Indication - Primary Immunodeficiencies
Lymphocyte subtype enumeration:CD3, CD4, CD8, B cells CD19 and/or CD20, CD16/56, T cells and NK cells (Refer to HIV infection for enumeration of CD4 cells only)
Facility level:
Assay formats
Flow cytometry
Status history
First added in 2019
Changed in 2020
Purpose type
Aid to diagnosis
To aid in the diagnosis of primary and secondary immunodeficiencies
Specimen types
Venous whole blood
WHO prequalified or recommended products
WHO supporting documents
ICD11 code: 4A0Z

Summary of evidence evaluation

No detailed evidence or summary of evidence was submitted to support this intended use. There is evidence of the accuracy and value of flow cytometry in differentiating lymphocyte subsets, particularly for diagnosis of leukaemia, extended to HIV infection and lymphoma. There is also clear evidence of the importance of accurate, early diagnosis in reducing morbidity and mortality and of cost–effectiveness. As flow cytometry is a routine diagnostic technique, with immunoglobulin estimation in high-income settings, the test has not been investigated individually. Its importance has been accepted by association.

Summary of SAGE IVD deliberations

Immunodeficiency consists of a wide variety of conditions and is underdiagnosed even in high-income countries. It contributes to a significant disease burden, which can often be relieved if the condition diagnosed early and treated appropriately. While estimates of immunoglobulin are widely used, they do not identify the cellular-based abnormalities, and a combined diagnostic approach is required. Both specific treatment and long-term care of chronically infected patients are expensive, with wide implications for the families of sufferers. The capital costs of a flow cytometric facility are high, as a dedicated laboratory with access to a reliable power supply and consumables is required. A flow cytometry facility for following up HIV patients and/or for diagnosis of leukaemia can also be used for immunodeficiency testing. This IVD for enumeration of lymphocyte subtypes is used in protocols to ensure swift diagnosis according to the clinical presentation; however, the technique requires significant manpower, training and maintenance, a dedicated machine and expertise and training for interpretation. The test is used and is recommended by a number of professional associations.

SAGE IVD recommendation

The SAGE IVD recommended conditional inclusion on the EDL of the IVD for enumeration of lymphocyte subtypes for diagnosis of immunodeficiency, pending submission of evidence for its clinical usefulness and use in LMICs within 1 year. The Group noted that the test is expensive and requires highly skilled laboratory technicians. No evidence was provided of its use in LMICs. 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). In a cohort of 2212 patients with common variable immunodeficiency, each year of diagnostic delay and each year of age at diagnosis were associated with a 1.7% and a 4.5% increase in the risk of death, respectively. 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 IVD is used in protocols to ensure swift diagnosis according to the clinical presentation. 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

None reported

Evidence for clinical usefulness and impact

Use of these tests in the diagnosis of immunodeficiency is well established in international practice and recommended by the American Academy of Allergy, Asthma and Immunology, the Jeffrey Modell Foundation and the European Society for Immunodeficiencies as best practice.

Evidence for economic impact and/or cost–effectiveness

Few comparative data are available on cost–effectiveness for this large group of rare diseases. Flow cytometry requires high initial costs for analysers and staff and may be suitable only for hub laboratories in resource-poor areas. The typical cost is £ 50–70 (US$ 64–90) in the United Kingdom. In India, the cost to the hospital is 720–940 INR (US$ 10–13), and that to the patient is 900 INR (US$ 12.45). This technique requires significant manpower, training and maintenance and a dedicated machine. Expertise and significant training are required for interpretation.

Ethical issues, equity and human rights issues

Consent is required to obtain a blood 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, and, according to their doctor’s advice. patients can lead a normal life with a lower risk of infections. 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).