THE COMMITTEE FOR THE STANDARDIZATION AND QUALITY ASSESSMENT OF COMPLEMENT MEASUREMENTS
Chair: Prof. Dr. Michael Kirschfink, Heidelberg, Germany
Co-Chairs: Prof. Dr. Zoltán Prohászka, Budapest, Hungary
Prof. Dr. Bo Nilsson, Uppsala, Sweden
Founding members of the Complement Analysis Standardization Committee 2009 Budapest
Numerous clinical and experimental studies indicate that complement is not only important for the protection against microorganisms, but also contributes to the pathophysiology of a number of non-infectious diseases. Furthermore, 5-10% of all primary immunodeficiency disorders are due to complement deficiencies.
Complement analysis in the clinic is traditionally associated with C3 and C4 quantification, measurement of C1-inhibitor and, in some better equipped laboratories, extended to functional complement screening tests, all parameters that have been available as routine diagnostic tests for decades. In recent years this field has grown, introducing novel assays to detect complement activation and expanding to include genetic analysis to reveal complement deficiency, as well as mutations and polymorphisms. These novel techniques are becoming very useful to define diseases such as atypical haemolytic uremic syndrome (aHUS) and age-related macular degeneration (AMD).
Another important application of traditional and novel complement diagnostic techniques is the assessment of the effect of emerging therapeutic drugs for complement-mediated diseases, such as eculizimab.
The improvement of medical care of patients requires high-quality laboratory diagnostic procedures and reagents that enable early detection of diseases and optimize oversight of therapy.
Improving diagnostic strategies requires the correct choice of analytes and the use of well-characterized methods that will yield consistent results between laboratories.
In the diagnosis of complement disorders, as in many fields of immunodiagnostic, there is considerable need for consensus and standardisation of analytical methods, which will be a major challenge for the complement society in the future.
Clinical analysis of the proteins of the complement system varies widely between laboratories because, except for a few proteins such as C3 and C4, there are no well- characterized standard preparations available on a wide scale. This is especially true for the inter-laboratory variation of functional assays such as the CH50 or AH50 (APH50), or lectin pathway function. An additional need exists for standardization of the measurement of the fragments of complement activation that can be used to determine whether clinically relevant complement activation has occurred in vivo. Finally, auto- antibodies to complement proteins (e.g. anti-C1q), C3 convertases (C3 nephritic factor) or antibodies to regulatory proteins (e.g. anti-C1inhibitor, anti-factor H) are of considerable importance in defining autoimmune processes and diseases based on complement dysregulation.
Subcommittee: Structure, Aims and Tasks
At the 2008 International Complement Workshop in Basel, Switzerland, a group of interested members of the International Complement Society (ICS) met to discuss the formation of a standardization committee and to define the major aims of this quality management initiative. Initiated by Prof. George Füst, Budapest, Hungary, a group of 18 complement scientists from 11 countries first met in Budapest in May 2009 (Fig. 1) . At this meeting, the need for standards was discussed and a plan was evolved to create several large pools of plasma and serum that would be evaluated in labs across Europe, the United States and other countries worldwide for measurement of defined proteins of the complement system. Prof. Hans Reinauer of INSTAND e.V, Düsseldorf, Germany, a non-profit, interdisciplinary scientific medical society for promotion of quality assurance in the medical laboratories offered the assistance of his organization in storage and distribution of the final product. INSTAND e.V. has been a Collaborating Centre for Quality Assurance and Standardization in Laboratory Medicine of the World Health Organization since 1994.
During the 12th European Meeting on Complement in Human Disease (2012), the Sub-Committee for the Standardization and Quality Assessment of Complement Measurements, belonging to the IUIS Quality Assessment and Standardization Committee (http://www.iuisonline.org), was formally established (the 'Complement EQA Group'). Six external quality assessment rounds were organized by the group between 2010 and 2016 with the organizational and financial help of INSTAND e.V., a Düsseldorf (Germany) based institute for promoting quality assurance in medical laboratories. From 2017 on INSTAND fully administers the annual EQA from online registration to samples distribution, data online acquisition. An official certificate is provided to all, meeting the quality standards for the respective complement analysis.
The subcommittee with its associated laboratories adopted the following goals:
To initiate and organize measures to improve the quality of complement analysis.
To make several standard materials available to the scientific and clinical laboratories which apply.
To define standardized methods of modern complement analysis.
To organize national and international workshops and training courses on modern complement analysis.
The Complement EQA group met in Budapest on January 22-23, 2016, with 31 participants representing 21 complement laboratories (Fig. 2 and 3). The group reviewed the accomplishments of the first five years of the program and discussed the path forward. Participants critically assessed their achievements and defined the next steps for improvement. The focus was to develop recommendations on assay preference, calibration, presentation and interpretation of results. Small working groups were established for various assays, wet lab experimentation will be done for assay evaluation and a final document will be released by the group documenting guidelines and recommendations for diagnostic complement analysis.
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