EBV-associated lymphoproliferative disorders (LPDs) are common in hematopoietic stem cell transplantation (HSCT) with T-cell-depleted grafts, but are extremely rare in HSCT patients with ...T-cell-replete grafts with post-transplant cyclophosphamide (PTCy). Here we present the cases of two pediatric patients who developed EBV-related LPD after T-cell-replete haplo-HSCT with PTCy. One of these is the first reported case of EBV-positive mucocutaneous ulcer (EBVMCU) developing after PTCy. EBV-related diseases are rare in T-cell-replete haplo-HSCT patients with PTCy. However, in patients with risk factors, it is reasonable to screen for EBV viremia for LPD.
Background
Despite the increasing performance of allogeneic hematopoietic cell transplantation over the last decades, graft‐versus‐host disease (GVHD) remains the main cause of morbidity and ...mortality. The efficacy of ruxolitinib against GVHD has been demonstrated in adult studies; however, very few studies have been conducted in children.
Procedure
This study aimed to evaluate the efficacy of ruxolitinib in 29 children with steroid‐refractory acute or chronic GVHD. Twenty‐five (87%) patients received at least three different immune modulator agents, including methylprednisolone, before initiating ruxolitinib.
Results
All grade 2 acute GVHD patients completely responded to ruxolitinib treatment; 82% of high‐grade (3‐4) acute GVHD patients and 80% of chronic GVHD (moderate‐severe) patients had at least a partial response. Of seven patients with bronchiolitis obliterans, five had a partial response after ruxolitinib. Of 29 patients, 22 were administered steroids at any time in the first month of acute GVHD or the first three months of chronic GVHD during ruxolitinib usage, which was significantly tapered by the end of the observation period.
Conclusion
Steroid‐refractory acute and chronic pediatric GVHD patients treated with ruxolitinib had a high overall response rate, with the additional benefit of steroid sparing.
Subacute sclerosing panencephalitis (SSPE) is a progressive and fatal disease caused by reactivation of a mutated measles virus in brain tissue. The process of reactivation is yet to be elucidated. ...In this study, the possible roles of the Th1 (interleukin IL-12, interferon IFN-γ) and the Th17 axis (IL-23, IL-17, IL-22), particularly of IL-17, in the pathogenesis of SSPE were investigated. Briefly, mononuclear cells from SSPE patients were stimulated using measles virus peptide, and the release of IL-12, IL-23, IL-22, IFN-γ, and IL-17 cytokines was measured using enzyme-linked immunosorbent assay and/or enzyme-linked immunosorbent spot assay (ELISpot). We found that in comparison to the mononuclear cells obtained from healthy donors, cells from SSPE patients exhibited increased levels of IL-12, IL-23, IL-17, IL-22, and IFN-γ cytokines in response to measles virus stimulation. However, the same result was not obtained with cytomegalovirus and phytohemagglutinin. Using flow cytometry, mononuclear cells obtained from SSPE patients and healthy controls were also analyzed for the presence of intracellular IL-17 in response to measles virus stimulation. On stimulation, the number of IL-17-positive cells were found to be higher among mononuclear cells obtained from the patients. In addition, the numbers of IL-17- and IFN-γ-positive cells were significantly increased in SSPE patients. In conclusion, this study demonstrates that both the IL-12/IFN-γ and the IL-23/IL-17/IL-22 pathways are functionally abnormal in SSPE pathogenesis. Targeting these pathways and their specific pro-inflammatory mediator production may provide a new strategy to suppress SSPE development.
Severe combined immunodeficiency (SCID) is the most serious PID, characterized by T cell lymphopenia and lack of antigen-specific T cell and B cell immune responses, inevitably leading to death ...within the first year of life if hematopoietic stem cell transplantation (HSCT) is not performed.
Purpose and Methods
Since SCID is a common type of PID with an estimated incidence of 1/10.000 in Turkey, a retrospective analysis of HSCT characteristics, survival, immune recovery, and the major clinical features of SCID prior to HSCT is the aim of this multi-transplant center-based analysis.
Results
A total of 234 SCID patients transplanted between the years 1994 and 2014 were included in the study. Median age at diagnosis was 5 months, at transplantation, 7 months, B− phenotype and RAGs were the most common defects among others. Immune phenotype did not seem to have an effect on survival rate (
p
> 0.05), Immunoglobulin (Ig) requirement following HSCT did not differ between B+ and B− phenotypes (
p
> 0.05). Overall survival rate was 65.7% over a period of 20 years. It increased from 54% (1994–2004) to 69% (
p
= 0.052) during the last 10 years (2005–2014). Ten-year survival after HSCT has improved over time although the difference was not significant. Infection at the time of transplantation (
p
= 0.006), mismatched related donor (MMRD) (haploidentical parents), and matched unrelated donor (MUD) donor transplants
p
< 0.001 were the most important factors, significantly affecting the outcome.
Conclusions
This is the first multicenter study with the largest data obtained from transplanted SCID patients in Turkey. Early diagnosis with newborn screening (NBS) together with emerging referrals, treatment by transplantation centers, and specialized teams are mandatory in countries with high parental consanguinity such as Turkey.
Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children, with a particularly poor prognosis in infants under one year of age. Hematopoietic stem cell transplantation (HSCT) ...is an effective therapy for relapsed or refractory ALL; however, relapse after HSCT remains a significant challenge. Many children cannot undergo HSCT because of serious adverse events from previous treatment. In this case report, we present the case of an infant with relapsed/refractory ALL who received blinatumomab as salvage therapy after a second haploidentical HSCT and remained in remission for 15 months without subsequent HSCT. The patient was a 4-month-old male diagnosed with high-risk infant B-cell ALL with KMT2A/AFF1. He received induction chemotherapy according to the INTERFANT-06 protocol and achieved complete remission. He underwent 10/10 matched-sibling bone marrow transplantation but experienced an isolated marrow relapse 2 months post-transplant and then received a second haploidentical HSCT. He was treated with one cycle of blinatumomab after the relapse that occurred after the second HSCT. Due to toxicity, the patient did not receive a third transplant but was followed up after blinatumomab. And the patient remained in complete remission for 15 months after the blinatumomab therapy. Blinatumomab has been known as a bridging therapy. We suggest that blinatumomab could be a promising curative therapy option for patients who cannot receive further HSCT.
Background
Dedicator of cytokinesis 8 (DOCK8) deficiency is the main cause of the autosomal recessive hyper‐IgE syndrome (HIES). We previously reported the selective loss of group 3 innate lymphoid ...cell (ILC) number and function in a Dock8‐deficient mouse model. In this study, we sought to test whether DOCK8 is required for the function and maintenance of ILC subsets in humans.
Methods
Peripheral blood ILC1‐3 subsets of 16 DOCK8‐deficient patients recruited at the pretransplant stage, and seven patients with autosomal dominant (AD) HIES due to STAT3 mutations, were compared with those of healthy controls or post‐transplant DOCK8‐deficient patients (n = 12) by flow cytometry and real‐time qPCR. Sorted total ILCs from DOCK8‐ or STAT3‐mutant patients and healthy controls were assayed for survival, apoptosis, proliferation, and activation by IL‐7, IL‐23, and IL‐12 by cell culture, flow cytometry, and phospho‐flow assays.
Results
DOCK8‐deficient but not STAT3‐mutant patients exhibited a profound depletion of ILC3s, and to a lesser extent ILC2s, in their peripheral blood. DOCK8‐deficient ILC1‐3 subsets had defective proliferation, expressed lower levels of IL‐7R, responded less to IL‐7, IL‐12, or IL‐23 cytokines, and were more prone to apoptosis compared with those of healthy controls.
Conclusion
DOCK8 regulates human ILC3 expansion and survival, and more globally ILC cytokine signaling and proliferation. DOCK8 deficiency leads to loss of ILC3 from peripheral blood. ILC3 deficiency may contribute to the susceptibility of DOCK8‐deficient patients to infections.
• Peripheral blood ILC3 and ILC2s are reduced in DOCK8 but not STAT3 mutant HIES patients.
• DOCK8 deficient human ILCs have reduced IL‐7 receptor expression, impaired IL‐7, IL‐23 and IL‐12 signaling and are more prone to apoptosis.
• DOCK8 is required for maintenance and function of human peripheral blood ILC3s. ILC3 depletion may contribute to susceptibility of DOCK8 deficient patients to infections.
Aim: In hematopoietic stem cell transplantation (HSCT), the phase of engraftment which can be described as an "immunogenic storm", is also vulnerable to infections and it has been always very hard to ...discriminate the cause of fever in this special period of HSCT. In this study, we aim to determine if procalcitonin (PCT) could be used to define the cause of fever in the engraftment phase of HSCT. Materials and Methods: This study involves 81 patients who consecutively underwent allogeneic HSCT between October 2017-June 2020 in our pediatric HSCT unit. The patients were divided into two groups due to the origin of the fever during engraftment as infectious fever group (n=42) and the non-infectious fever group (n=39). Results: The median duration of fever for all groups was 4 days (1-11 days) and it was significantly lower in the non-infectious fever group compared to the infectious fever group (3 vs. 4 respectively p=0.001). The median PCT levels was 0.6 ng/mL (0.04-83) for all groups and it was significantly higher in the infectious fever group compared to non-infectious (1.4 vs. 0.3 p<0.001). According to ROC analysis, the cut-off PCT level of 0.515 ng/mL or more had an AUC of 0.817 and may predict the infectious fever with a sensitivity of 81% and a specificity of 76.9%. Conclusion: We observed that PCT may be used to discriminate infectious fever from non-infectious fever at the engraftment phase of HSCT and PCT could be a useful marker for antibiotic treatment strategy. Keywords: Engraftment, hematopoetic stem cell transplantation, procalcitonin
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Pneumatosis intestinalis (PI) is a rare disease, which presents a wide range of severity. Numerous etiologies, including trauma, inflammation, infections, autoimmunity, drugs, and mechanical ...procedures, gave rise to this complication. Abdominal computerized tomography is the preferred diagnostic tool with high sensitivity. The diagnosis depends on free air detection in the intramural portion of the gastrointestinal system and main and intrahepatic branches of the portal venous structures. However, the exact mechanism is unknown. The clinical scenario may vary from benign to life-threatening. One of the etiological factors that cause PI is the chronic graft-versus-host disease (cGVHD), which must be considered in patients with solid organ or hematological malignancies. Especially, patients who received long-term immunosuppressive therapies and were diagnosed with cGVHD are prone to developing a PI. Many patients experience unnecessary operational risks if underdiagnosed. A multidisciplinary approach by the primary physician, general surgeon, and radiology specialist is necessary for the proper treatment of these patients. This case report aimed to discuss the clinical presentation of PI in the course of cGVHD in the intensive care unit.
The aim of the study was to assess the incidence and clinical relevance of active Human Herpes Virus 6 (HHV6) infections in pediatric patients after allogeneic stem cell transplantation.
...Retrospective analysis of samples prospectively collected at Akdeniz University Medical Faculty Hospital, Antalya, Turkey, between May 2006 and July 2007 from 15 pediatric patients with allogeneic hematopoietic stem cell transplantation (HSCT).
A commercial quantitative real-time polymerase chain reaction kit was used to analyze plasma samples collected from 15 pediatric allogeneic HSCT recipients.
HHV6 DNA was found positive in 8 (53%) patients. HHV6 DNA levels above 1000 copies/mL were found only in 2 patients and they were also consecutively positive for HHV6 DNA. Age at transplantation, use of ATG, and receiving grafts other than HLA identical siblings increased the risk, with a statistically significant difference, of having HHV6 reactivation with levels exceeding 1000 copies/mL (P values, respectively, P=.03, .001, .025). Active HHV6 infections with HHV6 viremia levels higher than 1000 copies/mL were associated with subsequent delayed platelet engraftment (P=.001), acute graft versus host disease (P=.001), skin rash, and fever of unknown origin.
More than half of pediatric allogeneic HSCT patients develop active HHV6 infection, and especially in patients with high viremic loads, the infection can result in serious clinical situations. A clinically significant cutoff value for viremia seems to be necessary to predict serious clinical complications.
Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term ...follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant.
This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant.
We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices.
Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 70.6%). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome.
The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.
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