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.

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).

None reported

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.

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.

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.