Volume 126, Issue 2 , Pages 392-394, August 2010
Successful long-term immunologic reconstitution by allogeneic hematopoietic stem cell transplantation cures patients with autosomal dominant hyper-IgE syndrome
Article Outline
To the Editor:
The hyper-IgE syndromes (HIESs) are rare primary immune deficiencies characterized by increased serum IgE levels, eczematous rash, and recurrent skin and lung infections. Both autosomal recessive and autosomal dominant inheritance have been described, but most HIES cases are sporadic.1, 2, 3 Autosomal dominant HIES (AD-HIES), the most common form, has various immunologic and nonimmunologic abnormalities arising as consequences of impaired cytokine signal transduction and TH17 cell deficiency caused by mutations in the signal transducer and activator of transcription 3 gene (STAT3).4, 5 Although correction of the immunologic defect with allogeneic hematopoietic stem cell transplantation (HSCT) could be expected, the first transplantation attempts in 2 patients with HIES reported in 1998 and 2000 failed to show long-term benefits.6, 7
We report the cases of 2 unrelated boys with sporadic HIES complicated by high-grade non-Hodgkin lymphoma, who were cured with myeloablative HLA-matched sibling bone marrow transplantation. Before presenting for HSCT, both patients had experienced recurrent infections despite receiving antibiotic prophylaxis. Non-Hodgkin lymphoma was treated by 7 and 4 CHOP (Cyclophosphamide Hydroxydaunorubicin Oncovin Prednisone) chemotherapy cycles in patients 1 and 2, respectively, achieving complete remission in patient 1 only.
Demographic, clinical, and laboratory characteristics of the 2 patients are shown in Table I. An HIES-scoring system based on both clinical and laboratory criteria was used to support the likelihood of a STAT3 gene mutation. Both patients scored greater than 60, which is strongly correlated with STAT3 mutations.4 In addition, samples from both patients and their relatives were obtained at the time of the last follow-up visit, and sequence analysis of the STAT3 gene identified patient 1 to be heterozygous for 1145G>A nucleotide substitution (R382Q) and patient 2 to be heterozygous for 1144C>T (R382W).
Table I. Characteristics of patients with HIES
| Patient 1 | Patient 2 | |
|---|---|---|
| Age at transplantation (y) | 15 | 16 |
| Sex | Male | Male |
| Skin abscesses | Multiple | Multiple |
| Pneumonias | >3 | >3 |
| Systemic candidiasis | Yes | No |
| Parenchymal lung abnormalities | No | Bronchiectasis pneumatocele |
| Newborn rash | Yes | Yes |
| Eczema | Yes | Yes |
| Retained primary teeth | Yes | Yes |
| Osteoporosis | Yes | No |
| Lumbar BMD t score/z score | −4.04/−1.86 | Not determined |
| Pathologic bone fractures | No | No |
| Characteristic face | Yes | Yes |
| Scoliosis | No | No |
| Highest serum IgE level (IU/mL) | 50,000 | 20,000 |
| Eosinophilia | Yes | No |
| Lymphoma | High-grade NHL | High-grade NHL |
| Phenotype score at transplantation time | 77 | 79 |
| Genotype | R382Q/wild-type | R382W/wild-type |
Both patients underwent allogeneic bone marrow stem cell transplantation after written informed consent, each from their respective healthy HLA-identical sibling. After myeloablative conditioning with 16 mg/kg busulfan, 40 mg/kg VP-16, and 200 mg/kg cyclophosphamide, donor bone marrow nucleated cells 5.4 × 108 and 4.5 × 108 per kilogram containing 8.6 × 106 and 8.2 × 106 CD34+ cells per kilogram of patients 1 and 2, respectively were infused. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine (until day 180) and methotrexate, 15 mg/m2 on day 1 and 10 mg/m2 on days 3 and 6 after transplantation. Myeloid engraftment (absolute neutrophil count >0.5 × 109/L) for patients 1 and 2 occurred on days +11 and +14, respectively, whereas platelet engraftment (count >20 × 109/L) occurred on days +20 and +27, respectively. In the early posttransplantation period, both patients had severe hemorrhagic enteritis caused by adenoviral infection on days +5 and +9, respectively, which resolved soon after stable engraftment was achieved. In addition, patient 1 had severe hemorrhagic cystitis on day +24 that resolved completely after 5 weeks. Neither patient had acute or chronic GVHD. Complete donor-derived hematopoietic chimerism has consistently been detected after day +60 after transplantation by studying short tandem repeats. Full donor chimerism was also detected on purified CD3+ cells at both patients' most recent follow-up visit. IgE levels were normal (<250 IU/mL) 2 months after transplantation for the first time and remain normal 14 and 10 years after transplantation for patients 1 and 2, respectively. Transplantation outcome and immune reconstitution are summarized in Table II.
Table II. Outcome and immune reconstitution after HSCT
| Patient 1 | Patient 2 | |
|---|---|---|
| Follow-up (y) | 14 | 10 |
| Donor chimerism (%) | 100 | 100 |
| GVHD, acute/chronic | No/no | No/no |
| IgE (IU/mL) | 107 | 14 |
| CD3+CD4+ cells/μL | 1,020 | 1,061 |
| CD3+CD8+ cells/μL | 616 | 695 |
| NK cells/μL | 190 | 238 |
| B cells/μL | 474 | 650 |
| TH17 cells (% CD4+ cells) | 1.0 | 0.8 |
| IgG (mg/dL) | 936 | 876 |
| IgM (mg/dL) | 192 | 39 |
| IgA (mg/dL) | 82 | 104 |
| Revaccination (18 mo after transplantation) | Protective anti-Haemophilus b and tetanus responses | Protective anti-Haemophilus b and tetanus responses |
| Osteopenia/osteoporosis | No | No |
| Lumbar BMD t score/z score | −0.8/−0.8 | Not determined |
During the last year of follow-up, we repeatedly assessed the proportion of peripheral blood TH17 cells; in both patients the IL-17+ cell populations were always found to be 0.8% or greater of CD4+ cells, which was comparable with those seen in healthy donors (1.2% ± 0.30%, n = 8). There was no need for rehospitalization during the entire follow-up period; neither patient revealed pneumonia, skin infection, or other problems associated with AD-HIES or bone marrow stem cell transplantation or lymphoma recurrence. AD-HIES–related nonimmunologic manifestations, including skin lesions (in both patients) and osteoporosis (in patient 1), also resolved. Specifically, osteoporosis in patient 1, as determined by means of bone mineral density of the lumbar spine (t score and z score, −4.04 and −1.86, respectively), diagnosed 1 year before lymphoma diagnosis resolved after transplantation without other specific treatment (at the last visit, the t and z scores were −0.8 and −0.8, respectively). Even the coarse appearance of the skin of the face with pronounced pores gradually disappeared. In addition, careful monitoring during follow-up did not detect any other AD-HIES–associated nonimmunologic manifestations thus far, including those that are known to progress later in the life of patients with AD-HIES, such as coronary artery aneurysms, brain lesions, or degenerative joint disease.8
Despite improved supportive treatment, there are patients with HIES who experience severe recurrent pulmonary infections starting in early childhood. Even when they are treated aggressively and promptly, these patients will eventually have chronic lung disease associated with increased mortality.9 For such patients, a curative treatment leading to the prevention and even reversal of AD-HIES manifestations would be highly beneficial. Two bone marrow transplant attempts have been reported with the expectation that at least the immunologic defect would be cured by replacing the immune system. The first case concerned an adult who died of transplantation-related complications 6 months after transplantation but with decreased serum IgE levels and fewer HIES-related symptoms,6 and in the second case a 7-year-old girl experienced a relapse of HIES 4 years after transplantation, despite full donor chimerism in all leukocyte lineages. The authors of the second case report entitled their article “Bone marrow transplantation does not correct the hyper IgE syndrome,” suggesting another as yet unrecognized defect affecting other cells of unknown origin rather than lymphohematopoietic cells.7
Since this report, no further transplantation attempts in patients with HIES have been reported. The clinical course of the patients presented here demonstrates that manifestations of AD-HIES related to the STAT-3 defect in lymphohematopoietic cells can be resolved by myeloablative allogeneic HSCT. The length of follow-up enables us to suggest that the progression of other significant deficits associated with AD-HIES, including neurological, musculoskeletal, and vascular abnormalities, might also be delayed or halted. Allogeneic HSCT for patients with AD-HIES presenting progressive lung disease or lymphoproliferative disease should be considered, despite the possibility of long-term complications, such as GVHD, especially if an HLA-identical sibling is available.
We thank Alexandra Soldatou, MD, for carefully reading the manuscript and helpful discussions.
References
- Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J Allergy Clin Immunol. 2009;124:1289–1302e4
- STAT3 mutations in the hyper-IgE syndrome. N Engl J Med. 2007;357:1608–1619
- Dominant–negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007;448:1058–1062
- Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. J Allergy Clin Immunol. 2010;125:424–432
- Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008;452:773–777
- . Effects of allogeneic peripheral stem cell transplantation in a patient with Job syndrome of hyperimmunoglobulinemia E and recurrent infections. Am J Med. 1998;108:162–164
- . Bone marrow transplantation does not correct the hyper IgE syndrome. Bone Marrow Transplant. 2000;25:1303–1305
- . The hyper IgE syndromes. Immunol Allergy Clin North Am. 2008;28:277–291
- Causes of death in hyper-IgE syndrome. J Allergy Clin Immunol. 2007;119:1234–1240
Supported by the Greek Ministry of Health.
Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.
PII: S0091-6749(10)00739-6
doi:10.1016/j.jaci.2010.05.005
© 2010 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Volume 126, Issue 2 , Pages 392-394, August 2010
