Primary immunodeficiencies (PIDs) are usually considered to be rare disorders but this may be a misconception
The diagnosis of a primary immunodeficiency disorder (PID) can be lengthy. Most countries do not routinely screen patients with recurrent infection for PIDs, of any age group – children or adult, and many doctors are not aware of potential risk of organ dysfunction associated with disturbances of the immune system. Therefore, a number of publications point out critical delays of correct diagnosis in immunodeficiencies and furthermore, describe a higher number of organ sequelae and a higher number of fatal disease courses associated with delayed diagnosis. In Germany, for example, possibly 100,000 people are affected. The management of PIDs depends on their clinical effects and often includes a combined approach. About 50 % of patients with a PID have an antibody deficiency that requires life-long treatment with an antibody concentrate. These are obtained from human blood plasma under stringent regulations controlling the quality of plasma collection and manufacturing, ensuring that the standards for viral safety, tolerability and clinical effectiveness are very high. This Expert Round Table, chaired by Professor Hermann Füeßl, Munich, was convened in Frankfurt on November 14th 2016 so that specialists from across Europe could discuss and review the quality of therapy standards and their effectiveness especially regarding the use of immunoglobulins in the treatment of PIDs in adults and children.
The medical need for immunoglobulin in patients with primary immunodeficiencies
Professor Ulrich Baumann, Paediatric Pulmonology, Allergy and Neonatology, Hanover Medical School, Germany
Since agammaglobulinaemia was first described in 1952,1 at least 300 types of immunodeficiency have been defined and novel disorders are being reported every year.2 Approximately 11,000 cases are recorded in the European Society for Immunodeficiencies registry.3 Most are antibody deficiency disorders (Figure 1), of which common variable immunodeficiency (CVID), isolated IgG subclass deficiency and transient hypogammaglobulinaemia of infancy are the most frequent. About 6,500 patients in the registry are currently treated with immunoglobulins; of these, 65 % are receiving intravenous therapy, 34 % are receiving subcutaneous therapy and a small number are receiving intramuscular injections.3
Patients with untreated immunodeficiency can experience frequent infections, primarily at the upper and lower airway site, but also meningitis, septicaemia, and joint and gastrointestinal infections. Immunoglobulin replacement therapy substantially reduces the risk of infection. The trough IgG serum level correlates directly proportional to the immunoglobulin dose and there is a dose-response relation between trough level and risk of pneumonia in patients with PID (Figure 2).4,5
Some challenges have not been overcome. Chronic sinusitis, chronic bronchitis and bronchiectasis are more common during long-term immunoglobulin replacement therapy than in untreated patients.6-8 Data gathered by the European Chest CT in ADS Group show that the prevalence of bronchiectasis in patients with CVID or X-linked agammaglobulinaemia (XLA) increases with age and severity increases with duration of disease, therapy and delay before diagnosis.9
Quality standards in the production of immunoglobulin: the way from the donor’s selection to the final product
Dr Matthias Germer, Senior Director Preclinical Research, Biotest AG, Dreieich, Germany
Patient confidence in human plasma products was severely damaged during the 1980s when some blood donations were contaminated by HIV. Fortunately this problem was tackled quickly and the implicated preparations were promptly removed. In parallel, requirements for blood plasma collection were upgraded. As an additional safety measure modern manufacturing processes employ multiple steps for the inactivation or removal of viruses. Human plasma products such as intravenous or subcutaneous immunoglobulins (IVIG, SCIG) are now manufactured in an environment that is highly regulated by the WHO, FDA, EU, the European Directorate for the Quality of Medicines and the Plasma Protein Therapeutics Association. Production standards at Biotest exceed these requirements.
Since many years, clinicians and manufacturers mainly focus on natural properties and functionality of the immunoglobulin molecules but, as production standards have improved, attention has shifted to the tolerability of the products. The risks of thromboembolic events and haemolysis after IgG use are not new and can be related to the manufacturing process and the therapy management by the physician.
Haemolysis associated with immunoglobulins is a rare event and is caused by antibodies against blood group antigens and by complement activation by anti-A and anti-B isoagglutinins or the cellular immune system. Multiple patient risk factors have been identified, e.g. inflammatory or autoimmune disorders, HLA sensitivisation. The outstanding treatment risk factor is a total intravenous dose above 2 g/kg. Mitigation strategies include avoiding products with anti-A and anti-B titres >1:32, high infusion rates and preparations with a protein concentration of >10 %. Immunoglobulins are never free from anti-A and anti-B because these isoagglutinins are present in all blood groups except AB (which accounts for only 10 % of the global population). The risk of haemolysis differs between preparations of immunoglobulins (Figure 3).10
Thromboembolic events associated with immunoglobulin treatment are due to residual coagulation factors. In the manufacture of Intratect (an intravenous immunoglobulin from Biotest), these are largely removed during a four-stage process, the most important steps of which are ethanol fractionation and treatment with octanoic acid. The European Pharmacopoeia requires since 2012 that only production processes can be used that lead to a final product that does not exhibit procoagulant activity. The standardization of the commonly used tests for thrombogenic activities, nonactivated partial thromboplastin time (NAPTT) and the thrombin generation assay (TGA), is ongoing. Patient-related risk factors include a history of thromboembolic events, hypertension, vascular disorders, renal insufficiency, prolonged periods of immobilisation, age >65, diabetes mellitus, overweight, severe hypovolemia and increased blood viscosity. They may influence the tolerability of intravenous immunoglobulins.11