Specific Conditions |
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Indication for Ig Use |
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Level of Evidence | Evidence of probable benefit – more research needed (Category 2a) |
Description and Diagnostic Criteria |
More than 280 inborn errors of immunity (IEI, also known as primary immunodeficiency diseases (PIDs)) have been identified. Many of these cause antibody deficiency. In some cases, antibody deficiency is associated with B-cell deficiency (e.g. X-linked agammaglobulinaemia), while in others, B-cells are present. Antibody deficiency can be the only manifestation of IEI, or there can be other defects as well (e.g. T-cell deficiency, autoimmunity). Not all IEIs cause antibody defects, therefore immunoglobulin replacement is not always indicated. Recognised inborn errors of immunity for which immunoglobulin replacement is universally indicated are: X-linked agamma/hypogammaglobulinaemia, severe combined immunodeficiency, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome, hyper IgM syndrome and severe T-cell immunodeficiency. The European Society for Immunodeficiency Diseases (ESID) diagnostic criteria for PID have been used as a guide in the development of the qualifying criteria for Ig therapy in Australia. It is acknowledged that a low IgG alone is not a sufficient indication for immunoglobulin replacement. Genetic diagnoses are continually being updated as described in the classification system for the International Union of Immunology Societies (IUIS). It is recognised that genetic diagnoses are not always possible. |
Justification for Evidence Category | The Biotext (2004) review reported level 2a evidence for the use of intravenous immunoglobulin (IVIg) in the treatment of common variable immunodeficiency and primary hypogammaglobulinaemia. |
Diagnosis Requirements |
A diagnosis must be made by an Immunologist. |
Qualifying Criteria for Ig Therapy |
Replacement therapy in common variable immune deficiency (CVID) – ESID diagnostic criteria met
Note: If less than two years the request must be under the indication Transient hypogammaglobulinaemia of infancy (children aged less than four years)
AND
Blood samples for IgG and IgA testing should be taken on two occasions, at least one hour apart and at least one sample taken when the patient does not have an infection
AND
AND
The review criteria for inborn errors of immunity are to ensure adequate replacement of antibody deficiency and to demonstrate clinical benefit from treatment. Replacement therapy in possible common variable immune deficiency (CVID) – (below normal serum IgG but normal serum IgA level)
A low IgG (normal IgA with or without a low IgM) alone is not a sufficient indication for immunoglobulin replacement therapy. Many patients will be well despite the finding of a serum IgG below the normal range for age.
AND
Blood samples for IgG testing should be taken on two occasions, at least one hour apart and at least one sample taken when the patient does not have an infection
AND
AND
Cessation of Ig therapy should be considered at least after each 12 months of treatment. If serum IgM and IgA levels are trending upwards and near normal, this may suggest recovery of the immune system and a trial might be considered if the patient is well. Once the patient has normal IgA and IgM levels, the IgG is also likely to be normal and a trial off therapy may be undertaken. Ig therapy should be extended as required to enable cessation of therapy in September/October, with repeat clinical and/or immunological evaluation before re-commencement of therapy. This should particularly be considered in patients who do not have active bronchiectasis and/or suppurative lung disease. An immunoglobulin washout period of four to six months is necessary to enable an accurate assessment. Prophylactic antibiotics may be considered to cover the period of cessation of immunoglobulin therapy. *Please note: a diagnosis of bronchiectasis and/or suppurative lung disease must be consistent with the guideline of the Thoracic Society of Australia and New Zealand and the Australian Lung Foundation (Chang et al 2014). Replacement therapy in transient hypogammaglobulinaemia of infancy (children aged less than 4 years)
The majority of young children with transient hypogammaglobulinaemia do not require immunoglobulin (Ig) therapy. However, if the patient has had recurrent suppurative infections that threaten organ function, review by an immunologist is recommended for consideration of Ig therapy. Some patients may require treatment during the winter months only and others will benefit from more prolonged treatment.
Blood samples for IgG testing should be taken on two occasions, at least one hour apart and at least one sample taken when the patient does not have an infection.
AND
Cessation of Ig therapy should be considered at least after 24 months of treatment. If serum IgM and IgA levels are trending upwards and close to normal, this may suggest recovery of the immune system and a trial might be considered if the patient is well. Once the patient has normal IgA and IgM levels, the IgG is also likely to be normal and a trial off therapy should be undertaken. Ig therapy should be extended as required to enable cessation of therapy in September/October, with repeat clinical and/or immunological evaluation before re-commencement of therapy. When the child is four years old, a decision must be made regarding a trial off treatment or qualification may be appropriate under a different indication such as possible or confirmed CVID. Replacement therapy in recognised inborn errors of immunity for which immunoglobulin replacement is universally indicated (e.g. SCID, Wiskott-Aldrich syndrome, etc.)
Blood samples for IgG testing should be taken on two occasions, at least one hour apart and at least one sample taken when the patient does not have an infection.
Where a diagnosis has initially been suspected, confirmation will be required for access to continuing Ig therapy. |
Exclusion Criteria |
Acquired hypogammaglobulinaemia secondary to haematological malignancy or post HSCT Specific antibody deficiency IgG subclass deficiency Secondary hypogammaglobulinaemia unrelated to haematological malignancy or stem cell transplantation |
Review Criteria for Assessing the Effectiveness of Ig Use |
Replacement therapy in common variable immune deficiency (CVID) – ESID diagnostic criteria met
Initial review by an immunologist is required at six months and annually thereafter. Documentation of clinical effectiveness is necessary for continuation of Ig therapy.
The review criteria for inborn errors of immunity are to ensure adequate replacement of antibody deficiency and to demonstrate clinical benefit from treatment. Clinical effectiveness of Ig therapy may be assessed by: On review of the initial authorisation period
On review of a continuing authorisation period
Replacement therapy in possible common variable immune deficiency (CVID) – (below normal serum IgG but normal serum IgA level)
Initial review is required by an Immunologist at six months and ongoing reviews at least annually to assess clinical benefit. Documentation of clinical effectiveness is necessary for continuation of Ig therapy.
Cessation of Ig therapy should be considered at least after each 12 months of treatment. If serum IgM and IgA levels are trending upwards and near normal, this may suggest recovery of the immune system and a trial might be considered if the patient is well. Once the patient has normal IgA and IgM levels, the IgG is also likely to be normal and a trial off therapy may be undertaken. Ig therapy should be extended as required to enable cessation of therapy in September/October, with repeat clinical and/or immunological evaluation before re-commencement of therapy. This should particularly be considered in patients who do not have active bronchiectasis and/or suppurative lung disease. An immunoglobulin washout period of four to six months is necessary to enable an accurate assessment. Prophylactic antibiotics may be considered to cover the period of cessation of immunoglobulin therapy. Clinical effectiveness of Ig therapy may be assessed by: On review of the initial authorisation period
AND
On review of a continuing authorisation period
AND
*Please note: a diagnosis of bronchiectasis and/or suppurative lung disease must be consistent with the guideline of the Thoracic Society of Australia and New Zealand (Chang et al 2014). Replacement therapy in transient hypogammaglobulinaemia of infancy (children aged less than 4 years)
Initial review is required by an Immunologist, at six months, and ongoing reviews at least annually to assess clinical benefit. Documentation of clinical effectiveness is necessary for continuation of Ig therapy.
Cessation of Ig therapy should be considered at least after 24 months of treatment. If serum IgM and IgA levels are trending upwards and close to normal, this may suggest recovery of the immune system and a trial might be considered if the patient is well. Once the patient has normal IgA and IgM levels, the IgG is also likely to be normal and a trial off therapy should be undertaken. Ig therapy should be extended as required to enable cessation of therapy in September/October, with repeat clinical and/or immunological evaluation before re-commencement of therapy. When the child is four years old, a decision must be made regarding a trial off treatment or qualification may be appropriate under a different indication such as possible or confirmed CVID. Clinical effectiveness of Ig therapy may be assessed by: On review of the initial authorisation period
AND
On review of a continuing authorisation period
AND
*Please note: a diagnosis of bronchiectasis and/or suppurative lung disease must be consistent with the guideline of the Thoracic Society of Australia and New Zealand (Chang et al 2014). Replacement therapy in recognised inborn errors of immunity for which immunoglobulin replacement is universally indicated (e.g. SCID, Wiskott-Aldrich syndrome, etc.)
Initial review by an Immunologist is required at six months, with reviews annually thereafter. Documentation of clinical effectiveness is necessary for continuation of IVIg therapy.
The review criteria for inborn errors of immunity are to ensure adequate replacement of antibody deficiency and to demonstrate clinical benefit from treatment. Clinical effectiveness of Ig therapy may be assessed by: On review of the initial authorisation period
On review of a continuing authorisation period
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Dose |
Replacement therapy in common variable immune deficiency (CVID) – ESID diagnostic criteria met
The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.
Refer to the current product information sheet for further information on dose, administration and contraindications. Replacement therapy in possible common variable immune deficiency (CVID) – (below normal serum IgG but normal serum IgA level)
The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.
Refer to the current product information sheet for further information on dose, administration and contraindications. Replacement therapy in transient hypogammaglobulinaemia of infancy (children aged less than 4 years)
Subcutaneous administration of immunoglobulin can be considered as an alternative to IVIg. A suggested dose is 0.1 g/kg lean body mass every week, modified to achieve an IgG trough level of at least the lower limit of the age-specific serum IgG reference range.
The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient. Refer to the current product information sheet for further information on dose, administration and contraindications. Replacement therapy in recognised inborn errors of immunity for which immunoglobulin replacement is universally indicated (e.g. SCID, Wiskott-Aldrich syndrome, etc.)
The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.
Refer to the current product information sheet for further information on dose, administration and contraindications. |
Bibliography |
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Biotext 2004, ‘Summary data on conditions and papers’, in A systematic literature review and report on the efficacy of intravenous immunoglobulin therapy and its risks, commissioned by the National Blood Authority on behalf of all Australian Governments, pp. 218. Available from: https://www.blood.gov.au/system/files/A-systematic-literature-review-and-report-on-the-efficacy-of-IVIg-therapy-and-its-risks.pdf Bonilla, FA, Bernstein, L, Khan, DA, et al 2005, ‘Practice parameter for the diagnosis and management of primary immunodeficiency’, Annals of Allergy, Asthma and Immunology, vol. 94, no. 5, suppl. 1, pp. S1–63. Chang, AB, Bell, SC, Torzillo, PJ, et al 2014, ‘Thoracic Sodiety of Australia and New Zealand Chronic Suppurative Lung Disease and Bronchiectasis in children and adults in Australia and New Zealand – Clinical Practice Guideline’. Available from: https://www.thoracic.org.au/journal-publishing/command/download_file/id/36/filename/TSANZ-ChronicSuppurativeLungDisease-Guidelines-2016-web.pdf. Cooper, MD & Schroeder, Jr HW 2005, ‘Primary immune deficiency diseases’, in DL Kasper, E Braunwald, AS Fauci, et al (eds), Harrison’s Textbook of Medicine, 16th edn, McGraw-Hill, New York, pp. 1939–47. Orange, JS, Hossny, EM, Weiler, CR, et al 2006, ‘Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology’, Journal of Allergy and Clinical Immunology, vol. 117, no. 4, pp. S525–53. Al-Herz, W, Bousfina, A, Casanova, J-L, et al 2014. ‘Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency.’ Frontiers in Immunology, Vol 5, article 162, pp1-33. doi: 10.3389/fimmu.2014.00162. Available from: http://journal.frontiersin.org/article/10.3389/fimmu.2014.00162/full |