Primary immune deficiency disorders (PIDs) are rare genetic defects resulting in compromised host defences.1Consequently, affected patients are susceptible to recurrent and severe infections, as well as autoimmunity and malignancy as a result of immune dysregulation.2-5The severity of PIDs range from asymptomatic IgA deficiency, to life-threatening infections from severe combined immune deficiency (SCID). The prevalence of these disorders vary, from being relatively common (1:300) for IgA deficiency, to extremely rare conditions, some of which have not been identified in New Zealand (population: 4.4M).1,6It is imperative PID patients are identified in a timely manner.7 Early identification of these conditions, and establishing appropriate treatment, may prevent or mitigate disabling complications such as bronchiectasis. If identified and treated promptly, the majority of patients can lead a full and active life with minimum morbidity.8Severe PIDs, such as SCID are a paediatric emergency and require immediate referral to Paediatric Immunology at Starship Children s Hospital, Auckland (Starship) for evaluation and treatment. In other cases, there is less urgency, such as patients with IgA deficiency suffering from upper respiratory tract infections. The potential severity of a disorder may not be apparent in the early stages, but there may be rapid deterioration if not identified and referred promptly. This occurs in patients with SCID, who may initially be well until they contract CMV or Parainfluenza 3 viral infections, making subsequent management very difficult. Similarly, patients with X-linked lymphoproliferative disease can remain well until they suffer a catastrophic EBV infection.9 In this example, early identification of males carrying the genetic defect, and pre-emptive bone marrow transplantation, is potentially curative with a much improved prognosis.10 These examples underscore the need for timely evaluation by specialists in clinical immunology.Once diagnosed, PID patients should be under the long-term care of an immunology service. This is essential, as there are many aspects of ongoing patient care which require regular input from an immunologist. Some patients may have persistent infections, while others may develop autoimmune and inflammatory sequelae. Furthermore, an immunologist is in the best position to undertake genetic studies, which can have profound benefits to the patient and the family.Currently, there is a serious maldistribution of clinical immunologists, and particularly immunopathologists, in New Zealand. Most immunologists work in Auckland. The Immunology Department at Auckland District Health Board (ADHB) employs seven part-time consultants, and one fellow. There are three part-time paediatric immunologists at Starship. Two clinical immunologists, and three allergy specialists, are exclusively in private practice in Auckland. The only public paediatric immunology service is based at Starship. also in Auckland.Christchurch and Wellington have two adult immunologists. A part-time paediatric allergist works in Wellington. The adult Immunology Department at ADHB offers a monthly outreach clinic in Whangarei. One part-time immunologist conducts monthly clinics at Waikato Hospital. The Immunology Department at ADHB has contracts to review a modest number of patients from other hospitals within the Auckland area, and other DHBs in the upper North Island. Other cities, as well as other hospitals in Auckland, do not have a visiting adult immunology service. Visiting paediatric immunology outreach clinics are conducted in Hamilton, Rotorua, Tauranga and Invercargill.As a consequence of the maldistribution of public hospital immunologists, some adult PID patients, and many with non-haematological secondary immunodeficiencies, have not had the opportunity to undergo a thorough immunology review, and regular follow-up. Current contractual arrangements between DHBs may result in financial disincentives for patient referrals for subspecialty reviews.11 For example, patients referred from DHBs without a contract with ADHB may be seen, but no funding follows these consultations, which may disadvantage local patients within the ADHB catchment area. By default, some adult patients remain under the care of general physicians or haematologists. In some cases, long-term subcutaneous or intravenous immunoglobulin (SCIG/IVIG) replacement has been initiated and continued without immunology consultation. The cost of SCIG/IVIG over a lifetime is more than $1M and is funded by the local DHB. As shown below, in many cases the inappropriate use of SCIG/IVIG has resulted in a major unnecessary financial burden to individual DHBs.In this Viewpoint, we present the case for a national service for patients with PIDs. A national PID service would significantly reduce healthcare costs, and more importantly improve patient care. This is similar to HIV medicine, where patients under the care of physicians with appropriate training and experience have significantly better outcomes.12 We describe some areas where input from an immunologist would make a significant difference to patient management, and would also substantially reduce healthcare expenditure.Hypogamma-globulinemia/Common Variable Immunodeficiency Disorder and SCIG/IVIG treatmentPatients presenting with hypogammaglobulinemia are a common clinical scenario. Within the spectrum of hypogammaglobulinemia, it is very important that patients with Common Variable Immunodeficiency Disorder (CVID) are identified at an early stage. CVID is the most common symptomatic PID in adults, with a prevalence of approximately 1:25 000.6 Symptoms can begin in adulthood in many patients.13 Failure to identify and treat CVID patients may place them at risk of bronchiectasis and/or life-threatening infections, including meningitis and septicaemia. Once identified, patients with CVID should receive long-term subcutaneous or intravenous immunoglobulin (SCIG/IVIG) replacement. Our recently published diagnostic criteria for CVID will allow a diagnosis of probable CVID to be made with more precision (Table 1).14 CVID is no longer a diagnosis of exclusion. Treatment guidelines are closely linked to diagnostic categories (Figure 1).15,16Table 1: Ameratunga et al (2013) diagnostic and treatment criteria for CVID.14,15 Category A: Must meet all major criteria Hypogammaglobulinemia IgG <5 g/l4 No other cause identified for immune defect17 Age >4 years2 Category B: Sequelae directly attributable to immune system failure (ISF) (1 or more) Recurrent, severe or unusual infections Poor response to antibiotics Breakthrough infections in spite of prophylactic antibiotics Infections in spite of appropriate vaccination eg HPV disease Bronchiectasis and/ or chronic sinus disease Inflammatory disorders or autoimmunity18 Category C: Supportive laboratory evidence (3 or more criteria) Concomitant reduction or deficiency of IgA (<0.8 g/l) and/or IgM (<0.4 g/l)3,19 Presence of B cells but reduced memory B cell subsets and/ or increased CD21 low subsets by flow cytometry20,21 IgG3 deficiency (<0.2 g/l)22,23 Impaired vaccine responses compared to age-matched controls24 Transient vaccine responses compared with age-matched controls25 Absent isohemagglutinins (if not blood group AB)26 Serological evidence of significant autoimmunity eg, Coombes test Sequence variations of genes predisposing to CVID eg, TACI, BAFFR, MSH5 etc27,28 Category D: Presence of relatively specific histological markers of CVID (not required for diagnosis but presence increases diagnostic certainty, in the context of Category A and B criteria) Lymphoid interstitial pneumonitis29 Granulomatous disorder 30,31 Nodular regenerative hyperplasia of the liver32,33 Nodular lymphoid hyperplasia of the gut34 Absence of plasma cells on gut biopsy35,36 Patients must be symptomatic to have CVID. To qualify as having probable CVID, patients must have supportive laboratory evidence of immune system dysfunction (Category C) or characteristic histological lesions of CVID (Category D). Patients with mild hypogammaglobulinemia (IgG >5 g/l) are termed hypogammaglobulinemia of uncertain significance (HGUS). Patients meeting Category A criteria but not other criteria are deemed to have possible CVID. Most patients with probable CVID are likely to require IVG/SCIG. Some patients with possible CVID will require SCIG/IVIG but most patients with HGUS are unlikely to need IVIG/SCIG replacement. We have suggested HGUS patients are categorised based on their symptomatic state ie sHGUS or aHGUS. Some patients with bronchiectasis with HGUS will need to be treated with SCIG/IVIG irrespective of vaccine responses.16 Figure 1: Treatment algorithm for CVID (Ameratunga et al 2013).14 As part of the clinical evaluation, predisposing factors for infections should be thoroughly assessed. It is possible the hypogammaglobulinemia is not the dominant cause for infections.14 In our experience, treatment of conditions such as chronic tonsillitis or chronic sinus disease may result in major improvement in the frequency of infections in some patients with hypogammaglobulinemia, without the need for SCIG/IVIG replacement.Given the very high cost of SCIG/IVIG, all PID patients should have an immunology evaluation prior to commencing treatment. We also strongly recommend that patients already placed on long-term SCIG/IVIG for PID should be regularly reviewed by an immunologist. We have recently identified an adult patient who had been on long-term IVI,G but was subsequently able to discontinue treatment as he had recovered from \u201ctransient hypogammaglobulinemia of infancy\u201d as an adult. As a result, we were able to successfully discontinue his IVIG. He remains well, with no increase in infections with an IgG of 6.5 g/l (7-14 g/l).Our diagnostic criteria may allow CVID to be confirmed, without the need to stop SCIG/IVIG in some patients, particularly if they have characteristic histological features (Table 1, category D).16 This could reduce the need to stop SCIG/IVIG treatment to undertake vaccine challenge responses, which can take several months. The patient may be vulnerable to sepsis during this time. Equally, these criteria may identify individuals who can safely discontinue SCIG/IVIG treatment permanently, if they have minimal symptoms, with normal memory B cells and normal plasma cells on gut biopsy (Table 1).It may not be initially clear if a patient presenting with hypogammaglobulinemia has a primary or a secondary immune deficiency. We have shown that our diagnostic criteria can also be useful in identifying patients with secondary immunodeficiencies.37-39 These criteria may also help in complex situations where an underlying primary immunodeficiency is aggravated by a secondary immunodeficiency, such as an anticonvulsant drug.38 Several other patients with secondary hypogammaglobulinemia have also been able to discontinue IVIG replacement uneventfully and remain well. These patients were commenced on IVIG by other services and successful discontinuation has resulted in significant cost savings.Once patients are placed on long-term SCIG/IVIG treatment, they need regular immunology review. Patients residing outside centres with immunology units would share their care with local paediatricians and physicians, in the case of adult patients. The frequency of the follow-up visits to immunologists will depend on the individual patient and their disorder. SCIG/IVIG treatment usually results in significant improvement of the frequency and severity of infections, but may not alter the risk of inflammatory disorders or malignancy. IVIG, and to lesser extent SCIG, can cause adverse effects,40 and having an immunologist involved in the patient s care can facilitate timely review and management of any complication from treatment. Other options, including an alternative immunoglobulin product, may need to be considered. These decisions are best made by immunologists, who are thoroughly familiar with alternative SCIG/IVIG preparations, which may need to be imported for a specific patient.Some patients with CVID have severe antibiotic allergies because of immune dysregulation. Managing these patients can be challenging and requires the expertise of an allergy/ immunology specialist. Diagnostic evaluation may include skin testing and drug challenges to confirm remission. Acute antibiotic desensitisation may be needed for management of severe bacterial infections. Again, this service is available in specialist immunology units.Patients with CVID are at risk of chronic upper and lower respiratory tract suppuration. We routinely share their care with the respiratory and ORL services. Many patients require functional endoscopic sinus surgery for chronic sinus disease. Having access to respiratory and ORL specialists with experience in PIDs is likely to improve outcomes in these medically complex patients. These are strong clinical arguments for placing patients with PIDs under the care of immunologists, which may be best done through a national service for PIDs. This would ensure uniformity of clinical care.The New Zealand Blood Service (NZBS) audit of SCIG/IVIG usePerhaps the strongest economic argument for a national PID service comes from a recent SCIG/IVIG audit conducted by the New Zealand Blood Service (NZBS, Blood Issues 28, October 2015, http://www.nzblood.co.nz/assets/Transfusion-Medicine/Blood-Issues-Newsletter-No-28-October-2015.pdf). The case notes of patients receiving SCIG/IVIG in 2012/2013 from 10 DHBS were reviewed. Access to old notes was sometimes difficult, given that some patients have been on IVIG for decades. Where notes were not available, the prescribing doctor was contacted for further information. This audit was undertaken by nursing staff in each NZBS area. NZBS has indicated there are limitations to the audit. It is likely there was some observer inconsistency. The audit did not determine if the patient was reviewed by an immunologist. Furthermore, the case notes were not critically reviewed by an immunologist and subtle nuances, such as responses to alternative treatments, were not recorded.The cost of SCIG/IVIG is $88 per gram, and the total cost to the New Zealand taxpayer is $29M per year. The NZBS determined compliance of SCIG/IVIG use against criteria published in the UK and Australia. The audit uncovered inconsistencies in the use of IVIG within the ten DHBs it audited (Tables 2 \u20135). It can be seen there was a high compliance rate in Auckland for PID patients, but relatively poor rates in some of the smaller DHBs without access to immunology services.Table 2: NZBS audit showing major indications for SCIG/IVIG. Diagnosis % total grams use Number of patient episodes and % of all episodes NBA guideline NHS guideline Number and % patients complying with qualification criteria Number and % patients complying with review criteria Number and % patients complying with qualification criteria Number and % patients complying with review criteria Primary Immunodeficiency 30% 172 (19.5%) 152 (88%) No criteria 152 (88%) No criteria Secondary Immunodeficiency 18% 186 (21%) 83 (45%) 136 (73%) 9 (5%) 165 (89%) CIDP 16% 65 (7.4%) 47 (72%) 49 (75%) 25 (38%) 50 (77%) ITP 6% 98 (11.1%) 92 (94%) 98 (100%) 90 (92%) 95 (97%) Guillain-Barr\u00e9 Syndrome 6% 65 (7.4%) 48 (74%) 58 (89%) 49 (75%) 52 (80%) Other conditions 24% 297 (33.6%) 219 (74%) 200 (67%) 242 (81%) 221 (74%) Total evaluable patients episodes 100% 883 (100%) 641 (73%) 541 (76%) 567 (64%) 583* (82%) NBA: National Blood Authority of Australia NHS: National Health Service UK. CIDP: chronic inflammatory demyelinating peripheral neuropathy. ITP: immune thrombocytopenia. Qualification criteria refer to the NBA and NHS guidelines, while the review criteria refer to ongoing clinical reviews. Table 3: NZBS audit showing use of SCIG/IVIG by various District Health Boards in New Zealand. DHB Intragam P use pa (g) Audit episodes Population* Intragam P use pa (g) per 1000 population Average age (years) Average weight (kg) Status Auckland 56,010 257 404,619 138 29 52 audited Canterbury 31,995 141 466,407 69 39 59 audited Capital and Coast 30,522 119 266,658 114 43 68 audited Counties Manukau 12,351 75 433,086 29 44 62 audited Hawkes Bay 7,260 27 148,248 49 40 66 audited MidCentral 9,630 41 158,841 61 45 70 audited Northland 8,349 35 148,440 56 36 61 audited Southern 21,063 80 286,224 74 53 67 audited Tairawhiti 2,250 7 44,463 51 40 54 audited Waikato 28,362 109 339,192 84 50 71 audited Bay of Plenty 17,343 73 194,931 89 not audited Hutt Valley 5,571 21 136,101 41 not audited Lakes 7,251 30 98,319 74 not audited Nelson Marlborough 5,787 26 130,062 44 not audited South Canterbury 666 5 53,877 12 not audited Taranaki 5,043 22 104,277 48 not audited Wairarapa 2,889 8 38,613 75 not audited Waitemata 8,655 73 481,611 18 not audited West Coast 855 4 31,326 27 not audited Whanganui 2,583 9 62,211 42 not audited In audit 207,792 891 Audited % 79% 77% Not audited 56,643 271 * based on population data 2012 Table 4: NZBS audit showing compliance in treating PIDs. The NZBS data do not subcategorise the specific type of PID. Therefore, it is difficult to determine if this is the expected number of PID patients in New Zealand who should be receiving SCIG/IVIG. DHB NBA compliant NHS compliant Overall use grams patients grams patients grams patients Auckland 23,952 (100%) 70 (100%) 23,940 (100%) 69 (99%) 23,952 70 Canterbury 8,043 (100%) 22 (100%) 8,043 (100%) 22 (100%) 8,043 22 Capital and Coast 9,012 (91%) 22 (92%) 9,588 (96%) 23 (96%) 9,948 24 Counties Manukau 876 (81%) 6 (86%) 1,086 (100%) 7 (100%) 1,086 7 Hawkes Bay 972 (82%) 2 (67%) 1,188 (100%) 3 (100%) 1,188 3 MidCentral 1,650 (100%) 4 (100%) 1,650 (100%) 4 (100%) 1,650 4 Northland 4,386 (90%) 12 (92%) 4,386 (90%) 12 (92%) 4,854 13 Southern 1,563 (30%) 5 (36%) 1,563 (30%) 5 (36%) 5,211 14 Waikato 3,627 (63%) 9 (60%)