A National PID Service?

Home , Hereditary angioedema, Starship Hospital

VIEWPOINT

The case for a national service for primary immune deficiency disorders in New Zealand Rohan Ameratunga, Richard Steele, Anthony Jordan, Kahn Preece, Russell Barker, Maia Brewerton, Karen Lindsay, Jan Sinclair, Peter Storey, See-Tarn Woon

ABSTRACT Primary immune deficiency disorders (PIDs) are rare conditions for which effective treatment is available. It is critical these patients are identified at an early stage to prevent unnecessary morbidity and mortality. Treatment of these disorders is expensive and expert evaluation and ongoing management by a clinical immunologist is essential. Until recently there has been a major shortage of clinical immunologists in New Zealand. While the numbers of trained immunologists have increased in recent years, most are located in Auckland. The majority of symptomatic PID patients require life-long immunoglobulin replacement. Currently there is a shortage of subcutaneous and intravenous immunoglobulin (SCIG/IVIG) in New Zealand. A recent audit by the New Zealand Blood Service (NZBS) showed that compliance with indications for SCIG/IVIG treatment was poor in District Health Boards (DHBs) without an immunology service. The NZBS audit has shown that approximately 20% of annual prescriptions for SCIG/IVIG, costing $6M, do not comply with UK or Australian guidelines. Inappropriate use may have contributed to the present shortage of SCIG/IVIG necessitating importation of the product. This is likely to have resulted in a major unnecessary financial burden to each DHB. Here we present the case for a national service responsible for the tertiary care of PID patients and oversight for immunoglobulin use for primary and non-haematological secondary immunodeficiencies. We propose that other PIDs, including hereditary angioedema, are integrated into a national PID service. Ancillary services, including the customised genetic testing service, and research are also an essential component of an integrated national PID service and are described in this review. As we show here, a hub-and-spoke model for a national service for PIDs would result in major cost savings, as well as improved patient care. It would also allow seamless transition from paediatric to adult services.

rimary immune deficiency disorders establishing appropriate treatment, may (PIDs) are rare genetic defects result- prevent or mitigate disabling complications Ping in compromised host defences.1 such as bronchiectasis. If identified and Consequently, affected patients are suscep- treated promptly, the majority of patients tible to recurrent and severe infections, as can lead a full and active life with minimum well as autoimmunity and malignancy as morbidity.8 2-5 a result of immune dysregulation. The Severe PIDs, such as SCID are a paediatric severity of PIDs range from asymptomatic emergency and require immediate referral IgA deficiency, to life-threatening infections to Paediatric Immunology at Starship from severe combined immune deficiency Children’s Hospital, Auckland (Starship) (SCID). The prevalence of these disorders for evaluation and treatment. In other vary, from being relatively common (1:300) cases, there is less urgency, such as patients for IgA deficiency, to extremely rare condi- with IgA deficiency suffering from upper tions, some of which have not been identi- respiratory tract infections. The potential 1,6 fied in New Zealand (population: 4.4M). severity of a disorder may not be apparent It is imperative these patients are in the early stages, but there may be rapid identified in a timely manner.7 Early deterioration if not identified and referred identification of these conditions, and promptly. This occurs in patients with SCID,

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who may initially be well until they contract As a consequence of the maldistri- CMV or Parainfluenza 3 viral infections, bution of public hospital immunologists, making subsequent management very some adult PID patients, and many with difficult. Similarly, patients with X-linked non-haematological secondary immunode- lymphoproliferative disease can remain ficiencies, have not had the opportunity to well until they suffer a catastrophic EBV undergo a thorough immunology review, infection.9 In this example, early identifi- and regular follow-up. Current contractual cation of males carrying the genetic defect, arrangements between DHBs may result in and pre-emptive bone marrow transplan- financial disincentives for patient referrals tation, is potentially curative with a much for subspecialty reviews.11 For example, improved prognosis.10 These examples patients referred from DHBs without a underscore the need for timely evaluation contract with ADHB may be seen, but no by specialists in clinical immunology. funding follows these consultations, which Once diagnosed, PID patients should be may disadvantage local patients within under the long-term care of an immunology the ADHB catchment area. By default, service. This is essential, as there are many some adult patients remain under the care aspects of ongoing patient care which of general physicians or haematologists. require regular input from an immunol- In some cases, long-term subcutaneous ogist. Some patients may have persistent or intravenous immunoglobulin (SCIG/ infections, while others may develop IVIG) replacement has been initiated and autoimmune and inflammatory sequelae. continued without immunology consul- Furthermore, an immunologist is in the best tation. The cost of SCIG/IVIG over a lifetime position to undertake genetic studies, which is more than $1M and is funded by the local can have profound benefits to the patient DHB. As shown below, in many cases the and the family. inappropriate use of SCIG/IVIG has resulted in a major unnecessary financial burden to Currently, there is a serious maldis- individual DHBs. tribution of clinical immunologists, and particularly immunopathologists, in New In this Viewpoint, we present the case for Zealand. Most immunologists work in a national service for patients with PIDs. Auckland. The Immunology Department A national PID service would significantly at Auckland District Health Board (ADHB) reduce healthcare costs, and more impor- employs seven part-time consultants, tantly improve patient care. This is similar and one fellow. There are three part-time to HIV medicine, where patients under paediatric immunologists at Starship. Two the care of physicians with appropriate clinical immunologists, and three allergy training and experience have significantly 12 specialists, are exclusively in private better outcomes. We describe some areas practice in Auckland. The only public where input from an immunologist would paediatric immunology service is based at make a significant difference to patient Starship. also in Auckland. management, and would also substantially reduce healthcare expenditure. Christchurch and Wellington have two adult immunologists. A part-time paediatric allergist works in Wellington. The adult Hypogamma- Immunology Department at ADHB offers a globulinemia/ monthly outreach clinic in Whangarei. One part-time immunologist conducts monthly Common Variable clinics at Waikato Hospital. The Immunology Immunodeficiency Department at ADHB has contracts to review a modest number of patients from other Disorder and SCIG/ hospitals within the Auckland area, and IVIG treatment other DHBs in the upper North Island. Other Patients presenting with hypogammaglob- cities, as well as other hospitals in Auckland, ulinemia are a common clinical scenario. do not have a visiting adult immunology Within the spectrum of hypogammaglobu- service. Visiting paediatric immunology linemia, it is very important that patients outreach clinics are conducted in Hamilton, with Common Variable Immunodeficiency Rotorua, Tauranga and Invercargill.

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Table 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

Disorder (CVID) are identified at an early (Table 1).14 CVID is no longer a diagnosis of stage. CVID is the most common symp- exclusion. Treatment guidelines are closely tomatic PID in adults, with a prevalence linked to diagnostic categories (Figure 1).15,16 6 of approximately 1:25 000. Symptoms can As part of the clinical evaluation, predis- 13 begin in adulthood in many patients. posing factors for infections should be Failure to identify and treat CVID patients thoroughly assessed. It is possible the may place them at risk of bronchiectasis hypogammaglobulinemia is not the and/or life-threatening infections, including dominant cause for infections.14 In our meningitis and septicaemia. Once iden- experience, treatment of conditions such as tified, patients with CVID should receive chronic tonsillitis or chronic sinus disease long-term subcutaneous or intravenous may result in major improvement in the immunoglobulin (SCIG/IVIG) replacement. frequency of infections in some patients Our recently published diagnostic criteria with hypogammaglobulinemia, without the for CVID will allow a diagnosis of probable need for SCIG/IVIG replacement. CVID to be made with more precision

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Figure 1: Treatment algorithm for CVID (Ameratunga et al 2013).14

Given the very high cost of SCIG/IVIG, all having probable CVID, patients must PID patients should have an immunology have supportive laboratory evidence of evaluation prior to commencing treatment. immune system dysfunction (Category We also strongly recommend that patients C) or characteristic histological lesions already placed on long-term SCIG/IVIG for of CVID (Category D). Patients with mild PID should be regularly reviewed by an hypogammaglobulinemia (IgG >5 g/l) immunologist. We have recently identified are termed hypogammaglobulinemia of an adult patient who had been on long-term uncertain significance (HGUS). Patients IVI,G but was subsequently able to discon- meeting Category A criteria but not other tinue treatment as he had recovered from criteria are deemed to have possible CVID. “transient hypogammaglobulinemia of Most patients with probable CVID are infancy” as an adult. As a result, we were likely to require IVG/SCIG. Some patients able to successfully discontinue his IVIG. He with possible CVID will require SCIG/IVIG remains well, with no increase in infections but most patients with HGUS are unlikely with an IgG of 6.5 g/l (7-14 g/l). to need IVIG/SCIG replacement. We have Our diagnostic criteria may allow CVID suggested HGUS patients are categorised to be confirmed, without the need to stop based on their symptomatic state ie sHGUS SCIG/IVIG in some patients, particularly or aHGUS. Some patients with bronchi- if they have characteristic histological ectasis with HGUS will need to be treated features (Table 1, category D).16 This could with SCIG/IVIG irrespective of vaccine 16 reduce the need to stop SCIG/IVIG treatment responses. to undertake vaccine challenge responses, It may not be initially clear if a patient which can take several months. The patient presenting with hypogammaglobulinemia may be vulnerable to sepsis during this has a primary or a secondary immune defi- time. Equally, these criteria may identify ciency. We have shown that our diagnostic individuals who can safely discontinue criteria can also be useful in identifying SCIG/IVIG treatment permanently, if they patients with secondary immunodefi- have minimal symptoms, with normal ciencies.37-39 These criteria may also help in memory B cells and normal plasma cells on complex situations where an underlying gut biopsy (Table 1). primary immunodeficiency is aggravated Patients must meet all major criteria by a secondary immunodeficiency, such 38 in Category A for consideration of CVID. as an anticonvulsant drug. Several other Category B confirms the presence of patients with secondary hypogammaglobu- symptoms indicating immune system linemia have also been able to discontinue failure (ISF). Patients must be symp- IVIG replacement uneventfully and remain tomatic to have CVID. To qualify as well. These patients were commenced

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on IVIG by other services and successful discontinuation has resulted in significant The New Zealand cost savings. Blood Service (NZBS) Once patients are placed on long-term audit of SCIG/IVIG use SCIG/IVIG treatment, they need regular Perhaps the strongest economic immunology review. Patients residing argument for a national PID service outside centres with immunology units comes from a recent SCIG/IVIG audit would share their care with local paedia- conducted by the New Zealand Blood tricians and physicians, in the case of adult Service (NZBS, Blood Issues 28, October patients. The frequency of the follow-up 2015, http://www.nzblood.co.nz/assets/ visits to immunologists will depend on the Transfusion-Medicine/Blood-Issues-Newslet- individual patient and their disorder. SCIG/ ter-No-28-October-2015.pdf). The case notes IVIG treatment usually results in significant of patients receiving SCIG/IVIG in 2012/2013 improvement of the frequency and severity from 10 DHBS were reviewed. Access to of infections, but may not alter the risk of old notes was sometimes difficult, given inflammatory disorders or malignancy. that some patients have been on IVIG for IVIG, and to lesser extent SCIG, can cause decades. Where notes were not available, adverse effects,40 and having an immu- the prescribing doctor was contacted for nologist involved in the patient’s care can further information. This audit was under- facilitate timely review and management taken by nursing staff in each NZBS area. of any complication from treatment. NZBS has indicated there are limitations Other options, including an alternative to the audit. It is likely there was some immunoglobulin product, may need to be observer inconsistency. The audit did not considered. These decisions are best made determine if the patient was reviewed by by immunologists, who are thoroughly an immunologist. Furthermore, the case familiar with alternative SCIG/IVIG prepara- notes were not critically reviewed by an tions, which may need to be imported for a immunologist and subtle nuances, such as specific patient. responses to alternative treatments, were Some patients with CVID have severe not recorded. antibiotic allergies because of immune The cost of SCIG/IVIG is $88 per gram, and dysregulation. Managing these patients can the total cost to the New Zealand taxpayer be challenging and requires the expertise of is $29M per year. The NZBS determined an allergy/ immunology specialist. Diag- compliance of SCIG/IVIG use against criteria nostic evaluation may include skin testing published in the UK and Australia. The and drug challenges to confirm remission. audit uncovered inconsistencies in the Acute antibiotic desensitisation may be use of IVIG within the ten DHBs it audited needed for management of severe bacterial (Tables 2 –5). It can be seen there was a infections. Again, this service is available in high compliance rate in Auckland for PID specialist immunology units. patients, but relatively poor rates in some of Patients with CVID are at risk of chronic the smaller DHBs without access to immu- upper and lower respiratory tract suppu- nology services. ration. We routinely share their care with It is also clear that compliance for the respiratory and ORL services. Many treating secondary immunodeficiencies patients require functional endoscopic with SCIG/IVIG is poor in most DHBs sinus surgery for chronic sinus disease. (Table 5). The poor compliance for Having access to respiratory and ORL secondary immunodeficiencies may simply specialists with experience in PIDs is likely reflect a lack of referral to immunology to improve outcomes in these medically services, including ADHB. Most patients complex patients. These are strong clinical with non-haematological secondary arguments for placing patients with PIDs immunodeficiencies are likely to benefit under the care of immunologists, which from an immunology review. Patients may be best done through a national service with drug induced immunodeficiencies for PIDs. This would ensure uniformity of for example may improve if the causative clinical care. drug is identified and discontinued.41 As

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Table 2: NZBS audit showing major indications for SCIG/IVIG.

Diagnosis % total Number NBA guideline NHS guideline grams of patient use episodes Number and Number and Number and Number and and % of all % patients % patients % patients % patients episodes complying with complying complying with complying qualification with review qualification with review criteria criteria criteria 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-Barré 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 100% 883 (100%) 641 (73%) 541 (76%) 567 (64%) 583* (82%) episodes

NBA: National Blood Authority of Australia NHS: National Health Service UK. CDP: 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.

noted above, the immunology service there are inconsistencies in the approval at ADHB has been able to discontinue process. This may explain use of IVIG/SCIG IVIG in several patients with secondary for disorders such as autism and chronic immunodeficiencies. The audit also fatigue syndrome. We feel decisions on uncovered patients who had been treated IVIG/SCIG usage in primary and non-hae- with IVIG for conditions such as autism matological secondary immunodeficiencies and chronic fatigue syndrome, which are should be made by clinical immunologists not supported by either the Australian or after thorough clinical evaluation of these UK guidelines. patients. The NZBS strongly supports the From these tables we have calculated creation of a national service for PIDs with that $6M of immunoglobulin prescrip- oversight for the prescription of SCIG/IVIG tions per year do not comply with UK or for PIDs and non-haematological immu- Australian guidelines. nodeficient patients (Dr Peter Flanagan, Director NZBS, personal communication, October 2015). Patients with secondary The current approval immunodeficiencies from haematological process for SCIG/ disorders should be reviewed a haema- tologist. A national PID service is likely to IVIG treatment result in a fairer and more transparent We are very concerned about the current process for IVIG/SCIG prescriptions. approval process for IVIG/SCIG treatment. We accept that there may be potential inac- At present, the NZBS has to vet SCIG/IVIG curacies with retrospective review of patient requests for immunodeficiencies. Each notes. However, we are confident there will requesting clinician contacts the regional be substantial financial benefits to each DHB blood service for approval for IVIG/SCIG. if a national PID service was established Guidelines for IVIG/SCIG are not strictly with oversight for immunoglobulin prescrip- enforced by the NZBS. It is currently not a tions for primary and non-haematological requirement for patients with primary or secondary immunodeficiencies. It is also non-haematological secondary immunodefi- likely hospitalisation costs would be reduced ciencies to have been reviewed by a clinical if patients were under the care of a clinical immunologist. Each blood service may not immunologist. These fiscal benefits are in be in a position to determine the appro- addition to the improvement in clinical care priateness of the request, and it is likely described previously.

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Table 3: NZBS audit showing use of SCIG/IVIG by various District Health Boards in New Zealand.

Intragam P Intragam P Audit Popula- use pa (g) per Average Average DHB use pa (g) epi- tion* 1000 popula- age weight Status sodes tion (years) (kg) 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

or Stanozolol). Fibrinolytic inhibitors have Hereditary a minor role in management. Patients angioedema (HAE) suffering an acute attack require infusions Hereditary angioedema (HAE) is a rare with purified or recombinant C1 inhibitor disorder resulting from mutations of the or Icatibant, which will soon be funded. C1 inhibitor or FX11 genes.42 Patients are Treatment of an acute attack with purified predisposed to recurrent angioedema and C1 inhibitor costs approximately $2,500, plus abdominal pain. Urticaria is absent. The costs of hospitalisation. Preventing attacks vast majority of patients with C1 inhibitor with attention to triggering factors and deficiency have reduced complement androgen therapy may result in major cost component 4 levels, as well as reduced C1 savings to healthcare services. inhibitor function, and/or antigen levels. There is also a strong economic argument HAE is currently considered a PID, even to allow HAE patients to self-infuse C1 though predisposition to infections and inhibitor to reduce the costs of hospital- autoimmunity are not a major feature of isation.43 This is similar to haemophilia, the disorder. where patients are encouraged to self-med- Standard treatment in New Zealand for C1 icate. Early treatment of angioedema inhibitor deficiency is androgens (Danazol attacks reduces morbidity. C1 inhibitor is

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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.

NBA compliant NHS compliant Overall use DHB 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%) 2,856 (49%) 7 (47%) 5,790 15

Overall 54,081 (88%) 152 (88%) 54,300 (88%) 152 (88%) 61,722 172

Table 5: NZBS audit showing compliance with SCIG/IVIG use in secondary immunodeficiencies. The audit did not determine if patients had consulted with a clinical immunologist.

NBA compliant NHS compliant Overall use DHB grams patients grams patients grams patients Auckland 3,396 (62%) 23 (56%) 987 (18%) 3 (7%) 5,448 41

Canterbury 3,954 (67%) 18 (67%) 384 (6%) 2 (7%) 5,928 27

Capital and Coast 912 (11%) 5 (14%) 363 (4%) 1 (3%) 8,451 37

Counties Manukau 1,749 (59%) 8 (53%) 0 (0%) 0 (0%) 2,988 15

Hawkes Bay 852 (47%) 2 (67%) 0 (0%) 0 (0%) 1,815 3

MidCentral 624 (39%) 3 (43%) 0 (0%) 0 (0%) 1,608 7

Northland 531 (100%) 3 (100%) 228 (43%) 1 (33%) 531 3

Southern 2,277 (67%) 13 (57%) 690 (20%) 2 (9%) 3,405 23

Waikato 2,037 (29%) 8 (27%) 0 (0%) 0 (0%) 6,912 30

Overall 16,332 (44%) 83 (45%) 2,652 (7%) 9 (5%) 37,086 186

more effective when used early, before the onset of severe gastrointestinal edema.44 Genetic testing Laryngeal attacks require immediate In recent years there have been rapid treatment with C1 inhibitor. The ability advances in the understanding of PIDs. of self-infuse C1 inhibitor has substan- The majority of PIDs are a consequence of tially reduced healthcare costs in Canada. monogenic disorders. Over 260 causative Having a national PID service could signifi- or predisposing genetic defects have been cantly reduce costs by providing clinical identified in PID patients.1 With the notable advice on how to prevent acute attacks exception of CVID, genetic tests play a major and by training patients to self-administer role in patient management (Table 6).46-48 C1 inhibitor at home.45 A national service As well as confirming the diagnosis, these would also provide a uniform approach tests allow family studies, and may allow to the management of these patients prevention of PIDS with prenatal diagnosis throughout the country. and pre-implantation genetic diagnosis.47

Table 6: Advantages of molecular analysis for PID diagnosis. The original case descriptions can be found in our review on PID genetic testing.47

Diagnosis of PID Distinguishing genetic from acquired disorders

Confirming the clinical diagnosis

Identifying novel presentations of PIDs

Identifying atypical presentations of PIDs

Urgent diagnosis in infancy where conventional diagnostic tests are unreliable

Treatment Assisting treatment decisions

Gene therapy- identifying those who may benefit from gene based therapy

Prognosis Determining long-term outcome

Pre-symptomatic testing Where presymptomatic diagnosis (at any age) is not possible with protein based tests

Early identification of disorders which present later in childhood

Screening Cascade screening of at-risk relatives

Population based screening

PID prevention Prenatal diagnosis

Pre-implantation genetic diagnosis

Research Characterising the role of molecules in cellular function

Assisting with the classification of primary immunodeficiency disorders

Identification of new genetic defects including animal models

Genetic testing should now be considered small, developed country.47 Genetic testing the standard of care for most monogenic for PIDs is also available in Christchurch. PID disorders (Table 6). The customised genetic testing service Genetic testing for PIDs has been under- is of particular significance to Māori, as it taken in New Zealand for over 20 years.49 conforms to Tikanga Recommended Best In the last decade, the immunology labo- Practice.47 It removes the need to send ratory at Auckland Hospital has offered samples to overseas laboratories. Long-term a customised genetic service for patients storage of samples in overseas research labo- with PIDs.48 This service is accredited by ratories may be of concern to some Māori. the New Zealand laboratory accreditation Currently, several regional and national agency, IANZ, and is publically funded for services based in Auckland depend on New Zealand citizens and residents. We two scientists for rapid sequencing of PID currently offer full-length genomic (Sanger) genes. These include adult and paediatric sequencing for any published PID gene. The immunology (PID syndromes), adult and service offers a rapid turn-around, with paediatric rheumatology (autoinflammatory results typically being available within disorders), adult and paediatric haematology 2–3 weeks, or sooner for urgent cases. This (haematophagocytic lymphohistiocytosis, service is a cost-effective solution for a HLH syndromes), and adult and paediatric

nephrology (atypical haemolytic uremic better understanding of the natural history syndromes) services. It would seem appro- of hypogammaglobulinemia is likely to save priate to integrate a PID testing service the health service large sums of money, into a national immunology service. This as not all patients with hypogammaglobu- would not preclude other laboratories from linemia have CVID, and not all require SCIG/ offering PID genetic testing for local patients. IVIG, especially if they are symptomatically well. Again, the project could be linked to a Immunopathology national PID service to ensure patients from around the country are enrolled and are not Immunopathology is a subspecialty lost to follow-up. within clinical pathology. Laboratory testing for immunological disorders is The laboratory at Auckland Hospital has complex. Many assays have not been auto- been undertaking whole exome sequencing mated, and a high level of operator skill (WES) as part of a research project. CVID is required for successful completion and families with more than one affected interpretation of results. relative have been invited to join the WES project seeking to identify new genes. The While immunopathology is broader program to date has identified two new than PID testing, a national service could genes associated with CVID-like disorders.50 allow immunopathology supervision of Identification of the causative gene has laboratories with intermittent visits. Alter- profound implications for the patient and natively, a national immunopathology family members as discussed above (Table service could be considered separately. 6). Again, having a national PID service will Considerable immunopathology expertise ensure uniform access to research studies exists in Christchurch, which would be such the ones described here. the hub for the South Island, and provide specialised testing nationally for specific autoimmune disorders. Discussion: advantages (and PID research disadvantages) of a New Zealand is currently involved in several PID research projects. Currently, national service for most patients with CVID are enrolled in a patients with PID long-term project evaluating their clinical A national service for patients with PID features and outcomes. Over 80% of known has many advantages (and a few disadvan- CVID patients in New Zealand are part of tages) as described above. Importantly, it this project. All patient notes and laboratory will allow thorough and timely evaluation results have been thoroughly audited as of patients with suspected primary and part of the study. As seen in the NZBS audit, non-haematological secondary immune we believe such a thorough review should deficiency disorders. It may be difficult be undertaken for all PID patients on SCIG/ to distinguish between a primary and IVIG, either as part of the study or as part secondary immune deficiency until the of ongoing clinical care. Having such a patient is reviewed by a clinical immunol- database (once approved by the Ministry of ogist. An immunology review will result Health ethics committee and current partic- in appropriate testing and a confident ipants) linked to a national service would diagnosis of a PID (or secondary immu- ensure patients are not lost to follow-up, nodeficiency). Careful evaluation of these and they continue to receive the appro- patients will result in major savings from priate care. Research is an essential part of more effective use of SCIG/IVIG. As outlined a national PID service. above, many patients with mild-moderate In addition, New Zealand has a long-term hypogammaglobulinemia remain well once hypogammaglobulinemia study for patients other predisposing factors for recurrent not on SCIG/IVIG. This study seeks to infections are treated. These patients may identify the long-term prognosis for these not need to be treated with SCIG/IVIG. patients. This cohort will also be used to They will of course require long-term validate CVID diagnostic criteria. Having a follow-up, as some will develop a symp-

tomatic immune deficiency disorder over tation genetic diagnosis, which will result in time. We believe these decisions, which cost savings as well as alleviating suffering carry substantial clinical risk, should only in future generations. be made by an immunologist. If a secondary The future of genetic testing lies in the 9,37 immune deficiency is identified, the development of NGS-based gene panels. patient can be treated or referred to the Gene panels are now offered by many diag- appropriate service. This would minimise nostic laboratories in the US.52 A diagnostic the inappropriate use of IVIG, as seen in service, based on targeted next-generation Table 5. This would result in more judicious sequencing (NGS) is being developed at and equitable use of SCIG/IVIG throughout LabPlus. Using targeted WES as a rapid New Zealand. screening method for known PID genes is There has been a substantial increase in a potential strategy, which could be much the use of SCIG/IVIG in recent years. The cheaper than sequentially testing multiple NZBS estimates there has been a 10.4% genes. Gene panels could be deployed when annual increase in demand for SCIG/IVIG the genetic defect is not clear from the over the last decade. As shown in Table history or protein based laboratory testing. 5, it is likely inappropriate use of IVIG The development of functional studies is an has also contributed to the increased use essential part of this program. of SCIG/IVIG in New Zealand. As a result, If the causative gene is not clear from supplies of Intragam P, manufactured from the initial targeted NGS panel, WES for local plasma donors, have not been able gene discovery could be deployed in the to meet this increased need. The NZBS has context of a research program. WES has confirmed that New Zealand is no longer a major role in identifying novel genetic self-sufficient in the production of SCIG/ defects in patients with unknown clinical IVIG. The NZBS has had to import SCIG/ conditions. A recent study from the NIH IVIG preparations, manufactured from identified the genetic defect in 24% of overseas donors, at considerable cost to the patients with undiagnosed disorders.53 taxpayer. This underscores the urgency to These research assays are best performed establish a national PID service which has within the framework of a national clinical oversight for SCIG/IVIG use in primary and immunology service with access to protein- non-haematological secondary immunode- based and functional studies. ficiencies. We would expect a national PID Newborn screening for SCID will be service to clinically review all primary and implemented in New Zealand in the near non-haematological secondary immuno- future. Prompt identification and bone deficient patients prior to the use of SCIG/ marrow transplantation of SCID patients IVIG. This will have the added clinical before the onset of severe, life-threatening benefit of optimising management of these infections, will result in major improve- patients. SCIG/IVIG treatment decisions ments in patient outcomes and reduction are by consensus at ADHB. We have shown in the cost from prolonged hospitalisation. how consensus decisions can work effec- The customised genetic testing program will tively in clinical practice.51 This would play a key role in identifying the causative reduce the risk of inconsistent decisions gene either through Sanger sequencing of a being made by local NZBS services. We are high probability genetic defect, or through very confident substantial immediate and deployment of NGS-based targeted gene sustained cost savings will result from the panels for SCID. establishment of a national PID service with oversight for SCIG/IVIG prescriptions for A national PID service could consist of a immunodeficiencies. hub-and-spoke model. For adult patients, Christchurch would provide the hub for the A national PID service will secure the South Island, while Auckland and Wellington future of the customised genetic testing would provide the hubs for the North Island. service, which has significantly improved The unit at Starship would provide the service health outcomes, and has also resulted for the entire country. Regular immunology in considerable cost savings to the New clinics in regional centres will reduce the Zealand taxpayer. After intense counselling, need for patients to travel to larger centres. several families are considering preimplan-

The model proposed is unique in that centres. Practical issues, such as reviewing both adult and child patients will be laboratory results and typing clinic letters, treated as part of the integrated national will need to be addressed. These issues PID service. Such a national PID service are not insurmountable and have been may allow combined adult and paediatric overcome by other national services, such immunology clinics in regional centres, as paediatric rheumatology. It is likely any which would help seamless transitioning additional costs for immunology positions of child patients to adult services, as and infrastructure will be easily offset by well as upskilling local physicians on the savings from the judicious use of IVIG/SCIG, management and monitoring required and reduced hospitalisation costs. for these complex diseases. Currently, a Other models for a nationally co-ordi- seamless transition between child and adult nated service could be considered, where services is only available in Auckland. each region with an immunology service A national PID service, facilitated by the remains autonomous. There will be disad- collegiality between adult and paediatric vantages with this model as there may be immunologists in New Zealand, will be of insufficient numbers of immunologists in great benefit to patients and their families. some areas to provide a visiting service to A schism often exists in other services regional cities. Funding formulas would between provision of care for children also need to be carefully considered to as they progress through adolescence to ensure regions with fewer immunolo- adulthood. In some countries, paediatric gists are not disadvantaged. Furthermore, immunologists continue care for their there is only one public hospital paediatric patients into late adulthood because of a immunology service (based at Starship) for lack of adult services for patients with PIDs. PIDs, which has been providing a de facto Many countries are addressing the chal- national service for PID patients. It will be lenges posed by rare disorders. Ireland, important for this service to be appropri- England, France and the EU as a whole ately resourced. are developing national strategies to deal In the past, there has been resistance to with patients with rare conditions.54,55 developing national services on account of There have been similar calls for a national each DHB having to financially contribute service for rare disorders in Australia.56 A to the program. As we have shown here, national service for PIDs would support smaller DHBs without an immunology patient-centred management, allowing service are likely to fiscally benefit most greater patient autonomy.57 from a national PID service. We are very We accept there may be some disadvan- confident a strong business case could tages for the proposed national PID service. be made for our proposal. We hope the A national PID service will require immu- Ministry of Health and the National Health nologists having to visit regional centres on Board will engage with stakeholders, a regular basis. Extra immunology positions especially the New Zealand Clinical Immu- will be needed for each hub, in Auckland, nology and Allergy Group (NZCIAG) for Wellington, and Christchurch. There are productive discussions on this proposal. currently several advanced trainees in Patient support groups (IDFNZ and HAE immunology who could fill these positions Australasia) will also play an important over time. A national PID service will also role in shaping a national PID service. The require some investment in infrastructure model proposed here may also be useful for to co-ordinate joint clinics in regional other countries with a centralised govern- ment-funded health system.

Competing interests: Rohan Ameratunga has received an unrestricted educational grant from Octapharma. Acknowledgements: We thank our patients for participating in our studies for the benefit of others. We hope this proposal will be implemented for the benefit of all PID patients in New Zealand. eW thank Dr Richard Charlewood for allowing us to publish Tables 2–5 from the recent NZBS audit. Author information: Rohan Ameratunga, Departments of Clinical Immunology, Virology and immunology, Auckland City Hospital, Auckland; Richard Steele, Virology and immunology, Auckland City Hospital, Auckland, and Department of Clinical Immunology, Wellington Hospital, Welling- ton; Anthony Jordan, Department of Clinical Immunology, Auckland City Hospital, Auck- land; Kahn Preece, Department of Immunology, Starship Hospital, Auckland; Russell Barker, Department of Clinical Immunology, Wellington Hospital, Wellington; Maia Brewerton, De- partment of Clinical Immunology, Auckland City Hospital, Auckland; Karen Lindsay, Depart- ment of Clinical Immunology, Auckland City Hospital, Auckland; Jan Sinclair, Department of Immunology, Starship Hospital, Auckland; Peter Storey, Department of Clinical Immunology, Auckland City Hospital, Auckland; See-Tarn Woon, Virology and immunology, Auckland City Hospital, Auckland, New Zealand. All authors are part of the New Zealand Clinical Immunology and Allergy Group (NZCIAG) Corresponding author: Rohan Ameratunga, Departments of Clinical Immunology, Virology and immunology, Auck- land City Hospital, Auckland, New Zealand [email protected] URL: www.nzma.org.nz/journal/read-the-journal/all-issues/2010-2019/2016/vol-129-no-1436-10- june-2016/XXXX

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