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Einstein (São Paulo)

Print version ISSN 1679-4508On-line version ISSN 2317-6385

Einstein (São Paulo) vol.9 no.2 São Paulo Apr./June 2011 

Original Article

Allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiencies: Hospital Israelita Albert Einstein experience

Juliana Folloni Fernandes1 

Fabio Rodrigues Kerbauy2 

Andreza Alice Feitosa Ribeiro3 

Jose Mauro Kutner4 

Luis Fernando Aranha Camargo5 

Adalberto Stape6 

Eduardo Juan Troster7 

Gabriele Zamperlini-Netto8 

Alessandra Milani Prandini de Azambuja9 

Bruna Carvalho9 

Mayra de Barros Dorna10 

Marluce dos Santos Vilela11 

Cristina Miuki Abe Jacob10 

Beatriz Tavares Costa-Carvalho12 

Jose Marcos Cunha13 

Magda Maria Carneiro-Sampaio10 

Nelson Hamerschlak14 

1Hematology and Bone Marrow Transplantation, Hospital Israelita Albert Einstein - HIAE - São Paulo (SP), Brazil. Children's Institute of Hospital da Clínicas of Medical College at Universidade de São Paulo - USP, São Paulo (SP), Brazil

2Hematology and Bone Marrow Transplantation, Hospital Israelita Albert Einstein - HIAE - São Paulo (SP), Brazil

3Hemotherapy, Hospital Israelita Albert Einstein - HIAE - São Paulo (SP), Brazil; Hematology and Bone Marrow Transplantation, Hospital Israelita Albert Einstein - HIAE - São Paulo (SP), Brazil

4Blood Bank, Hospital Israelita Albert Einstein - HIAE - São Paulo (SP), Brazil; Hematology and Bone Marrow Transplantation, Hospital Albert Eisntein - HIAE - São Paulo (SP), Brazil

5Clinical Trials Center of Instituto Israelita de Ensino e Pesquisa Albert Eisntein - IIEPAE - São Paulo (SP), Brazil

6Pediatrics, Hospital Israelita Albert Einstein - HIAE - São Paulo (SP), Brazil

7Pediatrics, Hospital Israelita Albert Einstein - HIAE - São Paulo (SP), Brazil; Institute for Treament of Cancer in Children - Children's Institute of Hospital das Clinicas of Medical College at Universidade de São Paulo - USP - São Paulo (SP), Brazil

8Pediatric Oncology, Hospital Israelita Albert Einstein - HIAE - São Paulo (SP), Brazil; Hematology and Bone Marrow Transplantation, Hospital Israelita Albert Einstein - HIAE - São Paulo - Brazil

9Hospital Israelita Albert Einstein - HIAE - São Paulo (SP), Brazil; Children's Institute of Hospital da Clínicas of Medial College at Universidade De São Paulo - USP - São Paulo (SP), Brazil

10Children's Institute of Hospital das Clínicas of Medical Colege at Unversidade de São Paulo - USP- São Paulo (SP), Brazil

11Medical Science College at Universidade Estadual de Campinas - UNICAMP - São Paulo (SP), Brazil

12Discipline of Allergy, Clinical immunology and Rheumatology of department of Pediatrics at Universidade Federal de São Paulo - UNIFESP - São Paulo (SP), Brazil

13Universidade Federal do Rio de Janeiro - UFRJ - Rio de Janeiro (RJ), Brazil

14Hematology and Bone Marrow Transplantation, Hospital Israelita Albert Einstein - HIAE - São Paulo (SP), Brazil



To report the experience of a tertiary care hospital with allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiencies.


Seven pediatric patients with primary immunodeficiencies (severe combined immunodeficiency: n = 2; combined immunodeficiency: n = 1; chronic granulomatous disease: n = 1; hyper-IgM syndrome: n = 2; and IPEX syndrome: n = 1) who underwent eight hematopoietic stem cell transplants in a single center, from 2007 to 2010, were studied.


Two patients received transplants from HLA-identical siblings; the other six transplants were done with unrelated donors (bone marrow: n = 1; cord blood: n = 5). All patients had pre-existing infections before hematopoietic stem cell transplants. One patient received only anti-thymocyte globulin prior to transplant, three transplants were done with reduced intensity conditioning regimens and four transplants were done after myeloablative therapy. Two patients were not evaluated for engraftment due to early death. Three patients engrafted, two had primary graft failure and one received a second transplant with posterior engraftment. Two patients died of regimen related toxicity (hepatic sinusoidal obstruction syndrome); one patient died of progressive respiratory failure due to Parainfluenza infection present prior to transplant. Four patients are alive and well from 60 days to 14 months after transplant.


Patients’ status prior to transplant is the most important risk factor on the outcome of hematopoietic stem cell transplants in the treatment of these diseases. Early diagnosis and the possibility of a faster referral of these patients for treatment in reference centers may substantially improve their survival and quality of life.

Key words: Immunologic deficiency syndromes; Hematopoietic stem cell transplantation; Child


Primary immunodeficiencies (PID) are inherited disorders affecting distinct components of the innate or adaptive immune systems that commonly lead to lethal complications. More than 150 different types of diseases have been described, with more than 120 different causative genes being already diagnosed(1). The most severe disorders, such as severe combined immunodeficiencies (SCID), are generally fatal in the first year of life if untreated. Since the first transplants performed in 1968, leading to the cure of a patient with X-linked SCID and a patient with Wiskott-Aldrich syndrome(23), hematopoietic stem cell transplantation (HSCT) has been the only curative treatment for a large variety of these diseases.

Survival after HSCT has improved over time. Better development of HLA typing techniques improved donor selection; better infection prophylaxis and treatment, as well as better management of graft versus host disease (GVHD) have reduced disease and transplant-related complications(4). With the use of alternative types of donor such as unrelated marrow donors, unrelated umbilical cord blood units (UCB) and mismatched related (haploidentical) family donors, the possibility to perform stem cell transplantation has been extended to virtually all patients with PID, and patients can be treated faster(57). We present here our experience in the treatment of PID with hematopoietic stem cell transplantation.


To report the experience of a tertiary care hospital in allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiencies.


The study was carried out at Hospital Israelita Albert Einstein (HIAE), which is aprivatetertiary care hospital in the city of São Paulo (SP), Brazil.

Patients and donors characteristics

From 2007 to 2010, seven patients with different types of PID underwent eight HSCT in our unit. Table 1 shows patients, donors and transplant characteristics. Patients aged from 1 to 6 years and six were males. The diagnoses were: severe combined immunodeficiency (n = 2); combined immunodeficiency (n = 1); hyper-IgM syndrome (n = 2); IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome (n = 1); and chronic granulomatous disease (n = 1). All patients had pre-existing infections (Table 1). Donor sources were: bone marrow from HLA identical sibling (n = 2); bone marrow from matched unrelated donor (n = 1) and UCB (n = 5). Unrelated marrow was HLA matched 10 out of 10 (class I and class II high resolution). All UCB units were 5 out of 6 HLA matched (considering class I (A, B) low resolution and class II (DRB1) high resolution).

Table 1 Characteristics of patients and transplants 

Patient Diagnosis Age at transplant year of transplant Pre-transplant characteristics Donor type Conditioning regimen GVHD prophylaxis transplant complications Neutrophil engraftment Chimerism Survival post transplant Status
1 Hyper IgM 6y 2007 liver failure, cryptosporidium infection UCB (5/6) Flu / Melph / ATG CsA / MMF SOS - - 20 days Dead
2 SCID 1y 2009 chronic diarrhea, failure to thrive, BCGitis, parainfluenza UBM (10/10) ATG CsA / steroids respiratory failure No - 70 days Dead
3 IPEX 2y 2009 Diabetes Mellitus, hypothyreoidism, chronic diarrhea, glomerulonephritis, failure to thrive UCB (5/6) Flu / Melph / Alemtuzumab Tacrolimus, MMF graft failure, CMV reactivation No 100% receptor - -
2010 UCB (5/6) Treo / Cy CsA / MMF sepsis, CMV reactivation D +14 100% donor 13 months Alive
4 CID 5y 2009 Recurrent HSV infections, Failure to thrive, Chronic diarrhea MSD Bu / Cy CsA / MTX none D +11 100% donor 14 months Alive
5 CGD 5y 2010 Liver abscesses, Pulmonary fungal infection, bacterial osteomielytis MSD Bu / Flu / ATG CsA / MMF none D +19 100% donor 7 months Alive
6 Hyper IgM 5y 2010 liver disturbances, cryptosporidium infection, EBV limphoprolifertaive disease UCB (5/6) Treo / Flu / Alemtuzumab CsA / MMF SOS, renal insufficiency, respiratory failure - - 24 days Dead
7 SCID 1y 2010 Diarrhea, Failure to thrive, Previous respiratory infection UCB (5/6) Bu / Flu / ATG CsA / steroids SOS, septic shock, systemic candidiasis, acute GVHD D +17 100% donor 60 days Alive

GVHD: graft versus host disease; UCB: unrelated cord blood; Flu: fludarabine; Melph: melphalan; ATG: anti-thymocyte globulin; CsA: cyclosporine A; MMF: mycophenolate mofetil; SOS: sinusoidal obstruction syndrome; SCID: severe combined immune deficiency; UBM: unrelated bone marrow; IPEX: immunedysregulation, polyendocrinopathy, enteropathy, X-linked; Treo: treosulfan; Cy: cyclophosphamide; CMV: cytomegalovirus; CID: combined immune deficiency; HSV: herpes simplex virus; MSD: matched sibling donor; Bu: busulfan; MTX: methotrexate; CGD: chronic granulomatous disease; EBV: Epstein-Barr virus.

Conditioning regimens and gVHD prophylaxis

One patient with SCID received only anti-thymocyte globulin (ATG) before transplant (due to bad performance status prior to transplant). Two patients received transplants with reduced intensity conditioning (fludarabine and melphalan, with ATG or alemtuzumab). The remaining six transplants received full myeloablative conditioning regimens with busulfan (Bu) or treosulfan and cyclophosphamide or fludarabine, with or without ATG. Two patients (Patient 5 and 7) had their Bu doses adjusted according to pharmacokinetics study after the first Bu dose. GVHD prophylaxis was assured by cyclosporine A in all eight transplants, associated with mycophenolate mofetil, methotrexate or steroids.

Supportive therapy

All patients were transplanted in rooms with HEPA filters and positive air pressure, at least until neutrophil recovery (neutrophil counts over 0,5 × 10/L for 3 consecutive days). All patients transplanted with UCB units received granulocyte colony-stimulating factor (G-CSF) from day 1 until neutrophil recovery. Antimicrobial prophylaxis during transplantation consisted of: ciprofloxacin from the beginning of the conditioning until neutrophil recovery; fluconazole until D+ 75; cotrimoxazole from neutrophil recovery until T CD4+ count recovery and acyclovir until T CD4+ count recovery. All patients received intravenous immunoglobulin to maintain IgG level over 500 mg/dL. Blood samples from all patients were screened weekly by polymerase chain reaction (PCR) for cytomegalovirus (CMV), Epstein-Barr virus and adenovirus, as well as for Aspergillus antigen (galactomannan).



One patient died 20 days after transplant and was not evaluable for engraftment. Three patients did not engraft: 1 patient with SCID did not have lymphocyte recovery until 70 days post-transplant, 1 patient died at day + 24 without neutrophil recovery and 1 patient with IPEX syndrome had an autologous recovery and underwent a second UCB transplantation 3 months later. He had full engraftment 14 days after transplant. The other three patients engrafted, with 100% donor chimerism (PCR-short tandem repeat (STR) on total leukocytes).

Regimen related toxicity

Three patients had sinusoidal obstruction syndrome of the liver, two of them severe and lethal, one moderate that responded to treatment with defibrotide. Only one patient developed acute grade II GVHD (skin and gut) that responded to steroids. None of the evaluable patients (alive 100 days after transplant) developed chronic GVHD. Two patients had bacterial sepsis that responded to antibiotics and volume replacement. Two patients had CMV reactivations detected by PCR, treated with foscarnet. One patient had Candida guilliermondi infection, which responded to liposomal amphotericin.

Survival and causes of death

Two patients with hyper-IgM syndrome and previous sclerosing cholangitis died at day +20 and D+ 24 of sinusoidal obstruction syndrome of the liver. One patient with SCID died with acute distress respiratory syndrome due to alveolar proteinosis following parainfluenza infection. Four patients are alive and well from 60 to 452 days after transplant. The patient with IPEX syndrome had total recovery from all autoimmune manifestations, except for diabetes.

Immune reconstitution

One patient with SCID was at 60 days post-transplant and was not evaluable for immune reconstitution. Absolute numbers of total lymphocytes, T CD3+, T CD4+ and T CD8+ cells were available for Patients 3 and 5 and are shown in figure 1. Two patients (Patients 3 and 4) were still receiving immunoglobulin replacement therapy.

Figure 1 Immune reconstitution: total lymphocytes, T CD3+, T CD4+ and T CD8+ cells counts of Patients 3 and 5 at 60 days, 100 days and 6 months after transplantation 


Severe PIDs are rare disorders that can be lethal early in life if untreated. In Brazil and other Latin American countries, public institutions and cooperative groups (Brazilian Group for Immunodeficiency/ Latin American Group for Primary Immunodeficiencies – BRAGID/ LAGID) have been doing a great effort on educating physicians and the general public about the warning signs for PID diagnosis. For this reason, the frequency of PID diagnosis has increased in the last years(8). In Brazil, the first transplant for a PID disease was made in Universidade Federal do Paraná (UFPR), Curitiba (PR), in 1992, in a patient with Wiskott-Aldrich syndrome. Since then, the number of transplants has increased, totalizing 76 transplants for PID diseases in Brazil until 2007(9).

In our institution, in 2008, we developed a program in collaboration with public institutions for the treatment of these patients with HSCT and we reported here our experience with these transplants. Seven patients received eight transplants for different PID diagnosis.

One of the most important prognostic factors for these transplants is related to patients’ condition prior to HSCT(4). Due to delayed diagnosis, all patients treated in our unit had or had had severe infectious episodes before being referred for treatment. The three patients who died from transplant-related causes had bad performance status at the moment of HSCT. This fact may have contributed for the less favorable outcomes of our patient series.

Since July 2010 we started a program in order to perform Bu dosing and pharmacokinetics. Bu levels present a large variability in children, leading sometimes to engraftment failure (underexposure) or increased toxicity (overexposure)(10). Two patients in our series (Patients 5 and 7) benefited from this study and had their Bu area under the curve (AUC) measured. The use of Bu adapted for AUC levels may also contribute for further reduction of regimen-related toxicities.


The experience of our unit in the treatment of severe PID with HSCT was shown. The opportunity to offer this expensive and specialized treatment for patients from the public health system contributes to improve survival in these severe disorders. The nationwide effort of cooperative groups to improve PID diagnosis is mandatory to ameliorate the conditions of patients referred for transplantation, thus improving their survival and quality of life.

Study carried out at the Hospital Israelita Albert Einstein- HIAE, São Paulo (SP), Brazil.


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Received: March 06, 2011; Accepted: April 13, 2011

Corresponding author: Juliana Folloni Fernandes – Unidade de Hematologia e Transplante de Médula Óssea do Hospital Israelita Albert Einstein – Avenida Albert Einstein, 627/701 – Morumbi – CEP 05409-011 – São Paulo (SP), Brasil – Tel.: (11) 2151-3203 – e-mail:

The authors declare there is no conflict of interest.

Creative Commons License This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.