Indication - Primary Immunodeficiencies
Plasma immunoglobulin levels (IgG, IgA, IgM)
First added in 2019
Changed in 2020
To identify patients with low plasma immunoglobulin levels and to monitor replacement
WHO prequalified or recommended products
WHO supporting documents
ICD11 code: 4A0Z
Summary of evidence evaluation
No detailed evidence or summary of evidence was provided to support this submission; however, the method has been the reference standard for estimation of immunoglobulins. Supporting evidence for inclusion of these tests is provided by the trials considered by the EML for listing immunoglobulin therapies based on reported low values of IgG, IgM and IgA.
Summary of SAGE IVD deliberations
Counterpart immunoglobulin replacement therapies are listed in the WHO EML for both adults and children. Use of the tests for diagnosis of immunodeficiencies is well established in international practice and incorporated into the best practice recommendations and diagnostic criteria of the American Academy of Allergy, Asthma and Immunology, the Jeffrey Model Foundation and the European Society for Immunodeficiencies. The test is recommended by a number of professional associations. The test methods have been standardized against the certified reference material in human serum of the Institute for Reference Materials and Measurements.
SAGE IVD recommendation
The SAGE IVD recommended conditional inclusion on the EDL of the IVD for measuring plasma levels of IgG, IgA and IgM for diagnosis of immunodeficiency, pending submission of evidence of its clinical usefulness, with testing in various regions in field surveys, within 1 year. The Group noted that use of the test is expensive and requires highly skilled laboratory technicians. No evidence was provided of its use in LMICs, except in a few countries in Central America. Furthermore, the submission did not include an evaluation of evidence that patients were treated with the associated EML drugs as a result of use of the test, and no evidence was given for its diagnostic accuracy or safety. No guidelines for its use appear to be available. 3rd EDL Edition: Additional evidence to support this listing was provided and reviewed by SAGE IVD. During their third annual meeting (held as a series of remote sessions from June to July 2020), SAGE IVD recommended reversing the conditional listing.
Details of submission from 2020
Disease condition and impact on patients: In a study of 32 patients with primary immunodeficiency, more than two thirds experienced diagnostic delay, which led to serious morbidity, including pneumonia, meningitis, osteomyelitis and septicaemia (1). In the USA, the proportion of hospital admissions for primary immunodeficiency increased each year between 2001 and 2005, and patients had significantly longer hospital stays. The most common comorbidities included non-specific fever, splenomegaly and failure to thrive, respiratory infections, pathogen-specific infections and chronic lung disease (2). Data from a service for over 1000 patients with suspected primary immunodeficiency in Asia showed that families had often lost one or more children to undiagnosed immunodeficiency before the current diagnosis (3). Long delays in diagnosis and many infectious episodes can reduce the quality of life and result in permanent functional impairment (1). Does this test meet a medical need? Primary immunodeficiency can often be diagnosed with two simple blood tests – a complete blood count with differential white cell count and serum immunoglobulin levels (3); however, although these tests are inexpensive, they are not necessarily available in all countries. Criteria for fast, reliable diagnosis of primary immunodeficiency include physician- friendly algorithms (4), with multi-stage diagnostic protocols for different clinical presentations so that patients are referred early for therapy (3). The target population is people with primary immunodeficiency, who have no protection against common pathogens and have life-threatening infections and increasing, permanent damage to various body organs, especially the lungs and intestines, making them more susceptible to severe infections. Many of the conditions that are present in childhood are genetic, and parental consanguinity is a risk factor for primary immunodeficiency. A positive family history is an important indication for screening. How the test is used: The IVDs listed in this application are part of diagnostic protocols to optimize a swift diagnosis. Examples of peer-reviewed published diagnostic protocols are reported in references 4 and 5.
Public health relevance
Prevalence: Primary immunodeficiency comprises over 350 inherited disorders due to malfunction of components of the immune system. The condition may be more common than previously estimated, with as many as 1% of the population affected. Socioeconomic impact: Diagnostic delays lead not only to deterioration of the patient’s condition and difficulty for carers but also to inappropriate use of health resources, including avoidable visits to specialists for recurring infections. Early diagnosis resulted in lower costs than in the previous year, even if regular immunoglobulin replacement therapy was required. The annual saving by the health care system for each diagnosed patient was US$ 85 882 (6). In a study of early diagnosis and management of primary immunodeficiency in the USA, the average annual cost to the health care system for each patient with undiagnosed primary immunodeficiency was US$ 102 552; early diagnosis and treatment saved an average of US$ 79 942 per patient per year (7).
WHO or other clinical guidelines relevant to the test
Evidence for clinical usefulness and impact
Use of these tests in the diagnosis of immunodeficiency is well established in international practice and in the recommendations of the American Academy of Allergy, Asthma and Immunology, the Jeffrey Modell Foundation and the European Society for Immunodeficiencies.
Evidence for economic impact and/or cost–effectiveness
Few comparative data on the cost–effectiveness of the test for these rare diseases were available. Nephelometry or turbidimetry to measure plasma levels of IgG, IgA and IgM involves high start-up costs for analysers and staff and may be suitable only for hub laboratories in resource-poor areas. The typical cost is £ 8–12 (US$ 10–15.5) in the United Kingdom and, in India, 75 INR (US$ 1.03) per test to the hospital and 100 INR (US$ 1.38) to the patient. Serum-free light chain involves high initial costs for analysers and staff and may be suitable only for hub laboratories in resource-poor areas. The typical cost is £ 8–12 (US$ 10–15.5) in the United Kingdom and, in India, 400 INR (US$ 5.55) per test for the laboratory and 500 INR (US$ 6.93) would be charged to the patient. The typical cost of radial immunodiffusion is £ 5.00 (US$ 6.4) in the United Kingdom and, in India, 175 INR (US$ 2.43) per test for the laboratory and 100 INR (US$ 1.39) to the patient. All the techniques require significant manpower, training and maintenance. Some, such as immunoglobulin measurement or ELISA/EIA for antibody detection in vaccine responses, are performed on multi-analyte platforms, which have many other uses. Automated tests are performed on random access platforms, with minimal hands-on time required, and semi-automated tests are performed on batch analysers, with slightly more hands-on time required. Nevertheless, these instruments must be operated by skilled and trained personnel. Expertise and significant training are required for interpreting the results. Significant skill and time are required to perform manual analyses.
Ethical issues, equity and human rights issues
Consent is required to obtain a sample. Antibody deficiency disorders are chronic and rare and are often diagnosed late or not at all, even in developed countries with effective, widely available access to health care. Once primary immunodeficiency is diagnosed, the right treatment can be prescribed. A prompt diagnosis is the priority, as it increases the chances of appropriate treatment, management and care. About 60% of patients require life-long treatment with immunoglobulin replacement therapy, which are WHO essential medicines for both adults (8) and children (9). The proposed IVD tests would help to close the gap between access to diagnosis and treatment and would probably be cost– effective. They would also help to reduce under-diagnosis: it is estimated that 70–90% of people worldwide have undiagnosed primary immunodeficiency (10). In the USA, the average time from symptom onset to diagnosis of primary immunodeficiency is 12.4 years (11). The first recommendation of the Asia-Pacific Economic Cooperation for enhancing access to safe therapy for people with immunodeficiency and bleeding disorders is to improve laboratory diagnosis (12). Inclusion of these tests would enable faster diagnosis of primary immunodeficiency and therefore increase equity for this patient population.
1. Jiang F, Torgerson TR, Ayars AG. Health-related quality of life in patients with primary immunodeficiency diseases. Allergy Asthma Clin Immunol. 2015;11:27. 2. Kobrynski L, Waltenburg Powell R, Bowen S. Prevalence and morbidity of primary immunodeficiency diseases, United States 2001–2007. J Clin Immunol. 2014;34(8):954–61. 3. Chapel H, Prevot J, Gaspar HB, Español T, Bonilla FA, Solis L, et al. Primary immune deficiencies – principles of care. Front Immunol. 2014;5:627. 4. Bousfiha AA, Jeddane L, Ailal F, Al-Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS primary immunodeficiency classification and diagnosis: guidelines for clinicians at the bedside. J Clin Immunol. 2013;33:1078–87. 5. De Vries E, Clinical Working Party of the European Society for Immunodeficiencies (ESID). Patient- centred screening for primary immunodeficiency: a multi-stage diagnostic protocol designed for non-immunologists. Clin Exp Immunol. 2011;167:108–19. 6. Modell V, Orange JS, Quinn J, Modell F. Global report on primary immunodeficiencies: 2018 update from the Jeffrey Modell Centers Network on disease classification, regional trends, treatment modalities, and physician reported outcomes. Immunol Res. 2018;66:367–80. 7. Condino-Neto A, Espinosa-Rosales FJ. Changing the lives of people with primary immunodeficiencies (PI) with early testing and diagnosis. Front Immunol. 2018;9:1439. 8. 20th Model List of Essential Medicines. Geneva: World Health Organization; 2017 (http://apps. who.int/iris/bitstream/handle/10665/273826/EML-20-eng.pdf?ua=1, accessed April 2019). 9. 6th Model List of Essential Medicines for Children: Geneva: World Health Organization; 2017 (http://apps.who.int/iris/bitstream/handle/10665/273825/EMLc-6-eng.pdf?ua=1, accessed April 2019). 10. Primary immunodeficiencies (PID) – driving diagnosis for optimal care in Europe. European reference paper. London: World PI week; 2019 (http://worldpiweek.org/sites/default/files/basic_ page_documents/PI_European_Reference_Paper.pdf, accessed April 2019). 11. Primary immune deficiency diseases in America: 2007. The third national survey of patients. Towson (MD): Immune Deficiency Foundation; 2009 (https://primaryimmune.org/wp-content/ uploads/2011/04/Primary-Immunodeficiency-Diseases-in-America-2007The-Third-National- Survey-of-Patients.pdf, accessed April 2019). 12. APEC recommendations for enhancing access to safe therapy for persons with immunodeficiency and bleeding disorders. Singapore: Asia–Pacific Economic Cooperation; 2018 (http://blood.apec. org/wp-content/uploads/2018/01/17_lsif2_agn05.7_Access-to-Safe-Therapy-recommendations- FINAL.-docx.pdf , accessed July 2019).