This brief history of the origin and development of ICSH must, inevitably, be selective as it has been extracted from the many pages of the records of the meetings of the ICSH board and its secretariat, the annual assembly and the reports of the various expert panels and working groups. It is hoped that it will give a picture of the way in which ICSH functioned and the many experts around the world who have contributed to its activities – but with an apology and appreciation, to other colleagues who have not been named in this annotation, but who made significant contributions to the activities that are described.
In the 1950s, there was confusion with the various methods used in erythrocytometry and the clinical interpretation of laboratory test results. For example, there were several methods for the measurement of haemoglobin, each with its own so-called standard. Thus, by the Haldane method in general use in the UK, 100% represented 13 g/dl, whilst with the Sahli method favoured in Europe 100% was 17 g/dl, and in the USA a number of laboratories were using the haemiglobincyanide (HiCN) method with Drabkin’s cyanide–ferricyanide reagent. A patient might well have been diagnosed as being either anaemic or polycythaemic, depending on where the test was performed. There had been sporadic attempts to standardize haemoglobinometry – Dr L. Heilmeyer, Prof. Medicine at the University of Freiburg im Breisgau, had established a German Haemometer Test Board (Hämometerprufstelle) in the 1930s, and had proposed the spectrophotometric constants of haemoglobin as the basis for standardization of haemoglobinometres. In the Netherlands, Dr Jan (Jip) Spaander, whilst working under wartime conditions at the Red Cross Blood Transfusion Service in Amsterdam, had studied the need for standardized methods for preservation of blood, and he had also been confronted with the problem of variations in syringe and needle fittings which had often led to inability to give an urgently required blood transfusion. He subsequently became the Director General of the Dutch Institute for Public Health [Rijks Institut voor de Volksgesondheid (RIV)], and was influential in the decision by the International Standardization Organization to establish Technical Committee TC/76 for Transfusion, infusion and injection equipment.
During a round-table discussion on haemocytometry at the 8th Congress of the European Society of Haematology in Vienna in 1961, the need for improved methods and for international collaboration to establish standardized methods were considered. In an attempt to assess the extent of the problem for haemoglobinometry, a small international trial was organized by J. F. Coster from the Dutch RIV and CG Boroviczeny from the German Society for Internal Medicine, with 50 participating laboratories in Netherlands, Belgium, Germany, Austria and Switzerland. Samples from a single blood specimen were reported by these participants to have haemoglobin anywhere between 11 and 18 g/dl – and the laboratories chosen for this trial included the most eminent laboratories who were recognized as being ‘extremely well qualified and aiming at high standards of accuracy and reliability’.
This study was reported at a symposium entitled Standardization of erythrocytometric methods during the 9th Congress of the European Society of Haematology in Lisbon on 31 August 1963, published in Bibliotheca Hematologica No. 18 (Table 1). The participants recognized the extent of the problem and the need for its resolution. They proposed to form the Standardizing Committee of the European Society of Haematology with the initial aim to develop a standardized method for haemoglobinometry. A managing board was elected with Prof. Heilmeyer as chairman, Jip Spaander as vice-chairman. The other members were G. Astaldi (Italy), G. Boroviczeny (Germany), J. Coster (Netherlands), S. M. Lewis (UK), B. Thorell (Sweden); subsequently, when Heilmeyer was honoured to become the President of the Committee, Spaander was appointed as Chairman and Lewis as Executive Secretary, a productive partnership that would continue for 20 years. The participants at the Lisbon meeting included representatives of Council of Europe Committee on Public Health, League of Red Cross Societies, International Standards Organization, all of whom expressed their interest, whilst a letter of support was also received from the Director General of WHO.
Table 1. ICSH monographs
Ch. G. de Boroviczeny (Ed.) 1961. Erythrocytometric Methods and their Standardization. Bibliotheca haematologica No. 18. Karger, New York.
Ch. G. de Boroviczeny (Ed.) 1965. Standardization, Documentation and Normal Values in Haematology. Bibliotheca Haematologica No. 21. Karger, New York.
Ch. G. de Boroviczeny (Ed.) 1966. Standardization in Haematology Ill: Blood cell counts, Packed cell volume determination. Bibliotheca Haematologica No. 24. Karger, New York.
S.M. Lewis (Ed.) 1967. Automation in Haematology. British Journal of Haematology, 13(suppl.), Blackwell Scientific Publications, Oxford.
G. Astaldi, C. Sirtori, G. Vanzetti (Eds) 1968. Standardization in Haematology. Fondazione Calo Erba: Franco Angeli Editore, Milan.
G. Izak and S.M. Lewis (Eds) 1972. Modern concepts in Haematology: Haemoglobinometry, Iron assay, Automation, Computers. Academic Press, New York/London.
G Astaldi, G. Gusso, L.Tentori, G. Torlontano (Eds) 1972. Standardization in Haematology and Clinical Pathology CISMEL Publication. Archivio Casa Sollievo, San Giovanni Rotondo, Foggia (Italy).
R.M Schmidt (Ed.) 1975. Abnormal Haemoglobins and Thalassaemia.- Diagnostic aspect Academic Press, New York/San Francisco/London.
S.M. Lewis, J.F. Coster (Eds) 1975. Quality Control in Haematology. Academic Press, London/New York/San Francisco.
O.W. van Assendelft, J.M. England (Eds) 1982. Advances in Hematological Methods: The Blood Count ICSH Reference Methods, Potential Selected Methods, Cell Size Distributions, Calibration and Control Materials, CRC Press, Boca Raton, FL.
A.M.H.P. van den Besselaar, H.R. Gralnick, S.M. Lewis (Eds) 1984. Thromboplastin Calibration and Oral Anticoagulant Control: Papers presented at Workshop held in Leiden under Auspices of ICSH. Martinus Nijhoff, Dordrecht, the Netherlands.
S.M. Lewis, J.A. Koepke (Eds) 1995. Hematology Laboratory Management and Practice: Role of Physician in Haematology Laboratory Practice, Laboratory Management, Analytic Methods and Systems, Quality Assurance. Butterworth-Heinemann, Oxford, UK.
RM Rowan, OW van Assendelft, F E Preston (Eds) 2002 Advanced Laboratory Methods in Haematology: Blood count, Haemoglobinometry, Abnormal haemoglobins, Erythrocyte sedimentation, Haematopoietic factors, Coagulation testing. Arnold, London, New York
The first action of the Board was to appoint an Expert Panel on Haemoglobinometry. After extensive study, the panel recommended the HiCN method with a modification of the Drabkin reagent and specified a stable solution of HiCN as the reference preparation (see below). This was adopted at the 10th Congress of the International Society of Hematology (ISH) in Stockholm in 1964, and subsequently, this standard was recognized by other authoritative bodies, inter alia, the International Union of Pure and Applied Chemistry (IUPAC), the US National Academy of Science, International Federation of Clinical Chemistry (IFCC) and, especially significant, the World Health Organization.
Following this success, the board and the ISH agreed that the scope of the work of the standardizing committee would be of global interest with participation of colleagues from outside Europe; this required that its name should be changed to International Committee for Standardization in Haematology (ICSH) and the board was accordingly augmented with international representation that included J. B. Chatterjea (India), W. H. Crosby and R. J. Eilers (USA), G. Izak (Israel), R. J. Walsh (Australia), S. Watanabe (Japan); also subsequently J. A. Koepke (USA), R. L. Verwilghen (Belgium), S. Miwa (Japan). Russell Eilers had attended the Stockholm meeting as the representative of the Standards Committee of the College of American Pathologists. He was later instrumental in establishing the National Committee for Clinical Laboratory Standards (NCCLS; now CLSI) in the US, and for ensuring a close relationship of that influential organization with ICSH.
The WHO Expert Committee on Biological Standards (ECBS) designated the ICSH haemoglobin reference preparation as an International (Biological) Standard, and invited continuing collaboration with ICSH with a commitment to provide fresh batches at intervals and to ensure their continuing conformity with the previous batch. The ICSH standard is now established as a national standard in many countries and has become a corner stone of diagnostic laboratory practice and epidemiological studies worldwide.
The success of the haemoglobin project provided a model for ICSH, but it was first necessary to define its scope and to establish the practices to be used to achieve its objectives in the context of haematological laboratory practice. The fundamental principles were set out as follows.
The International Committee for Standardization in Haematology was established to achieve improvements in haematology laboratory functions by undertaking the following activities:
• promoting the development of international standards that are needed to achieve international comparability of results of haematological analysis;
• encouraging improvements of methods and standards used in haematological practice;
• maintaining a forum of communication amongst constituent organizations to achieve the above aims.
Definition of standardization
In the context of the ICSH programme, it was decided that ‘standards’ should include:
• specifications for biological and chemical reagents or reference preparations;
• reference materials and reference procedures (see below);
• systems of nomenclature;
• operating procedures and routine test performance;
• controls and calibrators for analysers and for other test procedures;
• interlaboratory harmonization.
Test procedures were defined as follows:
A reference method is an exactly defined technique used in association with an international reference preparation to provide sufficiently precise and accurate data for assessing the validity of other methods. A standardized method is an alternative to a reference method when an appropriate international reference material is not available. A selected method is a procedure that has been approved by a defined authority as being suitable for routine use, taking account of the limits of its bias and imprecision in the context of its intended (clinical) purpose, economy of materials and labour, ease of performance and safety. ICSH might also recognize a routine method that may have a lower level of reliability but is, nevertheless, acceptable under certain circumstances where the selected method may be impractical, e.g. in rural clinics with limited resources. ICSH would try to ensure that results by such a method are harmonized to make them clinically useful and at least to eliminate avoidable errors.
The principle was to achieve consensus and education based on collaboration between appropriate experts and communication, at both national level and internationally, with the professions, health authorities and industry, all of whom would have the opportunity to participate in the process leading to ICSH recommendations and to ensure their application in practice. It would also require an agreed list of priorities – and an estimate of the necessary funding. These principles and practical actions to achieve these aims were agreed to when the ICSH board met in New York in 1968 at the 12th ISH Congress.
ICSH defined four inter-related categories of members, each having specified obligations, to reflect the above-mentioned aims (Figure 1). The main authority would be the assembly comprising representatives of national societies of haematology and related disciplines, and appropriate representatives of relevant manufacturers. The assembly would elect the board whose responsibilities included approval of nominees to the assembly and appointment of expert panels. The board, in turn, would appoint from amongst its members, a secretariat including a chairman, secretary, treasurer and archivist. The secretariat would report to the board at its annual meetings. On 29 April 1968, the secretariat was registered legally in the Netherlands as the Secretariat Foundation for the International Committee for Standardization in Haematology. This provided the framework for a financial structure with an account in a Dutch bank.
A member of the board would participate in the meetings of the expert panels, thus ensuring appropriate presentation of draft documents, and their consistency with previous publications and views of other international organizations. In due course, a tentative standard would be assessed by the board and, if approved, then presented to the assembly – when endorsed by the assembly it would be promulgated as an ICSH Standard.
Response to the new organization
As described above, the important objective was for the organization to revolve around the assembly and its link to national and international societies of haematology and allied disciplines. Thus, recommendations from the panels could be scrutinized by the national bodies to ensure that they are realistic and practical for the specific needs of their countries or regions. There was a good response from a number of countries, both industrialized and developing. The British Society for Haematology was very supportive, possibly encouraged by the fact that Mitchell Lewis, secretary of ICSH was also, at that time, secretary of the BSH Committee. This resulted in founding of the British Committee for Standards in Haematology (BCSH) – its name indicating its concern with standards of practice as well as standardization of technical procedures. In the USA, Eilers promoted the establishment of the NCCLS; liaison was also established with the College of American Pathologists, who appointed Douglas Triplett as their representative. Boroviczeny developed haematology activities in the German INSTAND and similar associations with ICSH were established in Italy (CISMEL), in the Scandinavian countries (NORDKEM), also in Spain, Japan, Korea and notably with a number of East European countries.
It was originally conceived that ICSH recommendations would be offered to the national bodies for their adoption as national practice standards. However, in some instances, the children have outgrown their parent, and many national standards are being developed in advance of ICSH; but adoption of international, as opposed to national standards, remains an essential component of present-day global health needs. As it was considered important to take into account the role of manufacturers; their technical experts would be invited to become members of panels where they would be encouraged to make relevant scientific observations.
The link with ISH developed into a close relationship. The meetings of the ICSH board usually took place at their international congresses, whilst a representative of the ICSH secretariat became a member of the ISH Board, and presented an annual report of its activities at the board meeting. To endorse this collaboration, ISH appointed Lewis, secretary, and then Chairman of ICSH, to be a counsellor-at-large of their council, and subsequently R. L. Verwilghen served as both ICSH Executive Secretary and Secretary General of the European-African Division of the Society. The scientific programme of the biannual World congresses and the Conferences of the European-African Division in the alternate years, regularly included a symposium organized by ICSH. These symposia attracted large audience and a number of them were published as ICSH monographs (Table 1).
The work of ICSH became increasingly recognized as authoritative by other professional societies associated with laboratory practice, notably International Society of Blood Transfusion (ISBT), International Society on Thrombosis and Haemostasis (ISTH), the IFCC and World Association of Societies of Pathology (WASP). Each of these organizations had a representative on the ICSH board and joint panels/working groups were established. The relationship with both ISTH and ISBT was reinforced when their most distinguished members, P. Mannucci and H. Gunson, respectively, were invited to serve in different years as the president of ICSH.
In recent years, there has been increasing appreciation of the need for intralaboratory quality control and interlaboratory comparability, by both the laboratory personnel and the organizations concerned with standards at global, regional and national levels. ICSH was aware of the importance of these links, and soon after it was founded the secretariat established a liaison with the International Standards Organization, specifically with their technical committee TC/76 (transfusion, infusion and injection equipment for medical and pharmaceutical use) as the only one relatively appropriate for ICSH activities. Subsequently, this association with ISO was transferred to TC/212 (clinical laboratory testing and in vitro diagnostic test systems). Liaison was also established in Europe with CEN/TC140 (in vitro diagnostic medical devices); ICSH had representatives at the meetings of both these committees and also with the European Community Bureau of Reference (BCR). An important development in 1997 was the CEN-based requirements for control of in vitro diagnostic devices (IVDD) which was to become a mandatory EC directive; this included standards for performance evaluation, testing of stability, standardized symbols and colour codes used for IVDs, specimen control, elimination or reduction of the risk of infection, consistent performance in an EQA/proficiency testing programme. The ICSH representatives (Verwilghen, Shinton, Heller, Lewis) were well versed in these aspects and made influential contributions to the documents.
From the outset, WHO had expressed an interest in the work of ICSH and approved of an official relationship as a non-government organization, with the right to participate in the annual World Health Assembly as well as the WHO Regional conferences. A working relationship with WHO was also developed for active consultations on relevant topics, including regular preparation of joint publications (Table 2) and participation in the annual meetings of the ECBS. Of particular note was a consultation in March 1975 to implement the 1974 World Health Assembly resolution (WHA/27.62) that called for ‘development of standards and standardization of health laboratory diagnostic methods and materials’. Following this consultation, a member of the ICSH secretariat was appointed as a WHO temporary adviser and the continuous collaboration with ICSH was also referred to at a subsequent World Health Assembly when the director of the Health Technology Department expressed the hope that close co-operation with ICSH would be maintained (WHA report A32/A/SR/6). Lewis, as secretary and then chairman of ICSH, played a pivotal role as he was at that time director of the UK National External Quality Assessment Scheme (NEQAS) and was instrumental in organizing the WHO/International EQAS that provided links to senior haematologists in many countries. At the request of WHO, he also organized national workshops on laboratory standardization in a number of developing countries and ensured that the role of ICSH was constantly brought to the attention of the participants at many WHO conferences. Following a WHO meeting on the relationship of haemoglobin to anaemia (WHO website: WHO/EHT/04.12) collaboration with ISH and ISBT was proposed, in order to assess appropriate haemoglobin level for blood donor screening in different situations. This project remains to be developed.
Table 2. Joint WHO-ICSH documents
Determination of the haemoglobin content of blood, 1971. WHO/BS/71.1026 and WHO/HLS/71.46.
Methods for the determination of packed cell volume, 1976. WHO/LAB/76.3.
Recommended method for the determination of the haemoglobin content of blood, 1980. WHO/LAB/80.3.
Recommended methods for the determination of packed cell volume, 1980. WHO/LAB/80.4.
Recommended method for the determination of the haemoglobin concentration of blood, 1984. WHO/LAB/84.10.
The principles and methods of quality assurance in haematology, 1984. WHO/LAB/84.3.
Anaemia: Fundamental Diagnostic Haematology. CDC/WHO in collaboration with ICSH, 1984.
Quality assurance in haematology: a training course manual and practical workbook, 1984. WHO/LAB/84.6.
Standardized Romanowsky staining of blood and bone marrow films, 1986. WHO/LAB/86.1.
Quality Assurance in haematology, 1986. WHO/LAB/86.6.
Recommended methods for the visual determination of white cell and platelet counts, 1988. WHO/LAB/88.3.
Recommended methods for the determination of packed cell volume by centrifugation, 1989. WHO/LAB/89.1.
The Bleeding and Clotting disorders: Fundamental Diagnostic Haematology. CDC/WHO in collaboration with ICSH, 1992
ICSH guidelines for reticulocyte counting by microscopy of supravitally stained preparations, 1992. WHO/LBS/92.3.
Calibration and maintenance of semi-automated haematology equipment, 1992. WHO/LBS/92.8.
Recommendations for standardization, safety and quality control of erythrocyte sedimentation rate, 1993. WHO/LBS/93.1.
Safety in health-care laboratories 1997. WHO/LAB/97.1.
Calibration and control of basic blood cell counters, 1997. WHO/LAB/97.2.
Laboratory services for primary health care: requirements for essential clinical laboratory tests. 1998 WHO/LAB/98.1
The activated partial thromboplastin time 1998. WHO/LAB/98.2.
Quality assurance in haematology 1998 WHO/LAB/98.4.
Use of anticoagulants in diagnostic laboratory investigations. 1999. WHO/LAB/99.1
Recommended method for the determination of packed cell volume by centrifugation. 2000: WHO/DIL/00.
These many collaborations established a close personal working relationship between the members of the ICSH secretariat and the director of the WHO Department of Essential Health Technologies (EHT) – also termed, at different times, Department of Blood Safety and Clinical Technology (BCT), Health Laboratory Technology (LAB), Diagnostic Imaging and Laboratory Technology (DIL), Laboratory Technology and Blood Safety (LBS).The successive directors were usually haematologists or general clinical pathologists, but more recently, priority given to other aspects of the extensive work programme of this department as well as financial constraints, have inevitably diminished the consultations with ICSH. However, ICSH continues to be recognized formally as a non-government organization in official relations with WHO; Dr Keith Hyde, director of the UK NEQAS, is also the director of the WHO Collaborating Centre for External Quality Assessment and he has been appointed by ICSH as their named representative to WHO. This gives the right to attend the annual World Health Assembly in Geneva as well as maintaining contact with the regional offices at their annual conferences worldwide.
ICSH also established a working relationship with the International Atomic Energy Agency who collaborated in the development of several standardized methods using radioisotopes, financing panel activities and providing the secretariat support and meeting facilities at their Vienna headquarters.
Initially, the work of ICSH was made possible by means of a grant from the Council of Europe to establish the haemoglobin standard; subsequently the RIV produced consecutive batches of the haemoglobin standard without charge. The Council of Europe also financed the work of the cytometry panel. But as ICSH expanded, so did the need for adequate funding. The experts who served on the panels and the secretariat gave their services freely. Fortunately, the secretariat was allowed, and even encouraged, to use the office facilities of their professional departments for what was accepted as a worthwhile academic activity whilst the expert panel members enjoyed academic freedom to pursue the relevant scientific studies. Funds for panel meetings were derived partly from annual subscriptions from ISH and national haematology societies, partly from WHO research grants and collaborative projects with WHO to cover the cost of joint meetings, and partly from donations from commercial companies. These companies were entitled to appoint representatives to participate in the panel meetings but these representatives were expected to be recognized scientists who would contribute, without bias, to the technical discussions and decisions of the panels. This policy was certainly successful – none more so than with the cytometry panel, whose early membership included Wallace Coulter himself as well as the most senior scientists from Technicon and Sysmex – all of whom provided valuable advice during the panel discussions and were concerned with the scientific excellence of the panel’s publications rather than with any personal ‘point scoring’.
The secretariat was appointed by the board with responsibility for running the organization. The first meeting of the secretariat, with Spaander as chairman, Lewis as executive secretary, took place in Freiberg as guests of Prof. Heilmeyer. Subsequent meetings were held in the Netherlands at the the RIV, and also during the congresses of the International Society of Hematology. In 1966, the original secretariat was extended to include Eilers and Izak. Thereafter, Koepke and Verwilghen became members of the secretariat in 1978, and O. W. van Assendelft in 1981. Under Spaander’s influence, the members of the secretariat developed a close-knit relationship with each other, to the benefit of ICSH as a whole. Their meetings were also attended by the chairmen or other members of several of the expert panels and also by representatives of WHO and the European BCR.
When Spaander retired in 1982, Lewis was appointed as chairman and Verwilghen as executive secretary – for a 12-year partnership that was to be as productive as had been that of the previous era. The new RIV Director General offered the secretariat the continued hospitality of his institute, but thereafter meetings began to take place in other centres, coincident with congresses or with meetings of the cytometry and other expert panels, and also at WHO headquarters in Geneva. In 1994, R. M. Rowan succeeded Verwilghen as executive secretary, and in 1995, van Assendelft became chairman. Lewis remained on the secretariat as liaison to WHO, as well as to ISH.
The expert panels
At the outset, 13 expert panels and three working groups on aspects of documentation were established. A brief review of their main activities is given below.
Some panels were disbanded as their work was considered to have been completed whilst others have extended their work to meet new challenges. An important role of the board is to constantly review all the published ICSH standards and to ensure that account is taken of new devices and developments in technical procedures that may affect laboratory practice.
Over the 40 years, over a 100 ICSH documents have been published in leading journals. A number of these are listed in the References. Many have been incorporated into WHO guidelines and national standard operating procedures.
This panel was initiated by two leading Dutch scientists, E. J. Van Kampen and W. G. Zijlstra, later joined by their student Onno van Assendelft, who became chairman, and continued the studies at the USA Center for Disease Control in Atlanta. The standard proposed by ICSH was a batch of HiCN produced at the RIV and checked by an international group of experts at eight centres. At approximately 5-year intervals, a new batch was provided, but further studies have shown a much longer period of stability.
The present (sixth) batch is held by the WHO International Laboratory at the UK National Institute for Biological Standards and Control (98/708) and part of the same batch has been adopted as a European standard and held by the European Union’s Institute for Reference Materials and Measurement (BCR-522). The stability of this material has been tested at intervals by a laboratory appointed by WHO. As this batch is nearing the end of its expected stability, another HiCN preparation has been developed by the new ICSH panel in partnership with Eurotrol, and this has been undergoing tests to ensure that it should be able to replace the existing WHO and BCR haemoglobin standards for general use.
The first paper on this topic was intended specifically in relation to collection of blood under standardized conditions for defining reference values. It was prepared as an introduction to studies on reference values by an ICSH task force in collaboration with an IFCC expert panel on the Theory of Reference Values (see later). Other studies were related to collecting, processing and storing blood specimens for routine haematological tests. In view of the fundamental importance of this, it is surprising that ICSH did not set out guidelines until 2002, when two documents were published: Haematologists should ensure that these documents are made known to phlebotomists and other health workers, including general practice staff who collect blood for despatch to the laboratory.
This became perhaps the most active and productive panel with a number of published papers that have had a significant influence on laboratory practice. Initially, there were separate groups: (i) blood cell counting, chaired by P. J. Crossland-Taylor (UK); (ii) packed cell volume, chaired by J. M. England (UK); and (iii) cell sizing, chaired by England with Rowan as secretary, together with the members of the PCV group.
The augmented panel chaired by England now included the Haemoglobin expert van Assendelft as well as W. H. Coulter and his medical director A. Richardson Jones who had originally been a clinical pathologist in the UK. Subsequently, with the increasing use of automated analysers, these groups merged into a single entity with the same members, but now augmented inter alia with B. S. Bull and G. Klee (USA), as well as with scientists from Technicon/Bayer (W. Groner), Sysmex (K. Fujimoto) and Abbott (L. van Hove).
With great skill, the chairman Victor Herbert achieved unanimity from his usually argumentative colleagues, and by means of a multilaboratory study the panel developed a vitamin B12 serum standard that was accepted by the WHO Expert Committee for Biological Standards (82/652), and the panel also proposed a whole blood folate standard. However, after some years these became obsolete and they have now been superseded by a serum vitamin B12 and serum folate standard (03/178) developed jointly by the UK National Institute for Biological Standards and Control and UKNEQAS Scheme for Haematinics66
This was a particularly important panel because of the need for reliable identification of iron deficiency at a global level. With J. Fielding (UK) as chairman, the panel provided standardized methods for measurement of serum iron, iron binding capacity and serum ferritin. WHO recognized the importance of this work at a global level by awarding the panel a grant of $6000 over a 2-year period. This enabled the panel to undertake a collaborative study of a human ferritin preparation that became a WHO International Biological Standard. The latter has subsequently been replaced by a human recombinant ferritin preparation.
Diagnostic applications of radioisotopes in haematology23–29
The panel on this highly specialized topic worked in collaboration with the International Atomic Energy Agency (IAEA) who supported several meetings at its headquarters in Vienna and had representatives on the panel. The membership included P. L. Mollison (UK), N. I. Berlin (USA), as well as medical physicists and a radiotherapist L. Szur (UK) who was its first chairman. Their recommendations on red cell and plasma volumes, red cell survival, surface counting of red cell destruction, were adopted in the 1970s as standard practice by the specialists in this field. A recommended method for Indium-111 platelet survival studies was established in 1985, and in 1995, the panel was reconstituted with T. C. Pearson as chairman, to revise the recommendations for measurement of blood volume and interpretation of results.
E. Beutler, and subsequently S. Miwa, led the panel that produced recommendations on assay of the red cell enzymes of the glycolytic pathways, characterization of red cell pyruvate kinase variants, and screening test for glucose-6-phosphate dehydrogenase deficiency and screening test for pyrimidine 5′-nucleotidase deficiency. Setting standards tend in general to create dogmatism; it is refreshing for a panel to be sufficiently flexible to comment that ‘The panel is aware of the fact that reliable results are obtained by laboratories using methods which are different from those included in this report; the exploration of other techniques is considered to be desirable and there will, no doubt, be modifications to these recommendations as more is learned about red cell enzyme defects’.
But, nonetheless, the recommendations from this panel have become established as the most reliable procedures for the particular assays.
This panel was established in 1972 with Herman Lehmann as its chairman and J. M. White as secretary. Lehmann was the director of the WHO International Reference Laboratory for Abnormal Haemoglobins, based in Cambridge at the Medical Research Council Abnormal Haemoglobin Unit and he established a truly global panel with 23 members from 19 countries. The panel’s activities resulted in five authoritative documents published in 1977–1979. They including methods for establishing an abnormal haemoglobin composite of Hbs J-A-F-S-C and reference standards for Hb A2 and Hb F. WHO reference preparations were established for Hb A2 (89/666) and Hb F (85/616). A later (1988) document by a working group of the panel, with H. Marti as chairman, and included R. G. Schneider and G. R. Serjeant, provided recommendation for neonatal screening for haemoglobinopathies.
It is over a 100 years since Romanowsky developed his eponymous stain for blood films, and various modifications were initiated by others. But they all show stain variation, mainly because of the presence of contaminants in the commercial dyes. This is likely to cause confusion when films are exchanged between laboratories who are accustomed to using significantly different stains. It was at the suggestion of the WHO LAB department that this should be a project for ICSH. Accordingly, ICSH invited D. Wittekind from Freiberg to set up an expert panel to develop a stain based on pure azure B and pure eosin Y, with their purity expressed by their specified molar extinction coefficient. However, the high cost of pure dyes for this high throughput test rendered this standard impractical for most laboratories; furthermore, it requires the use of DMSO which is a potentially toxic solvent; thus, it was recommended that its use in a laboratory should be only to confirm the staining characteristics of their routine stains and for standardizing automated pattern recognition methods.
In 1984, Dr A Shibata organized the first meeting of a panel that established reference methods for a range of cytochemical procedures. They included peroxidase, alkaline phosphatase, acid phosphatase, non-specific esterase and naphthol AS-D chloroacetate esterase. In 1993, the panel was reconstituted with some change in membership, now including C. S. Scott (as chairman). Their objective was to establish criteria for classifying acute leukaemias based on combining morphological appearances with primary cytochemistry, intracellular phenotyping and membrane immunophenotyping.
Dr A. Westergren described his method for the erythrocyte sedimentation rate in 1921, and it rapidly became common screening tests for acute phase proteins worldwide. Over the years, variations were being used – plastic tubes instead of glass, different tube length and bore, different anticoagulants. At its foundation, ICSH set up an expert panel to consider a reference method, with E. Rewald (Argentine) as chairman and with Dr Westergren as a distinguished member of the panel with the status of elder statesman. The first publication of the panel’s recommendations appeared in 1971 and in 1980 WHO published a technical ‘broadsheet’ especially for under-resourced countries. The ICSH recommendations have been reviewed with revised versions published in 1973, 1977 and also in 1993, with J. Stuart as chairman, when the recommendation was for a reference method, a standardized method and selected methods for routine practice.
Parallel documents have also been published by various national authorities, e.g. British Standards Institute (BS2554), in the USA by NCCLS and its successor Clinical Laboratory Standards Institute (H2A5). This panel has also provided guidelines on selection of laboratory tests for monitoring the acute phase response, including recommendations for measuring plasma viscosity and erythrocyte deformability. These documents on standardization become increasingly important with the development of automated ESR devices.
A joint expert panel of ICSH and the ISBT was established, and as a first initiative a working party was set up to review the use of antihuman globulin (AHG) in routine practice. With D. Voak as chairman, the working party included C. P. Engelfriet, together with P. L. Mollison as a consultant; they establish optimal conditions and quality control for the use of AHG in routine practice and also set out specifications for international reference polyspecific AHG reagents. For some years, ICSH continued to have a formal relationship with ISBT and in recognition of this, Dr Harold Gunson, Secretary General (and past president) of ISBT, was vice-president of ICSH in 1994 and president in 1998–2000.
A serious difficulty in control of oral anticoagulant therapy was caused by the use of various thromboplastin reagents with different sensitivities. Reliable anticoagulant dosage required a standardized method with a reference thromboplastin. To try to achieve this, an expert panel was established jointly by ICSH and the Scientific and Standardization Committee (SSC) of the ISTH together with the WHO expert committee on biological standards and also with the European Union’s BCR. With GIC Ingram as chairman, and subsequently J. A. Koepke, the initial aim was to recommend a standard method for the prothrombin time test and to standardize the reagent thromboplastin by providing a primary reference preparation against which the response of any other preparation can be calibrated by means of an international sensitivity index (ISI). One batch of human brain thromboplastin was established as the international primary reference preparation and to this was ascribed an ISI of 1.0 (subsequently, this preparation was replaced by a human recombinant thromboplastin). Batches of rabbit, bovine and human brain thromboplastin were then assigned ISI related to the primary reference preparation, so that any manufacturer could assign an ISI to their routine reagents of the same material. Thus, a measurement with any commercial reagent would give a result that would be the same as if the test had been carried out with the primary reference thromboplastin. It was also recommended that results of routine measurements should be expressed as an international normalized ratio (INR); extensive studies at many centres have provided data on the level of INR required for any patient to ensure adequate anticoagulation without risk of haemorrhage.
At present, two WHO International standards/reference preparations that are held by the UK NIBSC are Human recombinant (RBT/05) and Rabbit, plain (RTF/95).
The European Commission’s Centre for International reference materials and Measurement hold a lyophilized rabbit thromboplastin (ERM-AD149) and lyophilized bovine thromboplastin (ERM-AD148). The official certification of these standards was undertaken by a group of experts from various countries, so as to meet the formal requirements of both WHO and BCR. The joint ICSH/ICTH recommendations for reporting prothrombin time in terms of the INR has had profound effect on anticoagulant control.
As a separate activity, a subcommittee with Koepke as its chairman, provided performance guidelines for the partial thromboplastin time test.
Some items of importance for understanding laboratory test reports were topics for working groups established by the Board. These were concerned, respectively, with quantities and units, reference values, proficiency testing.
The metric system has been in use since 1901. In 1954, an expanded version of this system adopted the name Systemè international d’Unités (International System of Units) with the abbreviation SI. Its introduction into the medical laboratory was led by clinical chemists in Europe who had begun to report laboratory results in terms of the mole and the litre. ICSH was represented at a meeting in Munich in 1972 with the IFCC and the World Association of Pathology societies (WAPS) when it was agreed to recommend the use of SI ‘to the medical practitioners and all others concerned with health services throughout the world’. Whilst this would create no difficulty in reporting blood cell counts, ICSH was able to persuade the other parties that haemoglobin in molar concentration would be likely to confuse health workers in many countries for whom haemoglobin measurement was the fundamental screening test. It was therefore agreed that ‘for the time being, haemoglobin concentration in blood should be expressed in mass concentration either in g/l or g/dl’. When shortly thereafter the World Health Assembly recommended ‘adoption of the SI by the entire scientific community and particularly by the medical community throughout the world’, the ICSH stance was fully supported.
On another topic, the tradition of expressing the differential leucocyte count proportionately in percentage of each cell type can be misleading. To avoid confusion, ICSH recommended that for both clinical interpretation of data and publication purposes, the differential leucocyte count should always be expressed as the absolute numbers of each cell type per unit volume of blood. This has now been adopted extensively and is generally included in journal instructions on style.
An ICSH task force, in collaboration with the IFCC Panel on Theory of Reference Values, published recommendations on how to determine reference values for use in the rational interpretation of laboratory test results in haematology, taking account of the selection of the reference population, a reference sample group, reference distribution and reference limits. Together with appropriate statistical treatment of the data this provides a more precise and comprehensive interpretation than the traditional but inadequately defined ‘normal’ values. The recommendations also detail the standardized conditions for collecting the reference samples, inter alia, time of collection, precollection state, sampling method, whether from persons confined to bed or ambulant.
The College of American Pathologists had an interlaboratory survey programme functioning for laboratories in the USA in 1962. At about the same time, the international survey of haemoglobinometry described above, in the Introduction section, was being undertaken jointly by the German Society for Internal Medicine and the Dutch Institute of Public Health. In 1968, the newly formed British Committee for Standards in Haematology, in collaboration with the Department of Health established a national external quality assessment scheme (UKNEQAS). It is of interest to note that in 1974 the Council of Europe subcommittee of specialists on blood problems invited ICSH to prepare a report on quality control in haematology. Some years later, the World Health Assembly debated the urgent need for improvement in medical laboratory technology, especially in under-resourced countries; towards this objective, WHO consulted various international authorities, including ICSH. An international scheme (IEQAS) was started, with the ultimate goal of establishing EQA schemes at national and/or regional levels worldwide. Mitchell Lewis was invited to direct the haematology component of the IEQAS, which has become an important activity of the UKNEQAS. In 1998, a guideline document on the organization and management of external quality assessment was developed for ICSH by the cytometry panel, based on the requirements for the blood count, but with principles applicable to all aspects of haematology.
The later years
From 1990, the ICSH Presidents were, successively, Mannucci (Italy), Koepke (USA), Rozenberg (Australia), Gunson (UK), Bull (USA), Hughes (Australia) and Bellingham (UK). In 1993, Martin Rowan took over as executive secretary from Verwilghen. At the same time, Van Assendelft was appointed as chairman-elect of the secretariat, and succeeded Lewis when he retired as chairman in 1994, although he remained on the secretariat as liaison to WHO and ISH. A task force was set up by the secretariat to consider the future organization of ICSH.
They proposed to create a regional structure to achieve ‘effective interaction with management teams representing important geographical areas’. An important factor to be considered was the diversity of facilities and training in the different regions. There was some interest in the creation of such a regional ICSH in the former Eastern Europe, and in Central and South America; there was a much more positive response from Western Pacific-Asia, notably by the Japanese and Korean Societies of Laboratory Hematology. After much discussion at meetings in their region, it was agreed to establish the Asian Network for Laboratory Standardization and Harmonization, closely linked to ICSH, but as an independent entity.67,68
Another important aspect of the future role of ICSH was the need to ensure the practical utility of ICSH recommendations, and how to ensure that they would be passed on from the national ICSH contacts, usually from central laboratories, to the ‘foot-soldiers’ with limited facilities at the periphery. There have been previous WHO documents intended to meet this situation – e.g. the WHO Regional Office for South East Asia have published Guidelines on standard operating procedures for haematology (SEARO/HLM/320/2000) and Health laboratory services in support of primary health care in South East Asia (SEARO/Publication No. 24/1999).
In 2002, with Van Assendelft as chairman and Rowan as executive secretary, the secretariat members included Houwen (as treasurer-elect), Lewis (as ISH and WHO liaison). B. S. Bull, B. Fernandes (ISLH liaison), S. Heller, J. A. Koepke, and N. Tatsumi. This new ICSH team had an unenviable task. The 20th century had been a golden age for ICSH, but there was a changing era as institutional budgets were required to conform to administration-controlled prioritization, which does not include administration of the ICSH secretariat.
The International Society for Hematology still recognized the importance of the work of ICSH, and the traditional symposia at ISH congresses and Divisional conferences continued until 2005 with a symposium on nutritional anaemia at the European-African divisional conference in Istanbul. But the congress programmes were becoming increasingly orientated to clinical aspects of haematology, whereas the International Society for Laboratory Haematology had become the main international forum for laboratory-based topics. In 1998, Berend Houwen, President of ISLH, was invited to become a member of the secretariat to foster liaison and recipricocity between ICSH and ISLH. This led to collaborative studies and to the joint publication of a standard on platelet counting,15 as well as other ICSH documents relating to haematocrit that were published in the ISLH-linked journal Laboratory Hematology.16,17 Furthermore, Houwens strengthened the links between ISLH and ICSH by inviting the ICSH secretariat to hold some of its meetings alongside the Banff Springs symposia. Over the next few years, other topics were being proposed for collaborative projects –inter alia, definition of the reticulated platelets, the extended differential leucocyte count, rare-event analysis, statistical methods for instrument evaluations, detection of foetal cells. It was also proposed to establish a new panel on Applications of Information Technology and (in conjunction with the International Society of Blood Transfusion) a panel on molecular pathology, including standardized methods for PCR tests.
ICSH then had a major setback when Martin Rowan developed a serious illness that led to his death in 2005, and, shortly afterwards, Berend Houwen died suddenly. By then, the main panel activities were restricted to cytometry. This panel continued to meet annually and between 1998 and 2003 they published five further papers4, 14–17, as well as five documents for WHO (Table 2). Rowan and van Assendelft (together with the coagulation expert FE Preston, had also published an ICSH book on Advanced Laboratory Methods (Table 1).
By 2005, the time had come for ICSH to be reorganized to take account of the decreasing input from ISH, and the increasing contacts with ISLH. Discussions were initiated between members of the ICSH and ISLH boards. Notably, ISLH president Elkin Simpson had been invited to be ICSH president in 2006. A new structure for ICSH was adopted at the ISLH conference in Amsterdam in April 2006; this has been described by McFadden et al in an editorial in this journal. 69