Abstract
Background:
The use of hematopoietic stem cell transplantations (HSCTs) as a curative therapy for life-threatening immunodeficiencies has had a profound impact on clinical outcomes. A subset of patients may experience immune reconstitution inflammatory syndrome (IRIS) post-transplant affecting the thyroid gland, but this has received little attention in the pediatric literature. We present the clinical, biochemical, and cytological course of patients with Graves' disease after HSCT in the pediatric population.
Patients and Methods:
Four children (median age 1.5 years, range 2 months–9 years) underwent HSCT. The conditioning regimen included chemotherapy but not radiotherapy. None of the children or their donors had evidence of thyroid disease pre-HSCT or during the follow-up period. Engraftment was uneventful in all, with stable donor T-cell chimerism, and none had evidence of graft-versus-host disease.
Results:
Patients developed Graves' disease soon after undergoing HSCT, with a median time interval between HSCT and Graves' disease of 22 months (range 16–28 months). Graves' disease was diagnosed on the basis of clinical and biochemical parameters, including a suppressed thyrotropin, raised free thyroxine, and raised thyrotropin receptor antibodies. Three patients were hypothyroid initially (suggestive of a Th1 profile) before Graves' disease (suggestive of a Th2 profile). In three patients, the clinical picture changed rapidly with hypothyroidism abruptly followed by profound thyroid hormone excess. The onset of Graves' IRIS coincided with a rapid expansion in naïve and total CD4.
Conclusions:
Immunological dysregulation during T-cell engraftment is the most likely mechanism for developing Graves' IRIS after allogenic HSTC. Clinicians need to be aware that HSCT-engendered immune recovery may result in a particularly aggressive form of autoimmune thyroid disease in children with implications for the developing central nervous system. Careful surveillance of thyroid function post-HSCT is essential.
Introduction
Methods
Following the diagnosis of the underlying immunological disorder (detailed in Table 1), the patients described underwent allogeneic HSCT in our center. Hematopoietic stem cells were obtained from either human leukocyte antigen–matched related (family) or unrelated donors. All patients underwent a cytoreductive conditioning regimen according to European Guidelines current at the time (none received irradiation therapy). All received graft-versus-host disease prophylaxis with cyclosporin and mycophenolate mofetil. Engraftment was uneventful in all, with stable donor T-cell chimerism, and none had evidence of graft-versus-host disease. None of the patients or donors had evidence of thyroid disease pre-HSCT or during the follow-up period. Thyroid function tests were routinely performed during the follow-up post-HSCT as previously reported (3). Figure 1 shows the thyrotropin (TSH) and total and naïve CD4 T-cell counts as a function of time.
The temporal relationship between patient thyroid function and CD4 cell count. All patients appear to develop biochemical thyrotoxicosis in association with an expansion of T cells.
HSCT, hematopoietic stem cell transplantations; GvHD, graft-versus-host disease; GD, Graves' disease; BM, bone marrow; CGD, chronic granulomatous disease; SCID, severe combined immunodeficiency; NBS, Nijmegen breakage syndrome.
Results
Case 1
Eight months after HSCT (Table 1) for RAG2-deficient Omenn syndrome complicated pre-HSCT by multiple viral infections—cytomegalovirus (urine, blood, and broncho-alveolar lavage), Epstein–Barr virus (blood and cerebrospinal fluid), and Norovirus (feces)—this 10-month-old female child presented with an abnormal thyroid function suggestive of hypothyroidism (TSH 64.9 mIU/L [normal range 0.3–4.7 mIU/L], free thyroxine [fT4] 7.6 pmol/L [normal range 9.5–21.5 pmol/L], thyroid peroxidase autoantibody [TPOAb] 236 IU/mL [normal range 0–34 IU/mL]) and L-T4 treatment commenced. One month later, she became clinically and biochemically hyperthyroid with a moderate-sized goiter and mild ophthalmopathy (TSH 0.07 mIU/L, fT4 35.3 pmol/L). Persistently elevated thyroid receptor antibodies (thyroid-binding inhibitory immunoglobulin [TBII] at 16.1 U/L [normally <1.0 U/L]) confirmed the diagnosis of Graves' disease. Figure 1A illustrates the rapid change from an elevated to a suppressed TSH. L-T4 was discontinued and treatment with carbimazole (with the dose titrated according to prevailing thyroid hormone levels) commenced. Managing her Graves' disease was difficult and necessitated an increasing carbimazole dosage from 0.5 to 1.5 mg/kg/day over the course of 12 months. She finally became biochemically euthyroid 1.5 years after carbimazole was commenced. There was evidence of rapid growth, but her neurodevelopment was within normal limits.
Case 2
Nine months after HSCT for X-linked chronic granulomatous disease previously complicated by life-threatening infections (mycobacterial lymphadenopathy/abscesses, recurrent pneumonia caused by Burkholderia cepacea, and possible mycobacterial infection, with subsequent chronic lung disease; Table 1), this 10-year-old boy had a marginally elevated TSH (5.19 mIU/L) in the presence of a normal fT4 (13.8 pmol/L) and a normal TPOAb (5 IU/mL). About 25 months after HSCT, he complained of weight loss and diarrhea, with examination confirming both clinical and biochemical features of Graves' disease (fT4 21.1 pmol/L, TSH <0.05 mIU/L, TBII 34 U/L, and a borderline TPOAb of 37 IU/mL). Figure 1B demonstrates the mildly elevated TSH that suppressed around the time that the total and naïve CD4 cell count was rising. He was rendered euthyroid with carbimazole (0.7 mg/kg/day) and subsequently treated with radioactive iodine.
Case 3
Eleven months after HSCT for T−B+NK+ severe combined immunodeficiency of undetermined genetic origin (Table 1), this 2-year-old girl was found to have hypothyroidism (TSH 136 mIU/L, fT4 8.2 pmol/L, TPOAb >1300 IU/mL) and commenced on L-T4. After 6 months of L-T4 therapy, she became biochemically thyrotoxic (fT4 26.8 pmol/L, TSH <0.05 mIU/L), and an elevated TBII level (95.8 U/L) confirmed the diagnosis of Graves' disease. Figure 1C demonstrates the fluctuation in TSH around the time that the total and naïve CD4 cell count increased. Subsequently, her T4 was stopped and carbimazole was commenced.
Case 4
Two and a half years after HSCT for Nijmegen breakage syndrome, this 4.5-year-old girl presented with thyrotoxicosis (TSH <0.05 mIU/L, fT4 83 pmol/L, TBII 80 U/L, TPOAb >1300 IU/mL) and commenced on carbimazole (Fig. 1D). Concerns regarding the potential marrow suppressive effects of carbimazole, and issues around compliance resulted in her undergoing total thyroidectomy 1.5 years later. She subsequently commenced on L-T4 replacement. Radioactive iodine therapy was not selected because of concerns regarding the underlying radiosensitivity of Nijmegen breakage syndrome.
Addendum
After the manuscript was submitted, two additional patients were diagnosed. These patients are not included in Table 1 or Figure 1, but their clinicopathologic details are presented here.
Additional patient 1
A 2.5-year-old female was found to have a low TSH (0.07 mIU/L), elevated fT4 (47.6 pmol/L), and elevated fT3 (19.5 pmol/L), with positive TBII (16.6 U/L) and normal TPOAb (30 IU/mL) on routine follow-up. Moreover, 2.4 years earlier she had undergone an unrelated matched (10/10) umbilical cord HSCT for juvenile malignant osteopetrosis, following a myeloablative conditioning regimen with treosulfan, fludarabine, thiotepa, and serotherapy with anti–T lymphocyte globulin. She had transient skin and liver graft-versus-host disease (GvHD) with full donor chimerism and good immune reconstitution at 10 months post-HSCT. The patient was diagnosed with Graves' disease and has commenced on carbimazole therapy.
Additional patient 2
A 20-year-old female presented with clinical thyrotoxicosis with a low TSH (0.05 mIU/L), elevated fT4 (55.9 pmol/L), and elevated fT3 (30.4 pmol/L), with positive TBII (37 U/L). One and a half years earlier she had undergone a matched sibling (12/12) peripheral blood stem cell (PBSC) transplant for complex autoimmune disease including autoimmune hepatitis, hypothyroidism, interstitial lung disease, and panniculitis. She had undergone a low-intensity immunosuppressive conditioning regimen with fludarabine, low-dose cyclophosphamide (total dose, 1200 mg/m2), and serotherapy with alemtuzumab. She had prolonged immune reconstitution in spite of full donor chimerism and no GvHD. The abnormal thyroid function coincided with the mergence of naïve T cells. The patient was treated with total thyroidectomy with subsequent L-T4 replacement.
Discussion
We report four cases of Graves' disease occurring soon after allogeneic HSCT was undertaken in one of the two British national centers for HSCT in primary immunodeficiency disorders. Although immune reconstitution Graves' disease in adults has been described, to our knowledge this is the first case series of Graves' IRIS in a pediatric population.
The median time to presentation of Graves' IRIS in our series was 22 months (range 16–28 months). Another of our patients who underwent HSCT for chronic granulomatous disease is not listed in this series as his Graves' disease associated with IRIS presented at 22 years of age, 58 months after his HSCT. The calculated incidence of IRIS-associated Graves' disease in our HSCT population was 1012 per 100,000 (based on 395 HSCT over the period of 24 years) as compared with a British Graves' disease incidence of 0.9 per 100,000 (<15 years) (10). Hence, in excess of 1% of transplanted patients have subsequently developed Graves' disease.
The pathophysiology of newly emerging autoimmunity after allogeneic HSCT remains poorly understood (2). Organ-specific autoimmunity is more common than systemic disorders, particularly cytopenias, but thyroid dysfunction is common with an overall incidence of 25–40% (3,11). Patients can present with euthyroid sickness and inflammatory thyroiditis (virally induced or autoimmune), and in our experience autoimmune hypothyroidism is also common (3). Hashimoto's thyroiditis can precede IRIS-associated Graves' disease, which may reflect a change from an immune response characterized by a Th1-predominant response to one characterized by a Th2 response during a period of immunological instability after HSCT (8,9,12). While the patients in this series had Graves' disease as confirmed by thyroid hormone excess in association with antibodies to the TSH receptor and a suppressed TSH, three of our four patients became thyrotoxic after a phase of hypothyroidism and all had a raised TPO antibody titer.
The potential pathophysiological mechanisms resulting in increased susceptibility to thyroid autoimmune disease include an innate failure to delete TSH receptor–reactive T and B cells or a defect in immune tolerance, including abnormal T regulatory cell function (13). IRIS-associated Graves' disease post-allogeneic HSCT can also be caused by adoptive transfer, where TSH receptor–autoreactive lymphocytes are transferred from a donor with known or dormant Graves' disease (4,5). However, we know that none of the donors in our series had thyroid disease before or during HSCT.
We observed the expansion of total and naïve allogeneic CD4 T-cells post-HSCT during immune reconstitution to coincide with clinical and biochemical evidence of IRIS-associated Graves' disease (Fig. 1A–C). It is presumed that recovery of severe lymphodepletion by homeostatic expansion of naïve and antigen-experienced autoreactive T-lymphocytes may favor the development of autoimmune diseases (14). A good example is IRIS-associated Graves' disease after a highly active antiretroviral therapy in patients with HIV (6,7), where both defects of central tolerance resulting from thymic dysfunction (8) and impaired function of cytotoxic T lymphocyte antigen 4, which is important for the maintenance of T-cell tolerance to thyroid autoantigens (15,16), have been reported. Similarly, IRIS-associated Graves' disease is reported after lymphodepletion with alemtuzumab (anti-CD52 monoclonal antibody) as part of the treatment for multiple sclerosis (9). This failure of central tolerance mechanisms during vigorous de novo lymphopoiesis may lead to the generation of new autoreactive T- and B-cells and, if uncontrolled, to the development of new autoimmune diseases.
Similarly, the state of immunologic dysregulation during immune reconstitution after the HSCT procedure as well favors rapid expansion of lymphocyte clones, and may lead to loss of regulation of autoreactive T cells. This may explain the subsequent inability to effectively delete the TSH-reactive autoantibodies (13). Eventually, the restoration of immune regulation post-HSCT, in both autologous and allogeneic settings, is believed to be due to the crucial role of T-regulatory cells (17,18).
In conclusion, it is important for clinicians to be aware that HSCT-engendered immune recovery may result in a particularly aggressive form of thyroid dysfunction in childhood with hypothyroidism frequently preceding Graves' disease. Careful monitoring should be undertaken when a hypothyroid profile is observed with an awareness that the biochemical profile may shift to the opposite extreme. While Graves' disease may develop relatively quickly after transplantation, our experience also underlines the importance of ongoing vigilance for many years to come (19). This is particularly important in the pediatric population because of the critical role of thyroid hormone in brain maturation in early life and the potential implications of excessive T4 on long-term neurocognition.
Footnotes
Author Disclosure Statement
No competing financial interests exist.