Approach

Generally, if primary immunodeficiency (PID) is suspected, referral to appropriate specialist centres for further investigations and definitive treatment is necessary; protocols for the different forms of PID vary significantly.

Management of secondary hypogammaglobulinaemia typically involves treating the underlying cause, with specialist referral reserved for selected cases.[2]

The aim of treatments implemented by specialist centres is to reduce the risk of hypogammaglobulinaemia complications. This typically involves replacement immunoglobulin therapy (intravenous and subcutaneous therapies are both effective and well tolerated) and antibiotics (promptly or as prophylaxis).[35][36][37][38][39]

There are several immunoglobulin products (all primarily containing IgG), with availability being country dependent. Products vary in IgA, stabiliser, and sugar contents, and in viral purification steps. Limited evidence suggests that patients with a complete absence of IgA and presence of anti-IgA antibodies (some combined variable immunodeficiency [CVID] patients) require products with low IgA content in order to reduce the chance of immunoglobulin-related adverse reaction.[40]

Lifelong replacement immunoglobulin (with acute antibiotic courses as necessary) is important for patients with PID. There is evidence that patients receiving subcutaneous immunoglobulin at home may have improved health-related quality of life compared with patients administered intravenous immunoglobulin replacement therapy in a hospital setting.[41][42] Patients with secondary hypogammaglobulinaemia might require such treatment only until underlying causes are resolved.

Specialist centre treatment may involve polyethylene glycol-modified adenosine deaminase (PEG-ADA) replacement, Pneumocystis pneumonia prophylaxis, and emerging therapies such as haematopoietic stem cell transplantation (HSCT) and gene therapy.

Significantly reduced total IgG

If primary antibody deficiency syndromes causing marked reduction (<2 standard deviations below the mean) in IgG levels are suspected, patients should be referred to specialist centres. Specialist centres treat these conditions (including CVID, X-linked agammaglobulinaemia, autosomal-recessive agammaglobulinaemias, and immunoglobulin class-switch recombination defects) with replacement immunoglobulin therapy.

Evidence suggests achieving IgG levels >500 mg/dL reduces infection frequency, and levels >800 to 900 mg/dL may further improve respiratory outcomes.[43][44][45] In most cases of primary antibody deficiency, treatment with immunoglobulin replacement is lifelong.

Reduced IgA or IgG subclass, or impaired specific antibody production

PIDs with a normal total IgG, but reduction in specific components, are often less severe than those with a reduction in total IgG. For example, IgA or IgG subclass deficiency may not require any treatment. If symptomatic, they can usually be managed with antibiotics alone.

Immunoglobulin replacement may be considered in cases of impaired specific antibody production where there is severe disease or complications. However, initial management should be with prophylactic and/or therapeutic antibiotics alone. If immunoglobulin replacement is commenced, it is worth stopping (preferably in the spring in temperate countries) after a period of time to re-assess immunological status.

Suspected severe combined immunodeficiency (SCID)

SCID is a medical emergency, and patients should be referred to specialist centres for confirmed diagnosis and treatment as soon as it is suspected. It must be urgently excluded in patients with low absolute lymphocyte counts and low immunoglobulins.

Specialist treatment should be undertaken as quickly as possible; outcomes are better with earlier diagnosis and intervention.[46] Definitive treatment is HSCT. Gene therapy is an emerging technology that has also been used in X-linked SCID and SCID due to ADA deficiency. Supportive therapy, including immunoglobulin replacement, protection from exposure to infectious agents, and Pneumocystis pneumonia prophylaxis, is given while awaiting definitive treatment.

PEG-ADA replacement can also be considered in ADA-deficient SCID.[27]

Non-SCID cellular and antibody deficiency

In other combined immunodeficiencies (with both cellular and antibody defects), referral to specialist centres is important for definitive investigation and management. Specific treatment protocols are customised for the various individual diseases. Specialist therapy in the form of HSCT or gene therapy may be required. In these cases, immunoglobulin replacement and antibiotics are used for supportive care while awaiting treatment and after transplantation while awaiting B-cell reconstitution.

Secondary hypogammaglobulinaemia

Treatment of secondary hypogammaglobulinaemia mainly involves treating the underlying cause or discontinuing medications that might result in hypogammaglobulinaemia.[2]

Guidelines support the use of replacement immunoglobulin in patients with severe or recurrent infections, ineffective antimicrobial treatment, and either proven specific antibody failure or serum IgG level of <4 g/L (<400 mg/dL).[2][47][48] Supportive treatment in the form of replacement immunoglobulin and antibiotics may be considered for hypogammaglobulinaemia secondary to haematological malignancy (B-cell chronic lymphocytic leukaemia, non-Hodgkin's lymphoma, multiple myeloma, other B-cell tumours) and after HSCT.[49][50][51][52] Evidence supporting the use of immunoglobulin replacement in other causes of secondary hypogammaglobulinaemia, including following solid organ transplantation, is limited.[2][53][54][55]

There are increasing reports of prolonged and symptomatic hypogammaglobulinaemia following certain treatments, including biologicals such as rituximab and other B-cell targeted therapies.[22][23][24][25][56][57] While infectious risks are likely multifactorial, there is increasing adoption of sub-specialty guidelines which recommend screening with IgG levels and flow cytometry prior to initiation of rituximab, with monitoring after therapy in cases of recurrent infections.[2][58][59][60] Additionally, there is increasing data that paediatric patients treated with rituximab may be at higher risk for hypogammaglobulinaemia and immunoglobulin levels should be monitored.[25][59]

Supportive therapies

Acute/recurrent bacterial infection

  • If patients present with acute infection or with frequent recurrent infection, therapeutic/prophylactic antibiotics may be started.[9] Hypogammaglobulinaemia predisposes typically to encapsulated bacteria (e.g., Streptococcus pneumoniae, Haemophilus influenzae), but sputum can also be positive for non-encapsulated Haemophilus. Stool culture can be positive for Campylobacter or Giardia. Cryptosporidium may be detected in hyper-IgM syndrome.

  • Appropriate therapeutic antibiotics can be started promptly in patients with acute bacterial infection. These are ideally bactericidal rather than bacteriostatic. Most physicians advocate prolonged courses (at least 10-14 days), although evidence supporting this is limited. Single-agent prophylactic antibiotics (one antibiotic used continuously) or rotating prophylactic antibiotics (several different antibiotics changed at fixed intervals) can also be considered if infections are frequent despite immunoglobulin therapy. Prophylaxis is usually considered if there are >2 to 3 mild infections per year or at least one severe infection per year, but this has not been clearly defined.

  • It is widely accepted that antibiotic use for acute infection in hypogammaglobulinaemia is beneficial. Exact antibiotic regimens are developed based on local policy, individual microbiological susceptibility, and patient characteristics.

Established bronchiectasis

  • Chest physiotherapy is a potential adjunct in all patients with established bronchiectasis. Surgery would be offered only for selected cases of bronchiectasis, usually localised. This should only be carried out in specialist centres in liaison with chest physicians and cardiothoracic surgeons.

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