

• infections in the context of bronchiectasis require intensified treatment in a multidisciplinary setting with culture-guided antibiotics, anti-inflammatory therapy and close monitoring of disease progression.

• Antibiotic choice needs to take account of the possibility of unusual infections - eg, giardial enteritis and mycoplasma or ureaplasma arthritis.

Gene therapy¹⁵

Gene therapy uses autologous haematopoietic stem cell transplantation to deliver stem cells with added or edited versions of the missing or malfunctioning gene that causes the primary antibody deficiency.

Gene therapy has successfully treated several primary antibody deficiencies, including severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, X-linked chronic granulomatous disease and leukocyte adhesion deficiency-I.

Complications of primary antibody deficiency

Complications of PAD include acute infections, which may be due to unusual organisms such as Mycoplasma spp. and long-term complications:¹⁰

A number of chronic complications have been described, including:

• Chest: bronchiectasis, fungal infections, polyclonal lymphoid aggregates, granulomas, lymphoma.

• Sinuses: recurrent sinusitis.

• Bowel: infections (giardiasis, cryptosporidiosis), malabsorption, autoimmune enteropathy, atrophic gastritis, food-sensitive enteropathy, colitis, gastric carcinoma.

• Liver: hepatitis, associated autoimmune diseases (chronic active hepatitis, primary biliary cirrhosis, sclerosing cholangitis), non-infective granulomas.

• Joints: septic arthropathy, chronic sterile arthropathy and/or arthralgia.

• Blood: autoimmune haemolytic anaemia, immune thrombocytopenic purpura, iron-deficiency anaemia, anaemia of chronic illness, aplastic anaemia.

• CNS: acute enteroviral meningoencephalitis, chronic cerebral granulomas.

• Spleen: unexplained splenomegaly in 30% of patients.

• Eyes: keratoconjunctivitis, uveitis.

Prognosis¹⁶

• This depends on the nature and severity of the PAD.

• In general terms, the earlier the condition is recognised, the better the prognosis.¹⁷