Criteria for the clinical use of Intravenous Immunoglobulin in Australia - Second Edition

Development and maintenance of the Criteria

The purpose of the Criteria is to assist clinicians and transfusion medicine professionals identify the conditions and circumstances for which the use of intravenous immunoglobulin (IVIg) is clinically appropriate and able to be accessed under the National Blood Arrangements.

Development of first edition

In response to concerns that the AHMAC 2000 guidelines were in need of review, consultation about the development of criteria for IVIg use began in May 2004.

After a workshop was conducted in 2004 to gather information about the changes in the use of IVIg, the following activities, which led to the first edition of the Criteria being approved by Australian Health Minister’s in December 2007, were undertaken:

Further details of the arrangements and process for developing the first edition of the Criteria is provided at Appendix C.

2008 clarification process

As part of the process to implement the new Criteria, the National Blood Authority (NBA) established a clarification process in November 2008. A consultation group, comprising senior clinical advisers, IVIg Authorisers, clinical representatives from all jurisdictions and a Jurisdictional Blood Committee (JBC) representative, was consulted on specific queries that arose in relation to interpretation of the Criteria.

A Resolution Group, comprising the senior clinical advisers from the consultation group, and a JBC representative, was established to consider the input of the wider consultation group and to determine resolutions. The Criteria Resolution Group’s consideration of the queries and comments resulted in some amendments to specific indications in the Criteria. The revisions were published on the NBA’s website ( in February 2009.

Where agreement could not be reached on how to address the clarification matters, they were forwarded to the next formal review process. Any indications that were judged new indications were not considered as part of the clarification process.

2010–11 Criteria Review

In accordance with government commitments, JBC initiated a review of the Criteria in 2010. The 2010–11 Criteria Review was based on the following principles:

The focus of the 2010–11 Criteria Review was limited to proposals for any of the following:

In addition to providing evidence to support a proposal submitted to the review, each proposal also had to demonstrate international parity.

A National IVIg Criteria Review Working Group (NICRWG) was established to oversee the 2010–11 Criteria Review process.

The NICRWG comprised of representatives from both clinical and government sectors and individual experts who were engaged in the initial review.

The 2010–11 Criteria Review was undertaken using a rigorous and comprehensive process consisting of the following steps:

Throughout this process, experts from other clinical speciality areas were consulted for advice as required. Where possible, these individuals were sourced through relevant societies and colleges. Further details of the arrangements and process for developing the second edition of the Criteria is provided at Appendix C.

Assessment of evidence

During the development of the first edition of the Criteria and the 2010–11 Criteria Review, an assessment of the level of evidence was conducted.

The reviews followed the methods described in the National Health and Medical Research Council (NHMRC) handbook, How to review the evidence: systematic review and assessment of the scientific literature (NHMRC 2000)8 and the Evidence-based practice workbook published by BMJ Books (Glasziou et al 2007)9. Reviews were restricted to studies published since 2004 (the date of the last major systematic literature review conducted on the indications for IVIg use), and aimed to:

Biotext Pty Ltd was engaged by the NBA to undertake the systematic review. Biotext Pty Ltd worked closely with the NICRWG to develop review questions based on the ‘PICO’ method (population, intervention, comparator and outcome) for each condition included in the review.

Where appropriate, an evidence statement was developed for each clinical question using the NHMRC Evidence Statement Form as described in Additional levels of evidence and grades for recommendations for guideline developers (NHMRC 2008).10

An evidence report was prepared for each systematic review undertaken. The evidence reports included specific details of the review methods and search terms used for that particular condition.

As this was a partial review of the Criteria, and to ensure consistency in any revised edition, each evidence report includes an assessment of the alignment of the literature against the categories previously used in the Criteria, outlined in Table 1. As many of the systematically reviewed conditions are rare and there is limited published clinical evidence, this approach also assisted in the consensus process.

Table 1 Level of evidence categories

Level of evidence categories
Category Studies Evidence
1 High-quality randomised controlled trials (RCTs) Clear evidence of benefit
2a Some RCTs and/or case studies Evidence of probable benefit – more research needed
2b Some RCTs and/or case studies Evidence of no probable benefit – more research needed
2c High-quality RCTs with conflicting results Conflicting evidence of benefit
3 High-quality RCTs Clear evidence of no benefit
4a Small case studies only Insufficient data
4b No included studies -

Condition proforma

The clinical criteria are contained within condition proforma and have been set out to cover four major issues:

To establish if the patient is eligible to access IVIg funded under the National Blood Arrangements, the above clinical criteria are to be used in conjunction with:

Replacement and immunomodulation therapy

Most conditions considered for IVIg therapy comprise either an immunoglobulin replacement or an immunomodulatory indication. A few conditions involve both inflammatory and immunodeficiency phenomena and both indications may co-exist, or arise at different times.

Replacement therapy

In general, replacement therapy is indicated for patients who have primary or secondary immunodeficiency diseases only if they have recurrent and/or severe infections and deficient or absent antibody production.

In rare cases, recurrent infection may be related to a functional failure of the immune system to mount protective antibody responses to antigenic challenge despite normal serum total IgG. This is most often demonstrated by a lack of antibody response to polysaccharide and/or protein vaccines (i.e. antigenic challenge). Infection risk in immunodeficiency may also be related to deficits in peripheral blood subpopulations of memory B-lymphocytes defined by flow cytometry. However, serum levels of individual subclasses of IgG1–4 are relatively poorly predictive of infection risk.

Isolated IgG subclass deficiency is not sufficient to warrant IVIg therapy (see Specific antibody deficiency).

With very rare exceptions, replacement therapy is not indicated for patients who have laboratory evidence of immunodeficiency in the absence of clinical infections (i.e. primary prevention of infection). This is for three reasons:

Exceptions to this rule include the severe combined primary immunodeficiencies of childhood.

Immunomodulation therapy

IVIg can interrupt the pathological immune responses that result in a wide range of human diseases, including various diseases of the immune system, the nervous system, the blood and blood- forming organs, and the skin. The immunomodulatory effects of IVIg are likely to be exerted by several mechanisms that appear to act in concert. These mechanisms, which are not fully understood, include the following:

In general, immunomodulatory doses of IVIg are higher than replacement doses and some of the immunomodulatory actions are dose-dependent.

For each immunomodulatory indication, qualifying criteria are described and review criteria are listed. The qualifying criteria should be applied in deciding whether and how to use IVIg. The review criteria are intended as a guide to clinicians who are assessing the effectiveness of IVIg therapy in individual patients and, in many instances, facing a decision to continue or cease IVIg therapy.


The dosing of IVIg will vary, depending on whether IVIg is for replacement therapy or immunomodulation and the individual patient’s condition, clinical presentation, comorbidities, concurrent therapy and response. While there is some evidence for the use of dosing based on lean body weight, further research is required. The lowest dose for the shortest duration required to achieve the desired outcome should be chosen.

Research priorities

The systematic review of the available literature of treatment options for IVIg showed there was a paucity of high-quality studies. During the development of the Criteria and the 2010–11 Criteria Review, a number of gaps in knowledge and evidence were identified:


Governments recognise the need for the conditions identified for IVIg therapy and the clinical criteria for IVIg use to be reviewed regularly to take account of the evolving processes of disease diagnosis, treatment and outcome evaluation.