**9. Complications post HSCT**

Complications following transplantation for primary immunodeficiency are similar to those for patients with malignancy. Infection through the transplant period is a risk, particularly when patients are aplastic (Figure 4). Any primary immunodeficiency patients may carry pre-existing infection (particularly viral infection) into transplant, as the underlying condition means that they are unable to clear infections effectively. Careful assessment of

#### **Figure 4.**

pre-existing infection needs to be made pre-transplant so that treatment can be optimised as patients begin transplant to reduce the risk of infectious complications. Pneumonitis, particularly at engraftment is a risk, especially in those with pre-existing viral pneumonitis at time of transplantation[61]. Nebulised steroids may improve the outcome in these patients. Acute and chronic graft versus host disease may be significant complications in primary immunodeficiency patients post transplant. Unlike patients with malignancy, graft versus host disease is not encouraged as there is no graft versus leukaemia benefit to be gained. Therefore HLA matching, T cell depletion where appropriate and Graft versus host disease prophylaxis with a calcineurine inhibitor (with or without additional MMF/steroids/Methotrexate) should be utilised. Staging and treatment of established graft versus host disease (Table 3) is as for other transplant patients - methylprednisoline (2mg/kg) is standard first line treatment. If the patient fails to respond to this, then a variety of other agents may be tried including monoclonal antibodies such as infliximab, alemtuzimab, antithymocyteglobulin, mesenchymal stem cells and extra corporeal phototherapy but none have yet proven to be consistently effective. Veno occlusive disease is a risk factor particularly in those with osteopetrosis, with pre-existing liver disease or under going conditioning with busulphan or cyclophosphamide. Prophylaxis with defibrotide is effective at preventing veno-occlusive disease and treating if necessary[62]. Haemorrhagic cystitis is a rare complication following HSCT, associated with adenovirus or BK virus infection, associated with T cell depletion or prolonged immunosuppression. Treatment is as for patients undergoing HSCT for other indications[63].



Adapted from Jacobsohn DA[69]

18 Immunodeficiency

**Figure 4.**

obvious. A patient with IPEX syndrome was cured although T cells appeared to be recipient, because on detailed study, the only donor cells were found to be the FOXP3+ cells[59], required to cure the condition. On the other hand, donor B cells are required in CgC or JAK-3 deficient SCID to achieve independence from immunoglobulin substitution[51, 60], but

Complications following transplantation for primary immunodeficiency are similar to those for patients with malignancy. Infection through the transplant period is a risk, particularly when patients are aplastic (Figure 4). Any primary immunodeficiency patients may carry pre-existing infection (particularly viral infection) into transplant, as the underlying condition means that they are unable to clear infections effectively. Careful assessment of

pre-existing infection needs to be made pre-transplant so that treatment can be optimised as patients begin transplant to reduce the risk of infectious complications. Pneumonitis, particularly at engraftment is a risk, especially in those with pre-existing viral pneumonitis at time of transplantation[61]. Nebulised steroids may improve the outcome in these patients. Acute and chronic graft versus host disease may be significant complications in primary immunodeficiency patients post transplant. Unlike patients with malignancy, graft versus host disease is not encouraged as there is no graft versus leukaemia benefit to be gained. Therefore HLA matching, T cell depletion where appropriate and Graft versus host disease prophylaxis with a calcineurine inhibitor (with or without additional MMF/steroids/Methotrexate) should be utilised. Staging and treatment of established graft versus host disease (Table 3) is as for other transplant patients - methylprednisoline

recipient B cells are functional in SCID due to defects in IL7Ra.

**9. Complications post HSCT** 

**Table 3.** Staging of acute GVHD

#### **10. Post transplantation immuno-reconstitution**

Full immunoreconstitution can take up to 2 years post transplant. Most patients remain on immunoglobulin replacement for around 6 months post transplant or until evidence of immunoglobulin production (gauged by measuring IgM production). Ongoing immunosuppression or graft versus host disease will delay assessment of antibody production. Thymopoiesis can be measured by documenting an increase in recent thymic emigrants measured by TRECS or surrogate markers such as CD27 or CD31 on T cells. Thymopoiesis normally occurs around 120 days post transplant[64]. Graft versus host disease may impair or abrogate this process[65].

Once immunoglobulin production is established, immunoglobulin replacement should be discontinued. After a wash out period of 3 months, primary vaccinations with non-live antigens can begin, having assessed base line specific antibody levels. The response to vaccine antigens can be assessed once the primary vaccination schedule is complete. Vaccination with live vaccines such as MMR should only be considered once normal T cell proliferation has been demonstrated and an antibody response to the primary vaccination schedule has been confirmed. Prophylaxis against polysaccharide coated organisms should be continued for at least 2 years post transplant[66]. Patients should however have received the conjugated pneumococcal and meningococcal vaccines. Once the response to polysaccharide organisms has been demonstrated in those with normal splenic function, antibiotic prophylaxis can be discontinued. Patients should be monitored for evidence of endocrine dysfunction - particularly thyroid dysfunction[67]. Thyroid dysfunction occurs in up to 10% of post transplant patients. Usually this is hypothyroidism but more rarely hyperthyroidism has been described and each should be managed appropriately. In the long term there may be issues with fertility due to the conditioning regimens and patients should be counselled accordingly – referral to fertility clinics or endocrine specialists may be necessary. Growth is usually normal, and growth retardation due to the underlying illness may be reversed post transplant. Ongoing care of previous end organ damage such as bronchiectasis may require specialist input with regular monitoring of lung function and radiological changes. The quality of life post transplant has not been extensively assessed in primary immune deficiency patients. One study looking at the outcome of patients transplanted for severe primary immune deficiency demonstrated an increased risk of long term cognitive difficulties with associated emotional and behavioural difficulties. Specific genetic diagnosis and a severe clinical course were specifically associated with poor outcome[68]. Conversely a recent study looking at patients with CGD found significantly better quality of life skills in those who had undergone transplantation compared to those who were not transplanted, with the post transplant patients score similar to normal controls. As more patients survive the transplant procedure and a longer follow up is achieved further work will be needed in this area to determine quality of life.

Stem Cell Transplantation for Primary Immunodeficiency 21

of multiple cords or the combined use of haplo-identical stem cells with an umbilical cord blood stem cell unit may also speed of immune reconstitution and lessen the risk from viral infection. Increased use of viral specific cytotoxic T cells will have a role to play. Finally better and more effective treatment of steroid resistant Graft versus host disease is needed and the use of extra corporeal phototherapy, the role of regulatory T cells and of

*The Institute for Cellular Medicine, Newcastle upon Tyne University, Newcastle upon Tyne, UK* 

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[2] Bach FH, Albertini RJ, Joo P, Anderson JL, Bortin MM. Bone-marrow transplantation in a patient with the Wiskott-Aldrich syndrome. Lancet. 1968;2(7583):1364-6. Epub

[3] Rao K, Amrolia PJ, Jones A, Cale CM, Naik P, King D, et al. Improved survival after unrelated donor bone marrow transplantation in children with primary immunodeficiency using a reduced-intensity conditioning regimen. Blood.

[4] Lion T, Baumgartinger R, Watzinger F, Matthes-Martin S, Suda M, Preuner S, et al. Molecular monitoring of adenovirus in peripheral blood after allogeneic bone marrow transplantation permits early diagnosis of disseminated disease. Blood.

[5] Brown L, Xu-Bayford J, Allwood Z, Slatter M, Cant A, Davies EG, et al. Neonatal diagnosis of severe combined immunodeficiency leads to significantly improved survival outcome: the case for newborn screening. Blood. 2011;117(11):3243-6. Epub

[6] Jones LB, McGrogan P, Flood TJ, Gennery AR, Morton L, Thrasher A, et al. Special article: chronic granulomatous disease in the United Kingdom and Ireland: a comprehensive national patient-based registry. Clinical and experimental immunology.

[7] Wynn RF, Boelens JJ. Bone-marrow transplantation in non-malignant disease. Lancet.

[8] Gennery AR, Slatter MA, Grandin L, Taupin P, Cant AJ, Veys P, et al. Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: entering a new century, do we do better? The Journal of allergy and clinical

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and Andrew R. Gennery

**Author details** 

**12. References** 

1968/12/28.

1968/12/28.

2011/01/29.

Corresponding Author

 \*

Mary A. Slatter\*

#### **11. Future prospects**

Transplantation for primary immunodeficiency is a successful treatment leading to cure of disease and normal life quality for the majority of patients. Future work will need to address optimal timing of transplantation, which may be gauged as future registry data becomes available. Less damaging conditioning regimens, particularly for newborns identified with the newborn screening programmes will become important. Treosulfan, fludarabine containing regimens are less toxic than busulphan containing regimens but targeting conditioning using radiotherapy or monoclonal antibodies may play a great role in the future. Accelerating thymopoiesis and immuno-reconstitution will be important particularly when pre-existing viral infection is present. Agents including exogenous interleukin 7 or keratinous growth factor may have a role to play. Graft manipulation may improve outcomes for some patients - better use of T cell depleted donors when no matched donors are available and particularly improving immune reconstitution through TCR alpha beta depletion may be appropriate. Expansion of stem cells in cord blood transplantation, the use of multiple cords or the combined use of haplo-identical stem cells with an umbilical cord blood stem cell unit may also speed of immune reconstitution and lessen the risk from viral infection. Increased use of viral specific cytotoxic T cells will have a role to play. Finally better and more effective treatment of steroid resistant Graft versus host disease is needed and the use of extra corporeal phototherapy, the role of regulatory T cells and of mesenchymal stem cells needs to be explored.
