Human normal immunoglobulin products are derivatives of pooled normal donor plasma. They are used as long-term replacement therapy for missing or defective immunoglobulin in patients with antibody deficiency disorders and also, in much higher doses (usually in short courses), as immunomodulatory agents in patients with a range of autoimmune or inflammatory conditions.
Hyperimmune immunoglobulins are prepared from donors selected for possession of particular antibody specificities and are used for passive immunisation against specific infections or to avoid potentially harmful immune reactions. One such product, anti RhD immunoglobulin, is used to inhibit the immune response to the RhD antigen (see Anti D).
Primary antibody deficiency (primary hypogammglobulinaemia)
The term primary antibody deficiency (PAD) encompasses a range of inherited disorders characterised by defects in antibody production and/or function. Specialist advice on diagnosis and management should be sought as these patients require detailed assessment for selection and adjustment of treatment regimens. They also need to be monitored for acute and chronic complications of both disease and treatments and to assess the efficacy of treatment. Immunoglobulin replacement therapy should only be instituted for patients meeting defined diagnostic criteria for PAD or where there is strong suspicion that some other, indefinable antibody deficiency disorder is present. Immunoglobulin replacement is the mainstay of treatment for PAD.
Intravenous immunoglobulin (IVIgG) is formulated for intravenous administration and is usually given by infusion every three to four weeks. Subcutaneous immunoglobulin (SCIgG) is formulated differently to IVIgG and is given by weekly, pump-delivered subcutaneous infusion. SCIgG should never be given intravenously. Dose and frequency of administration of IVIgG or SCIgG should be adjusted to maintain serum IgG levels above a minimum of 5 g/l. In children with some types of PAD syndromes (e.g. x-linked agammaglobulinaemia) a higher level − above 8 g/l − may prevent chronic disease complications.(PMID14507280) Complications, such as chronic lung damage or mycoplasma arthritis, may also be indications to maintain higher IgG levels.
Intramuscular immunoglobulin (IMIgG) is no longer recommended for treatment of patients with PAD. The weekly injections required are painful, adequate IgG levels cannot be achieved or maintained, and adverse reactions are common. IMIgG should never be given by the intravenous route.
Guidelines are available at www.ukpin.org.uk
Secondary antibody deficiency
Defects of antibody production and/or function can occur in a variety of neoplastic, inflammatory infectious (including HIV), metabolic, traumatic, nutritional and drug-induced disorders. In many cases the antibody deficiency is minor and is corrected by effective management of the primary, underlying disorder. In some situations (e.g. in some patients with chronic lymphatic leukaemia or myeloma), antibody replacement therapy may be indicated and should be managed along the same lines as PAD.
Dosage and administration of IVIgG and SCIgG in primary or secondary antibody deficiency
Prior to commencement of immunoglobulin replacement therapy: The clinician responsible should assess the risks and benefits of immunoglobulin therapy for the individual patient. The patient should receive written information about his/her condition and the treatment options, and should give written, informed consent to the treatment. Pre-treatment liver function tests and a hepatitis RNA test should be done and a serum sample archived.
Dose: For most patients either IV infusion of 200−600 mg/kg every three to four weeks or subcutaneous infusion of 100−150 mg/kg weekly is appropriate. Infusion rates in the product information instructions must be followed, both at the start of treatment and during subsequent infusions. Incorrect infusion rate is a common cause of adverse reactions. Dosing and frequency of infusions should be adjusted according to symptoms and the results of monitoring so as to maintain serum IgG above minimum of 5 g/l. Batch numbers of all immunoglobulin products used should be recorded and retained indefinitely along with date(s) of administration.
Precautions: It is essential to adhere to the infusion rates specified in the package insert. These are designed to minimise the risk of acute reactions. The daily maximum dose of 1 g/kg must not be exceeded on any one day. The maximum dose of 2 g/kg must not be exceeded in any single course of treatment. In elderly patients a daily dose of 0.4 g/kg daily over five days may be a safer way of administering the course of treatment.
Monitoring of treatment: Regular weighing of the patient will help guide immunoglobulin dosage requirements and is particularly important in children. Laboratory tests should include regular liver function tests, C-reactive protein, and pre-infusion serum immunoglobulin levels. Patients should have an annual test for hepatitis C RNA. Serum samples should be archived on a regular basis. Batch numbers of all immunoglobulin products administered must be recorded.
Immunomodulatory therapy with high-dose intravenous immunoglobulin
High doses of IVIgG have shown benefit in many conditions, and the indications have broadened over the past 10 years. The mechanism(s) of action include blocking Fc receptors, anti-inflammatory effects and effects on T and B lymphocytes. IVIgG infusion can cause severe adverse reactions. Because the product is expensive and often in short supply, it should only be prescribed for conditions where there is good evidence of its effectiveness.
Indications: Indications are summarised in Table 15.(PMID14507280)
Table 15 Conditions where IVIgG may have benefit
Speciality | Condition | Prerequisites for consideration of IVIgG treatment | Dosing schedule | Monitoring |
Immunology | Primary immunodeficiency | Hypogammaglobulinaemia deficient total IgG or subclass deficiency | 0.2 g/kg 3−4 weekly | Titre dose against levels and bacterial infections |
Haematology | Idiopathic thrombocytopenic purpura + HIV-associated ITP | Life-threatening haemorrhage or rapid increase in platelet count required or steroid contraindicated | 1 g/kg with second dose at 24 hours dependent on response | Platelet count |
Allogeneic BMT for prevention of GvHD | Allogeneic BMT | 0.5 g/kg day weekly to d+90 | |
NAITP | Affected pregnancy with homozygous father or fetal platelet count < 100 x 109/l | 1 g/kg/week from 20/40 weeks | Fetal platelet count |
PTP | Severely affected patient | 1 g/kg/day x 2 days | Platelet count |
Secondary hypogam-
maglobulinaemia | CLL/myeloma with low IgG levels and > 2 bacterial infections in 12-month period | 0.2 g/kg monthly | Reduction in infections |
Neurology | GBS + Miller Fisher syndrome | Severe disease where TPE not immediately available | 0.4 g/kg/day x 5 days | May be repeated if some measure of response |
CIDP + multifocal motorneuropathy | Steroid treatment failed, not appropriate, or steroid side effects anticipated | 0.4 g/kg/day x 5 days, then 1 g/kg 4−6 weekly | Stop once plateau achieved |
Myasthenia gravis + LEMS | Acute exacerbations where TPE unavailable | 1 g/kg/day x 2 days | |
Acute disseminated encephalomyelitis | Failed high dose steroids | 1 g/kg/day x 2 days | |
Rheumatology | DM + PM | Active recalcitrant disease which has failed immunosuppression | 1 g/kg/day x 2 days | Repeated doses may be required |
SLE | Only where thrombocytopenia is the major complication | 1 g/kg/day x 2 days | Platelet count |
Kawasaki’s disease | | 1−2 g/kg over 2−5 days | |
Dermatology | Pemphigus Vulgaris/
Bullous Pemphigoid | Recalcitrant disease as an adjuvant to immunosuppressants | 1 g/kg x 2−5 days given monthly | Stop once lesions healed |
Toxic epidermal necrolysis | | 1−2 g/kg over 2−5 days | |
Chronic urticaria | Failed conventional therapy | 1−2 g/kg over 2−5 days | Stop after 3 courses |
Infectious diseases | Neonatal sepsis | | 1−2 g/kg over 2−5 days | |
Toxic shock/
necrotising fasciitis | Adjuvant treatment to antibiotics and supportive care | 1 g/kg x 1 day, then 0.5 g/kg x 2 days | |
[Table 15 resources: View large format or download as Word™ document]
Adverse events associated with high-dose IVIgG
Renal failure has occurred following administration of high doses of IVIgG, usually in elderly patients. Predisposing factors are pre-existing renal impairment, diabetes and paraproteinaemia. Rapid infusion increases the risk of anaphylactoid and other acute reactions. These reactions are at least in part due to the stabilisers used in formulating the products. Patients who react to one manufacturer's product may tolerate a different formulation.(PMID14571392)