Primary immune deficiencies and stem cell transplantation Sri Lanka Journal of Child Health , 2017; 46 (1): 3-15

Leading Article

Primary immune deficiencies and stem cell transplantation

Deenadayalan Munirathnam 1, Julius Scott 2, Vimal Kumar 3

Sri Lanka Journal of Child Health , 2017; 46 (1): 3-15 DOI: http://dx.doi.org/10.4038/sljch.v46i1.8224 (Key words: Primary immune deficiency, stem cell transplantation)

Introduction to autoimmune disorders, lymphomas and other Primary disorder (PID) can be malignancies. It is important that PIDs are broadly grouped into disorders of adaptive diagnosed accurately and in time to reduce immunity (T-cell, B-cell or combined morbidity and mortality 5,6 . ) and disorders of innate immunity (phagocyte defects in Toll-like receptor– Classification mediated signalling and complement disorders) 1,2 . It may be based on the chief component of the In the European Society for Immunodeficiencies deficient, absent or defective 3. (ESID) Registry 2010, of 10,747 children diagnosed 1. Predominantly deficiencies: with PID, humoral deficiencies were the most • X-linked agammaglobulinaemia common (Figure 1) 3. This is similar to the data from • Common variable immune deficiency Sri Lanka, where among 73 cases registered, • Selective IgA deficiency common variable immune deficiency (CVID) was • Specific antibody deficiency the commonest, followed by X linked • IgG subclass deficiency 4 agammaglobulinaemia . 2. Combined B & immunodeficiencies (predominantly T cell): • Hyper IgM syndrome • Severe combined immune deficiency • T negative B positive: γ chain deficiency, Janus kinase 3 deficiency • T negative B negative: Adenosine deaminase deficiency, Recombination activating 1/2 deficiency 3. Other well defined immunodeficiency syndromes: • Wiskott-Aldrich syndrome • Ataxia telangiectasia • Hyper IgE syndrome 4. Diseases of immune dysregulation: PIDs are different to secondary immunodeficiencies • Immunodeficiencies with which are caused by , malnutrition, or hypopigmentation immunosuppressive drug . PIDs are • Familial haemophagocytic associated with recurrent infections and predispose lymphohistiocytosis syndromes ______• X-linked lymphoproliferative 1Senior Consultant, Paediatric Haematology, syndrome and Stem Cell Transplantation, 2Senior • Autoimmune lymphoproliferative Consultant, Paediatric Oncologist, 3Consultant, syndrome Paediatric Haematology and Oncology and 5. Congenital defects of phagocyte number, Transplantation, Department of Paediatric function or both: Haematology and Oncology and Bone Marrow • Severe congenital neutropenia Transplant Services, Global Health City, Chennai. • Cyclic neutropenia Tamilnadu. India • X-linked or autosomal recessive *Correspondence: [email protected] chronic granulomatous disease The authors declare that there are no conflicts of 6. Complement deficiencies: interest • Deficiency in early complement Open Access Article published under the Creative pathway components • Deficiency in late complement Commons Attribution CC-BY License. pathway components

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Primary immune deficiencies and stem cell transplantation Sri Lanka Journal of Child Health , 2017; 46 (1): 3-15

7. Defects in innate immunity: Predominantly antibody deficiencies • Anhidrotic ectodermal dysplasia with deficiencies are the most common type of immunodeficiency PID. They usually present after 6 months of age with • IL-1 receptor-associated kinase 4 recurrent and severe sino-pulmonary infections deficiency mediated by and • Chronic mucocutaneous candidiasis Haemophilus influenzae. Diarrhoea and 8. Autoinflammatory disorders: autoimmune manifestations can also occur 6. These • Familial Mediterranean fever children often have deficient subtypes of • TNF receptor-associated periodic immunoglobulin levels. Figure 2 depicts the fever differentiation of B cells and the involved in • Hyper-IgD syndrome the various stages of maturation. • Cryopyrin-associated periodic syndromes

Defect in functioning of these genes results in kinase which causes an early block in B cell humoral immune deficiency 7. Antigen (Ag)- development, resulting in absence of B lymphocytes independent B cell differentiation occurs in the bone in peripheral blood and hence absent marrow, whilst Ag-dependent B cell differentiation immunoglobulin production. XLA constitutes 85% occurs in the periphery. After activation by Ag, B of all congenital agammaglobulinaemia. They cells develop in a T cell dependent way in the generally present with recurrent infections of the germinal centre and in a T cell-independent way in respiratory tract caused by common bacteria such as the marginal zone of the spleen (Figure 2) 7. Haemophilus influenzae or Pneumococcus . Chronic disease is the commonest long term Selective IgA deficiency: This is the commonest complication while chronic enteroviral PID worldwide and occurs in partial and complete meningoencephalitis is the commonest cause of forms. Most forms are asymptomatic, though they death 10 . can present with recurrent infections, autoimmunity or 8. Transient hypogammaglobulinaemia of infancy: In this condition the hypogammaglobulinaemia Common variable immune deficiencies (CVIDs): spontaneously reverts to normal, usually before the These occur in children older than 2 years and are child is 2 years old 11 . Most children remain characterised by hypoglobulinaemia (IgG <2SD of asymptomatic, though there is an increased risk of normal), decreased IgA and/or IgM levels, recurrent viral upper respiratory infections. infections and impaired response to immunization. They should be diagnosed only after defined causes Combined B and T cell deficiency of hypoglobulinaemia are excluded 9. Figure 3 depicts the development of B and T cells and the blocks associated in the process 12 . X-linked agammaglobulinaemia (XLA): This is due to a defect in the gene for Bruton’s tyrosine

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Primary immune deficiencies and stem cell transplantation Sri Lanka Journal of Child Health , 2017; 46 (1): 3-15

Severe combined immune deficiency (SCID): This disrupt this , causing autoimmune is the most severe form of PID and can be grouped polyendocrinopathy candidiasis ectodermal into cytokine signalling defects, T-cell receptor and dystrophy syndrome 15 . of the FOXP3 signalling defects, V(D)J recombination defects and gene, involved in regulation of Treg cells in the metabolic defects 13 . Bacille Calmette-Guérin (BCG) thymus causes immune dysregulation can give rise to disseminated BCG-osis polyendocrinopathy enteropathy X-linked (IPEX) in SCID patients and should be avoided at birth if syndrome, with severe and early-onset autoimmune there is any suspicion or family history of enteropathy, insulin-dependent diabetes, and immunodeficiency. Many infants also have chronic eczema 16 . diarrhoea and failure to thrive. SCID can lead to early death unless cured by stem cell Immunodeficiency with impaired cell mediated transplantation 12 . toxicity These disorders are characterized by impairment of Hyper IgM syndrome (CD40 ligand deficiency): the mechanisms of transport, docking, or release of This is inherited as an X-linked trait. Children with the lytic granules in cytotoxic T lymphocytes. CD40L deficiency have a severe defect of all Cytotoxicity defects include primary immunoglobulin isotypes other than IgM. They are haemophagocytic lymphohistiocytosis (HLH) that prone to opportunistic infections by Pneumocystis results from deficiency of perforin, Munc13-4, and carinii and Cryptosporidium parvum 14 . syntaxin 11, which result in defective intracellular killing. There is excessive production of TH1 DiGeorge syndrome: This is due to a developmental cytokines and IFN-gamma resulting in the defect of the third and fourth pharyngeal pouches ‘accelerated phase’ with haemophagocytosis. and arches, resulting in impaired development of the thymus and parathyroids, facial dysmorphism and Phagocytic defects conotruncal heart defects. Children with defects in phagocytosis, typically present with severe pyogenic infections of skin, Immunodeficiency with immune dysregulation respiratory tract and internal organs. These include Autoimmune regulator (AIRE) protein is expressed severe congenital neutropenia (SCN) and chronic by medullary thymic cells which are involved in granulomatous disease (CGD) 12 .. immune tolerance. Mutations of the AIRE gene

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Primary immune deficiencies and stem cell transplantation Sri Lanka Journal of Child Health , 2017; 46 (1): 3-15

SCN: Both X-linked and autosomal recessive forms by mutations of STAT3 gene and is characterized by exist, the most common being in the dental and bone anomalies 21 . neutrophil elastase gene at 19p13. G-CSF has significantly improved survival in children with Approach to diagnosis SCN though risk of transformation to acute myeloid A detailed history and physical examination leukaemia (AML) does exist 17. supplemented by immune function testing is essential for diagnosis. Pre-natal testing is indicated CGD : This is caused by a defect in genes encoding if there is a family history of immunodeficiency and nicotinamide adenine dinucleotide phosphate- the mutation has been identified in family members. oxidase complex leading to insufficient production of free radicals. It is characterized by recurrent History: This should focus on the age of onset, type pyogenic infections involving deep tissue and sepsis and severity of infections, immunization history and due to catalase positive organisms. The sustained family history of early deaths. Recurrent infections inflammatory response seen in CGD is responsible could give valuable clues to the diagnosis 22 . for the granulomatous manifestations causing gastric outlet obstruction, non-infective colitis, and Based on age of onset: hydronephrosis 18 . Neonatal period: , severe congenital neutropenia (SCN), DiGeorge syndrome, Complement defects leucocyte adhesion deficiency (LAD), reticular Deficiency of early components of the classical dysgenesis. complement pathway (C1q, C1r, C1s, C4, C2, and • Delayed separation of the umbilical cord C3) causes autoimmune manifestations resembling beyond 2 weeks is characteristic of type I systemic erythematosus 12 . Defects of late LAD. components (C5-C9) are associated with recurrent • Omphalitis is suggestive of a neutrophil and invasive neisserial infections. Deficiencies of disorder such as LAD or SCN. the regulatory components Factor H and Factor I • Erythroderma with lymphadenopathy and cause membranoproliferative hepatosplenomegaly is highly suggestive and recurrent atypical haemolytic uraemic of Omenn syndrome, an atypical variant of syndrome. Deficiency of the C1 esterase inhibitor, a SCID. regulatory component of the classical pathway of • Cardiac defects with hypocalcaemia and complement activation, causes hereditary facial dysmorphism suggest DiGeorge 12 . syndrome. • Reticular dysgenesis, a rare form of SCID Immunodeficiency syndromes usually presents in the neonatal period with These are disorders where other clinical features are cytopenia. present in addition to immunodeficiency. Before 6 months of age: SCID, CD40 ligand deficiency. Wiskott-Aldrich syndrome (WAS): This is caused • Presentation in early infancy is highly by mutations in the gene encoding WAS protein suggestive of a significant T lymphocyte or which regulates actin cytoskeleton. It is associated combined immunodeficiency, such as with thrombocytopenia, severe eczema, and SCID or CD40 ligand deficiency. susceptibility to autoimmunity and malignancy. 6 months to 5 years of age: WAS, DiGeorge Affected males rarely survive beyond the second 19 syndrome, CGD, chronic mucocutaneous decade of life . candidiasis and hypogammaglobulinaemia. • Antibody deficiency presents after 4–6 Ataxia telangiectasia: This is an autosomal months once placentally acquired maternal recessive disease caused by mutations of the ataxia- IgG has decayed. telangiectasia mutated gene. Patients have ataxia, • Defects in neutrophil function, such as ocular telangiectasia, increased risk of infections, CGD, may present in infancy, although the and tumours. There is a progressive decrease of T- diagnosis is often made later. lymphocyte counts and function and hypogammaglobulinaemia. Alpha fetoprotein levels • Immunodeficiency associated with DNA repair defects such as ataxia telangiectasia are usually increased 20 . present commonly with gait abnormalities

Hyper IgE syndrome (HIES): This is characterized or neurodevelopmental delay. by eczema, cutaneous and pulmonary infections by After 5 years of age: CVID, specific antibody deficiency, complement disorder. Staphylococcus aureus and Candida species, and grossly increased IgE levels. Superinfection of pneumatocoeles by Aspergillus species is not Based on system affected: Pattern of organ involved uncommon. Autosomal dominant variant is caused could give a clue to the type of PID.

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Primary immune deficiencies and stem cell transplantation Sri Lanka Journal of Child Health , 2017; 46 (1): 3-15

Respiratory: • Thromobocytopenia, small platelets and • Infants presenting with persistent or eczema occurring in boys suggests WAS. recurrent bronchiolitis may have SCID. • Autoimmune cytopenia might suggest • Prolonged interstitial pneumonia due to DiGeorge syndrome, autoimmune parainfluenza virus, cytomegalovirus or lymphoproliferative syndrome (ALPS) or pneumocystis carinii is suggestive of IPEX syndrome. human immunodeficiency virus (HIV), Skin: SCID or CD40 ligand deficiency. • Eczema, associated with thrombocytopenia • Recurrent sino-bacterial infections after 6 and small platelets suggests WAS. months of age is suggestive of a humoral • Eczema associated with staphylococcal immunodeficiency. pneumatocoeles suggests hyper IgE • Staphylococcal lung with syndrome. pneumatocoeles, if associated with eczema, • Mucocutaneous albinism may be a sign of should suggest hyper-IgE syndrome. disorders of cell-mediated killing, such as • Fungal pneumonias could be a presentation Griscelli syndrome or Chediak–Higashi of CGD. syndrome. • Recurrent sino-pulmonary infection • Perianal ulceration in the newborn, occurring later in childhood could be due to associated with a high neutrophil count but CVID or complement deficiency. a lack of pus is indicative of LAD. Gastrointestinal: • Systemic (SLE) is a • Recurrent infectious diarrhoea, feature of complement deficiency. malabsorption and failure to thrive might • Persistent mucosal candida infection may suggest SCID. be suggestive of SCID, chronic • Persistent non-infective diarrhoea in boys, mucocutaneous candidiasis or hyper-IgE with associated eczema and recurrent syndrome. respiratory infection, should suggest IPEX • Telangiectasia or photosensitivity with syndrome. recurrent infection is suggestive of ataxia • Hepatic abscesses, or abscesses due to telangiectasia. Staphylococcus aureus or fungal infection Neurological: are characteristic of CGD. • Unsteady gait might be associated with • Shwachman–Diamond syndrome should ataxia telangiectasia. be considered in children with exocrine • Spastic diplegia with dysarthria is a pancreatic insufficiency associated with common presenting feature of purine neutropenia. phosphorylase-deficient SCID. • Sclerosing cholangitis due to • DiGeorge syndrome may be associated Cryptosporidium parvum is associated with with developmental and speech delay. CD40 ligand deficiency. • Neurological deterioration is a late feature Haematological: of Chediak–Higashi syndrome. • Lymphocyte counts are comparatively • Enteroviral meningoencephalitis may be a higher in infancy and an absolute feature of humoral immunodeficiency. lymphocyte count less than 2·8 x 10 9/L is 2 Lymphoreticular malignancy: standard deviations below the mean until 1 • EBV-associated lymphomas are described year of age. Lymphopenia on more than 2 in XLP and Wiskott–Aldrich syndrome. occasions is highly suggestive of SCID. • Non-Hodgkin’s lymphoma is described in • Erythrophagocytosis might be suggestive ALPS and CVID. of familial HLH, Chediak Higashi syndrome or Griscelli syndrome. Based on type of infections: • Neutropenia occurring every 3–4 weeks, The spectrum of infections in a child could also give often with an associated fever, infection or a clue to the suspected diagnosis of PID. Table I mouth ulcers, is suggestive of cyclical presents the type of infections that occur in various neutropenia. subtypes of PIDs12 .

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Primary immune deficiencies and stem cell transplantation Sri Lanka Journal of Child Health , 2017; 46 (1): 3-15

Table I: Pattern of infections in various disorders

Whom to investigate? natural killer (NK) cells (CD16+, CD56+), and A high index of clinical suspicion is needed to serum immunoglobulins (Ig). diagnose PID. Child having recurrent infections in a single anatomic location will more probably have an Absence of B lymphocytes is associated with anatomic defect than an immune deficiency. congenital agammaglobulinaemia. Serum Ig levels Unusually severe or long lasting recurrent infections lower than age-appropriate reference values suggest or failing to respond to standard therapy, or infection B-cell immunodeficiency. However, serum specific with unusual organisms makes one to suspect PID. antibody titres (usually IgG) in response to vaccine The European Society of Immunodeficiencies antigens is ideal to confirm an antibody-deficiency (ESID) has suggested 10 warning signs for suspicion disorder. In this method, a patient is immunised with of PIDs 23 . protein antigens (e.g. tetanus toxoid) and polysaccharide antigens (e.g. pneumococcus) and 1. Four or more new ear infections within one pre- and post-immunization antibody levels are year. assessed. Most PIDs have diminished or absent 2. Two or more serious sinus infections antibody responses to these antigens 6. within one year. 3. Two or more months on antibiotics with Age specific lymphopenia, along with markedly little effect. reduced T-lymphocyte counts, is characteristic of 4. Two or more pneumonias within one year. SCID. Absolute lymphocyte count below 3000 per 5. Failure of an infant to gain weight or grow cu mm in a neonate is a useful cut off for T cell normally. disorder. A lymphocyte count less than 2 standard 6. Recurrent, deep skin or organ abscesses. deviations below the age-specific mean is 7. Persistent thrush in mouth or fungal abnormal 24 . T-cell receptor excision circles infection on skin. (TRECs), a by-product of V(D)J recombination, are 8. Need for intravenous antibiotics to clear exported to the periphery by newly generated thymic infections. T lymphocytes. TRECs levels in circulating 9. Two or more deep-seated infections lymphocytes are especially high in neonates and including septicaemia. infants and reduce with age. TRECs less than 30 10. A family history of PID copies per μL is 100% sensitive for T-cell disorder. Assessing TREC levels by PCR may be used for How to investigate? neonatal screening of SCID 25 . Markedly decreased The first-line investigations include a full blood levels of serum IgG and IgA together with normal or count with a differential count, lymphocyte subset high serum IgM levels, suggests CSR defects due to analysis for enumeration of CD3+, CD4+, CD8+ T either intrinsic B cell problems or impaired cross- lymphocytes, B lymphocytes (CD19+, CD20+) and talk between T and B lymphocytes 12 .

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Primary immune deficiencies and stem cell transplantation Sri Lanka Journal of Child Health , 2017; 46 (1): 3-15

Absolute neutrophil count (ANC) is greatly decreased in all types of SCN. Nitroblue tetrazolium Treatment test (NBT) is widely used as the screening test for The treatment of patients with PID is based on: (1) CGD, whereas neutrophil function assays like timely recognition, (2) adequate treatment and dihydrorhodamine response helps in confirming a surveillance and (3) nature of the underlying diagnosis of CGD. Diagnosis of LAD1 is disease . Immunoglobulin replacement and straightforward and is based on flow cytometric prophylactic antibiotics used judiciously may evaluation of CD18 expression on the leucocyte prevent significant end organ damage and improve surface. Measuring haemolytic activity of the long-term outcome and quality of life 26 . Broadly, the classical and alternative pathways of complement, supportive and definitive treatment options of the along with C3 and C4 levels may help in the various groups of PID are summarized in Table 2 27 . diagnosis of complement deficiencies. Increase of TCRαβ+CD4 neg CD8 neg T cells suggests ALPS.

Table 2: Outline of treatment of PID

However, definitive cure can only obtained through deaminase deficiency (ADA) and SCID in 1975, haematopoietic stem cell transplantation (HSCT), unrelated donor transplant in 1977 and haplo- though gene therapy may be a viable alternative in identical related donor transplants in 1983 29 . HSCT the future. In fact, prognosis of SCID has altered involves identifying a HLA matched donor, from invariably fatal to more than 90% survival with conditioning chemotherapy to enable recipient to timely HSCT with an HLA-matched donor 28 . accept new stem cells, infusion of donor stem cells into recipient, providing optimal supportive care Stem cell transplantation in primary immune until engraftment and continuing deficiencies for around 6 months to prevent The first allogeneic human leucocyte antigen graft rejection and graft versus host disease 30 . The (HLA)-matched sibling bone marrow transplants for potential immune deficiencies treated with HSCT SCID and WAS was performed in 1968, adenosine are shown in Table 3 31 .

Table 3

Severe Combined Immune Deficiency enzyme exists. Major factors influencing outcome The only curative therapy for SCID is allogenic post HSCT are: HSCT, except ADA for which a replacement 1. Type of donor, matched sibling donors having best outcome.

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Primary immune deficiencies and stem cell transplantation Sri Lanka Journal of Child Health , 2017; 46 (1): 3-15

2. Type of SCID, T-B- forms having poorer including: slower engraftment; lack of viral specific outcome. cytotoxic T-cells; and lack of availability of the 3. Preceding co-morbidity (pneumonitis, donor for a boost HSCT 34 . However, both matched septicaemia, viral illness, malnutrition) unrelated transplantation and using cord blood adversely affecting outcome. would need high dose chemotherapy for successful 4. Age at transplant, infants less than 6 engraftment. months having improved outcome. In children with SCID, HSCT is warranted as soon Conditioning as possible after diagnosis, preferably before 6 Conditioning prior to HSCT in SCID is not an months of age, when outcomes are very good 32,33 . absolute requirement. For those patients requiring According to Buckley et al. HSCT prior to 3.5 conditioning, a myeloablative regime of 16 mg/kg of months of age has 95% survival, compared to 76% busulfan and 200 mg/kg of cyclophosphamide is in older patients 34 . Transplants in the first 30 days of widely used 32 . Bertrend et al has shown good life are associated with superior T cell outcomes with reduced intensity conditioning of reconstitution 35 . T-cell negative, B-cell negative, 8mg/kg of busulfan and 200mg/kg of NK cell-positive SCID (T- B- NK+ SCID, the cyclophosphamide 39. Myeloablative therapy commonest subtype, is caused by a defect in the increases the chance for complete chimerism but common gamma chain or is due to Janus kinase 3 there is also an increased risk of transplant related (JAK3) deficiency and is associated with good T cell mortality and morbidity. Current EBMT reconstitution after engraftment 36 . T- B- NK+ SCID, recommendations include use of busulfan/ due to defects in recombination activating gene 1 fludarabine or treosulfan/fludarabine based (RAG1) or RAG2, has an inferior overall survival protocols. compared to the B+ subtypes with decreased chance of engraftment, increased incidence and severity of Non-SCID Immunodeficiency GVHD and slower T cell reconstitution 37,38 . The The major difference with non-SCID patients presence of NK cells also mediates graft rejection. compared to SCID patients is the usual requirement for a conditioning regimen to achieve engraftment. Source of stem cells Many children with non-SCID PID have significant The best results following HSCT are seen with a co-morbidities at the time of HSCT and HLA identical sibling where overall survival rates conventional myeloablative preparation with are more than 90% 34 . In children where a HLA busulfan/cyclophosphamide based regimes can be matched sibling is not available, the choices are associated with significant toxicity as well as long between a T cell deplete haplo-identical parent, a term sequelae. Recent alternatives have: matched unrelated donor or unrelated cord blood. 1. replaced cyclophosphamide with Virtually all children have haplo-identical parental fludarabine, as the busulfan/ fludarabine donors and this is an alternative option especially as combination appears to be better tolerated. the donor is readily available. If performed early 2. replaced busulfan with a structural before the onset of severe infections and with analogue, treosulfan, which is similarly effective T cell depletion strategies available, immuno- and myelo-suppressive, but does overall survival rates of 50-70% are seen with haplo- not cause hepatic veno-occlusive disease 41 . identical transplantation. The mother is ideally 3. used reduced intensity HSCT to achieve utilized as the stem cell source since the child is stable engraftment of immunocompetent already tolerant to maternal cells. However, there is donor cells with reduced procedure-related an increased likelihood of GVHD due to the morbidity and mortality. maternally engrafted T lymphocytes. The potential risk with haplo-identical transplantation is the Wiskott-Aldrich syndrome (WAS) delayed T cell reconstitution and increased risk of Only curative treatment is HSCT . A collaborative opportunistic infections 32 . Few studies have shown study of the International Bone Marrow Transplant overall survival with matched unrelated Registry and the National Marrow Donor Program transplantation to be superior to mismatched related showed transplant outcomes in 170 males with transplantation with faster immune reconstitution 28 . WAS. The overall 5-year probability of survival was But the long term results are not clear. 70%. HLA-identical sibling donor transplants had a superior overall survival of 87%. Unrelated donor Cord blood transplantation offers some theoretical transplants less than 5 years of age had an overall advantages including rapid availability, as with survival of 85%, while all children more than 5 years haplotype-matched parental donors but with no of age who underwent unrelated transplantation requirement for T-cell depletion, less risk of GVHD died 40 . Haplocompatible-related transplants were compared to adult unrelated donors, no medical risk less successful with an overall survival of 45–52% 40. to the donor and a greater proliferative life span. Umbilical cord blood transplants had a higher risk There are also some specific disadvantages of post-transplant complications such as graft

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Primary immune deficiencies and stem cell transplantation Sri Lanka Journal of Child Health , 2017; 46 (1): 3-15

failure, GVHD, autoimmunity and malignancy. at birth is also warranted to identify children with T Myeloablative conditioning was preferred earlier cell lymphopenia and SCID and allows for early since mixed chimerism due to reduced intensity HSCT. Newer developments like reduced intensity conditioning might lead to development of conditioning and tailoring the conditioning regime autoimmune diseases. UK experience using based on the type of PID like avoiding alkylating treosulfan/ fludarabine in WAS suggests that good agents or radiation might go a long way in immune reconstitution with 100% donor chimerism improving outcomes with haplo-identical and can be achieved without the need to use full unrelated donor transplantation. Newer methods of myeloablative conditioning 41 . T cell depletion are being increasingly used to facilitate haplo-identical transplantation. Finally, the Chronic granulomatous disease (CGD) advent of gene therapy for these disorders might The only curative treatment available for CGD is even prompt us to move away from HSCT in the HSCT. Regimens ranging from full myeloablation years to come 48 . to non myeloablative conditioning cured CGD 42 . Even mixed chimerism attained with reduced References intensity conditioning has sufficed to cure CGD. 1. Geha RS, Notarangelo LD, Casanova JL, Severe congenital neutropenia (SCN) Chapel H, Conley ME, Fischer A, et al. Early referral for HSCT is important if there is poor Primary immunodeficiency diseases: an response to G-CSF, considering the high risk for update from the International Union of AML transformation. A study from SCN Immunological Societies Primary International Registry has shown overall survival of Immunodeficiency Diseases Classification 82% in 11 children who underwent HSCT 43 . Committee. Journal of Allergy and Clinical 2007; 120 (4):776-94. Familial haemophagocytic lymphohistiocytosis https://doi.org/10.1016/j.jaci.2007.08.053 (HLH) PMid: 17952897 PMCid: PMC2601718 This autosomal recessive disease is characterized by defects in genes encoding NK and T cell 2. Bousfiha A, Picard C, Boisson-Dupuis S, cytotoxicity. It is invariably fatal, unless treated by Zhang SY, Bustamante J, Puel A, et al. HSCT. A report from HLH-94 showed a 62% 3 year Primary immunodeficiencies of protective event free survival in 65 children who underwent immunity to primary infections . Clinical HSCT 44 . Immunology 2010; 135 (2): 204-9. https://doi.org/10.1016/j.clim.2010.02.001 Chediak Higashi syndrome PMid: 20236864 Children, often die during the accelerated phase of the disease. A study by Eapen et al. showed that 35 3. de Vries E, Driessen G. Primary children who underwent HSCT had a 5 year overall immunodeficiencies in children: a survival of 62% 45 . diagnostic challenge. European Journal of 2011; 170 :169–177. CD40 ligand deficiency (Hyper-IgM syndrome) https://doi.org/10.1007/s00431-010-1358- Without HSCT about 50% of children with hyper 5 IgM syndrome survive to the fourth decade. A PMid: 21170549 PMCid: PMC3022152 survey of the European experience, 1993-2002 showed that HSCT cured 58% of patients overall 4. de Silva NR, Gunawardena S, Rathnayake and 72% of those without hepatic disease 46 . D, Wickramasingha GD. Spectrum of primary immunodeficiency disorders in Sri Leucocyte adhesion deficiency (LAD) Lanka. Allergy, Asthma & Clinical In a review of worldwide BMT experience amongst Immunology 2013; 9:50. 36 children with LAD, overall survival was 75%. https://doi.org/10.1186/1710-1492-9-50 Mortality was greatest after haplo-identical PMid: 24373416 PMCid: PMC3880003 transplants 31 . 5. Bonilla FA, Bernstein IL, Khan DA et al. Future perspectives Practice parameter for the diagnosis and To conclude, it is important that children with PIDs management of primary are transplanted as early as possible before the onset immunodeficiency. Annals of Allergy, of severe infections. In families with a history of Asthma and Immunology 2005; 94 (5 Suppl PID and an identified genetic mutation, prenatal 1):51- 63. diagnosis should be emphasized. Recently, in utero https://doi.org/10.1016/S10811206(10)61 HSCT for SCID have also been performed, though 142-8 survival rates are variable 47 . A screening programme

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