Clinical characteristics of Chinese neonates with neonatal-onset multisystem inflammatory disease: a case report and literature review.

Neonatal-onset multisystem inflammatory disease (NOMID) is not widely recognized in China. This study aimed to investigate the diagnosis and treatment of NOMID. To analyze the clinical characteristics and laboratory results including skin biopsy, gene analysis and serum interleukin 1β of a boy admitted to Peking University First Hospital in November of 2013. Reports on NOMID were searched and the clinical and laboratory characteristics of reported cases were summarized. The patient was a 1-year-old boy. He had urticaria since 2 days after birth, and presented with episodes of fever, aseptic meningitis, symptoms of joints, short statue, hearing loss, abnormal fundus findings, and leucocytosis, high level of c-reactive protein (CRP) and abnormal findings of head MRI including ventriculomegaly and white matter dysplasia. Urticaria was confirmed by skin biopsy. Gene analysis showed T1702T/A in exon 4 of NLRP3 gene, which causes Phe568lle. Serum interleukin 1β increased dramatically. The boy was diagnosed as NOMID. He did not respond to antibiotic therapy and anti-allergy therapy. Corticosteroid therapy induced normalization of body temperature, and alleviation of rash, but not improvement in cerebrospinal fluid cell numbers. After searching reports of NOMID at PubMed, and Chinese literature published before November 2013, we summarized cases from 8 reports and reviewed 148 cases. The results showed that fever, urticaria, meningitis and arthropathy are the most common manifestations of NOMID, only 57% (69/122) of patients had mutation of NLRP3. This is a rare report of NOMID in children in China. Fever, urticaria, aseptic meningitis and persistently high level of CRP are characteristics of NOMID. Gene analysis and serum interleukin-1β detection can aid in diagnosis.

Objective: To investigate the risk factors and outcomes of cytomegalovirus (CMV) infection post umbilical cord blood stem cell transplantation (UCBT) in children with primary immunodeficiency diseases (PID). Methods: Clinical data of 143 PID children who received UCBT in the Children's Hospital of Fudan University from January 2015 to June 2020 were collected retrospectively. CMV-DNA in the plasma was surveilled once or twice a week within 100 days post-UCBT. According to the CMV-DNA test results, children were divided into the CMV-infected group and the CMV-uninfected group. The incidence and risk factors of CMV infection were analyzed. At 1-month post-UCBT, the absolute lymphocyte count, ratio of lymphocyte subsets and immunoglobulin levels were compared between those whose CMV infection developed 1-month later post-UCBT and those not. Mann-Whitney U test and chi-squared test were used for comparision between groups. Kaplan-Meier survival analysis was used to analyze the impact of CMV infection on survival. Results: Among 143 patients, there were 113 males and 30 females, with a age of 14 (8, 27) months at UCBT. Chronic granulomatosis disease (n=49), very-early-onset inflammatory bowel disease (n=43) and severe combined immunodefiency (n=29) were the three main kinds of PID. The rate of CMV infection was 21.7% (31/143), and the time of infection occurring was 44 (31, 49) days post-UCBT. The incidence of recurrent CMV infection was 4.2% (6/143) and refractory CMV infection was 4.9% (7/143).There was no significant difference in the first time CMV-DNA copy and peak CMV-DNA copy during treatment between the recurrent CMV infection group and the non-recurrent CMV infection group (32.8 (18.3, 63.1)×106 vs. 22.5 (13.2, 31.9)×106 copies/L, Z=-0.95, P=0.340;35.2 (20.2, 54.6)×106 vs. 28.4 (24.1, 53.5)×106copies/L, Z=-0.10, P=0.920), so were those between the refractory CMV infection group and non-refractory CMV infection group (21.8 (13.1, 32.2)×106 vs. 25.9 (14.2, 12.2)×106copies/L, Z=-1.04, P=0.299; 47.7 (27.9, 77.6)×106 vs. 27.7 (19.7,51.8)×106copies/L, Z=-1.49, P=0.137). The CMV-infected group accepted more reduced-intensity conditioning (RIC) regimen than the CMV-uninfected group (45.2% (14/31) vs. 25.0% (28/112), χ2=4.76, P<0.05). The rate of CMV-seropositive recipients and Ⅱ-Ⅳ acute graft versus host diseases (aGVHD) are significantly higher in the CMV-infected group than the CMV-uninfected group (100% (31/31) vs. 78.6% (88/112), 64.5% (20/31) vs. 26.8% (30/112), χ2=7.98,15.20, both P<0.05). The follow-up time was 31.6 (13.2, 45.9) months, CMV infection had no effect on overall survival (OS) rate (χ2=0.02, P=0.843). There was significant difference in the survival rate among three groups of refractory CMV infection, non-refractory CMV infection and the CMV-uninfected (4/7 vs.95.8% (23/24) vs. 86.6% (97/112), χ2=5.91, P=0.037), while there was no significant difference in the survival rate among three groups of recurrent CMV infection, non-recurrent CMV infection and the CMV-uninfected (5/6 vs. 88.0% (22/25) vs. 86.6% (97/112), χ2=0.43, P=0.896). Children who developed CMV infection after 30 days post-UCBT had lower absolute count and rate of CD4+ T cells and immunoglobulin G (IgG) level than those in the CMV-uninfected group (124.1 (81.5, 167.6) ×106 vs. 175.5 (108.3, 257.2) ×106/L, 0.240 (0.164, 0.404) vs. 0.376 (0.222, 0.469), 9.3 (6.2, 14.7) vs. 13.6 (10.7, 16.4) g/L, Z=-2.48, -2.12,-2.47, all P<0.05), but have higher rate of CD8+T cells than those in CMV-uninfected group (0.418 (0.281, 0.624) vs. 0.249 (0.154, 0.434), Z=-2.56, P=0.010). Conclusions: RIC regimen, grade Ⅱ-Ⅳ aGVHD and CMV-seropositive recipients are the main risk factors associated with CMV infection in PID patients post-UCBT. Survival rate of children with refractory CMV infection after UCBT is reduced. Immune reconstitution in children after UCBT should be regularly monitored, and frequency of CMV-DNA monitoring should be increased for children with delayed immune reconstitution.

THU0474 Functional Analysis of Peripheral Blood Mononuclear Cells in a Fcas Patient with Novel NLRP3 Mutation

Involvement of nuclear factor kappa-B in development of neonatal onset multisystem inflammatory disease

Although intravesical Bacillus Calmette-Guérin (BCG) instillation is the standard treatment for carcinoma in situ of the bladder, it is generally contraindicated in immunocompromised patients. Here we report the first case, to our knowledge, of BCG treatment for a bladder cancer patient who had received umbilical cord blood stem cell transplantation (UCBSCT). BCG can be given safely and effectively in select cases where reconstitution of the immune system has been achieved at least 2years after UCBSCT.

The impacts of nutritional status on clinical outcomes in children receiving umbilical cord blood stem cell transplantation (UCBT) are not fully described. We evaluated the risk for malnutrition before transplantation admission and influence of weight loss during hospitalization on short-term clinical outcomes in children with UCBT. We conducted a retrospective study of pediatric patients up to age 18 years who received UCBT and were treated at the Children's Hospital of Fudan University between January 2019 and December 2020. The mean age of the 91 patients was 1.3 years, with 78 (85.7%) men and 13 (14.3%) women (p<0.001). UCBT was performed mostly for primary immunodeficiency disease (PID) (83, 91.2%). The weight loss differences among children with different primary diseases were statistically significant (p=0.003). Children with a large amount of weight loss during hospitalization (n = 24) had higher risks of skin graft-versus-host disease (GVHD) (multivariate OR=5.01, 95% CI: 1.35-18.65), intestinal GVHD (multivariate OR=7.27, 95% CI: 1.74-30.45), a longer median hospital stay (p=0.004), higher antibiotic costs (p=0.008) and higher total hospitalization costs (p=0.004). Malnutrition on admission was significantly positively correlated with longer parenteral nutrition (PN) time (p=0.008). Early nutritional intervention effects on clinical outcomes need further assessment. Underweight recipient child and excessive weight loss during transplantation increases the length and cost of hospital stay, and is associated with a high incidence of GVHD, which affects the prognosis of transplantation and medical resources consumption.

OP0286 PROTEOMICS AND RNA SEQUENCING APPROACHES HIGHLIGHT THE ROLE OF ENDOTHELIAL CELL DYSREGULATION IN IL-1 AND IFN MEDIATED AUTOINFLAMMATORY DISEASES, NOMID AND CANDLE

Clinical Outcome of UCBT for Children With CAEBV: A Retrospective Analysis of a Single Center.

StemEx®(Copper Chelation Based) Ex Vivo Expanded Umbilical Cord Blood Stem Cell Transplantation (UCBT) Accelerates Engraftment and Improves 100 Day Survival In Myeloablated Patients Compared To a Registry Cohort Undergoing Double Unit UCBT: Results Of a Multicenter Study Of 101 Patients With Hematologic Malignancies

Beneficial response to interleukin 1 receptor antagonist in traps

Neonatal-onset multi-system inflammatory disease (NOMID), a rare autosomal dominantly inherited disease, belongs to a growing spectrum of autoinflammatory diseases, is characterized by urticarial rash, arthropathy, and chronic aseptic meningitis, and is associated with mutations in the cold-induced autoinflammatory gene, CIAS1, the gene that encodes the protein, cryopyrin. As little is known about the anesthetic considerations of the disease, we sought to identify the main features and respective anesthetic and perioperative implications of NOMID. We examined perianesthetic records of children with NOMID who were anesthetized for invasive diagnostic and therapeutic interventions between 2003 and 2006. In addition, we conducted an extensive literature review of the genetic, clinical, and biochemical abnormalities of the disease. Seventeen children with NOMID (median age 8 yr, range 9 mo to 11 yr) were anesthetized for diagnostic and therapeutic procedures. All patients had neurological involvement, including increased intracranial pressure, chronic aseptic meningitis, and developmental delay; 7 had bony overgrowth, 15 ocular, and 14 otological manifestations of NOMID. Despite the complexity of the disease, the perioperative course was uncomplicated, and no serious adverse events were observed. This study is the first to investigate the anesthetic implications of NOMID, an autoinflammatory disease associated with arthropathy, recurrent fevers, urticarial rash, and chronic aseptic meningitis. While for the pediatric anesthesiologist, the presence of fever and aseptic meningitis might make the conduct of anesthetics for elective procedures less desirable, our findings suggest that without evidence of active infection, even in the presence of fever and chronic aseptic meningitis, general and regional anesthesia may be conducted in patients with NOMID without untoward complications.

Autoinflammation: The prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses

Background/Purpose:Neonatal onset multisystem inflammatory disease (NOMID) is a rare autoinflammatory disease caused by NLRP3 mutations that lead to constitutive NLRP3 inflammasome activation and IL‐1β release. Patients present with neutrophilic urticaria, chronic aseptic meningitis, and papilledema. IL‐1β inhibitors improve the inflammatory manifestations, normalize acute phase reactants, decrease CSF WBC and protein, and proinflammatory cytokine levels. We found that cytokine levels decrease with anakinra treatment, but do not normalize during clinical remission. The higher IL‐6 and IP‐10 levels in CSF than in the blood suggest local production in the brain/CSF. Our objective is to examine whether CSF cytokines, particularly IL‐6 and IP‐10, correlate with CSF subpopulations of immune cells and CSF characteristics.Methods:Immunophenotyping and cytokine data were available on 2 baseline and 16 anakinra treated patients, 9/16, fulfilled clinical remission criteria (ESR ≤25 mm/hr, CRP ≤0.5 mg/dl, CSF WBC ≤5 cells/μl and protein ≤40 mg/dl) and control patients (n = 7). Cytokines levels (IL‐1β, IL‐6, IL‐10, IP‐10, IL‐12 (p70) and (p40), IFN‐γ, TNF‐α, and IL‐18) were correlated to CSF WBC, protein, albumin quotient (AQ), and opening pressure at baseline, post‐treatment, and clinical remission. Correlation was assessed with Pearson and Spearman tests.Results:At baseline, monocytes, granulocyte, and T cells were higher in NOMID patients versus controls. Post‐treatment monocytes and granulocyte counts decreased but remained higher even in clinical remission, relative to control. Only IL‐6 and IP‐10 correlated with monocytes (r = .66, p = .051; r = .86, p = .002) respectively. A correlation of IP‐10 but not IL‐6 with granulocytes was weaker than with monocytes (r = .66, p = .058). IL‐6, IP‐10, and IL‐18 correlated with CSF protein, AQ, and WBC (except IL‐18). At baseline, IL‐6 and IL‐18 significantly correlated with CSF protein (r = .68, p = .027; r = .80, p = .0065) and AQ (r = .82, p = .011; r = .78, p = .029) respectively. At post‐treatment, IL‐18 significantly correlated and IL‐6 trend towards significance with CSF protein (r = .53, p = .022; r = .40, p = .096) and AQ (r = .83, p = .0002; r = .47, p = .087) respectively.Conclusion:1) Inflammatory cells significantly decrease in NOMID patients, especially monocytes which remain elevated even in patients in clinical remission, suggesting residual inflammation. 2) The correlation of monocytes with IL‐6 and IP‐10 suggests their contribution to IL‐6 and IP‐10 production, which may contribute to the recruitment of other inflammatory cells including granulocytes. 3) IL‐6, IP‐10, and IL‐18 may be a marker for blood brain barrier dysfunction in NOMID and their use in long term monitoring should be explored. 4) These results are consistent with the notion that NOMID is caused by dysfunction in innate immune cells, particularly monocytes.

Fatal Immune Hemolytic Anemia Following Allogeneic Stem Cell Transplantation: Report of 2 Cases and Review of Literature

Umbilical cord blood transplantation in Wiskott Aldrich syndrome