Noninfectious Fever Research Articles

Maternal Noninfectious Fever Enhances Cell Proliferation and Microglial Activation in the Neonatal Rat Dentate Gyrus

(Anesth Analg. 2019;128(6):1190–1198) Maternal fever during labor is a complication that poses many risks for the infant being delivered, and is frequently associated with epidural analgesia. Elevated levels of a proinflammatory cytokine called interleukin-6 (IL-6) are found in the maternal serum and umbilical cord blood of patients with fevers who received an epidural. These investigators have demonstrated through previous studies that higher IL-6 levels can cause temperature increases in rats, and are also connected with microglial activation and subventricular inflammation. In addition, the authors have conducted prior research that connected a higher IL-6 measurement to maternal systemic and fetal brain inflammation. This current study aimed to examine the effect of maternally administered IL-6 on neonatal brain development.

Non-infectious rhinitis is more strongly associated with early\u2014rather than late\u2014onset of COPD: data from the European Community Respiratory Health Survey (ECRHS)

PurposeChronic obstructive pulmonary disease (COPD) is associated with several co-morbidities and non-infectious rhinitis (NIR) has emerged as a new possible co-morbidity. The primary aim of this study is to confirm a previously reported association between NIR and COPD in a multicentre population over time. The secondary aim is to investigate the course over time of such an association through a comparison between early- and late-onset COPD.MethodsThis study is part of the European Community Respiratory Health Survey (ECRHS). A random adult population from 25 centres in Europe and one in Australia was examined with spirometry and answered a respiratory questionnaire in 1998–2002 (ECRHS II) and in 2008–2013 (ECRHS III). Symptoms of non-infectious rhinitis, hay fever and asthma, and smoking habits were reported. Subjects reporting asthma were excluded. COPD was defined as a spirometry ratio of FEV1/FVC < 0.7. A total of 5901 subjects were included.ResultsNon-infectious rhinitis was significantly more prevalent in subjects with COPD compared with no COPD (48.9% vs 37.1%, p < 0.001) in ECRHS II (mean age 43) but not in ECHRS III (mean age 54). In the multivariable regression model adjusted for COPD, smoking, age, BMI, and gender, non-infectious rhinitis was associated with COPD in both ECRHS II and III.ConclusionNon-infectious rhinitis was significantly more common in subjects with COPD at a mean age of 43. Ten years later, the association was weaker. The findings indicate that NIR could be associated with the early onset of COPD.

EULAR/ACR classification criteria for SLE

Supported by both the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) from the beginning, a large transatlantic, and in many phases worldwide, project has led to new classification criteria for systemic lupus erythematosus (SLE). The project had ambitious goals, particularly maintaining the high specificity of the ACR criteria, while reaching a sensitivity close to the Systemic Lupus International Collaborating Clinics (SLICC) 2012 criteria. The validation data suggest that the new criteria reached this goal, with a specificity of 93% (as for the ACR criteria) and a sensitivity of 96% (vs 97% for the SLICC criteria). The new EULAR/ACR classification criteria use positive antinuclear antibodies (ANA) as an entry criterion and have weighted items, ranging from 2 (for delirium, non-infectious fever and anti-phospholipid antibodies) to 10 (for class III or IV lupus nephritis). The cut-off for classification is 10, reached by class III/IV nephritis alone. Items are organized in domains, within which only the highest item is to be counted. Instead of many defined exclusions, one rule is used for all, namely that items are to be attributed to SLE and counted only if there is no more likely alternative diagnosis. These criteria are now expected to be externally validated in various other cohorts. The team spirit and collegiality characteristic for this EULAR/ACR criteria effort will hopefully facilitate future international projects on SLE.

Evomela® Significantly Increases the Risk of Engraftment Syndrome in Patients with Multiple Myeloma Treated with Autologous Stem Cell Transplantation

Evomela® Significantly Increases the Risk of Engraftment Syndrome in Patients with Multiple Myeloma Treated with Autologous Stem Cell Transplantation

Randomized Comparison of Rituximab Versus Bortezomib Plus Cyclophosphamide and Dexamethasone in Newly Diagnosed Waldenstrom Macroglobulinemia Patients

Background:Waldenstrom's macroglobulinemia (WM) is one type of lymphoma that had the characteristic of both lymphocytes and plasma cells. Rituximab-based or bortezomib-based regiments are commonly used treatment approaches in routine practice in previously untreated patients with LPL/WM. However, which regiment is better still unknown. The purpose of this study is to compare the efficacy of RCD (Rituximab,cyclophosphamide and dexamethasone) and BCD (Bortezomib, cyclophosphamide and dexamethasone)in newly diagnosed WM patients. Methods:30 newly diagnosed WM patients were randomly assigned to BCD or RCD group for introduction chemotherapy. Chemotherapeutic response was evaluated after 3 cycles. If a minor response (MR) or better response achieves, addition 3 cycles will be given. If not, patients will be crossed to control group for another 3 cycles. If a MR or better response comes out, addition 3 cycles will be given, otherwise, the patients will quit this study. Results: Finally, 15 patients were assigned to each treatment group. The basic characteristics of the two groups were similar. The median time to response in RCD and BCD group were 4 months and 3 months, respectively. The CR rate in RCD and BCD group was 20% and 26.7% respectively, with VGPR rate 26.7% and 6.7%, PR rate 46.7% and 40% in each group respectively. Additional 20% minor response was observed in BCD group. The overall response was 86.7% in both groups. However, RCD group had higher good response rate (≥VGPR) compared to BCD ( 46.7% vs 33.4%, p=0.05). The rate of major response (≥PR) in RCD group was higher than that in BCD group (86.7% vs 66.7%, p=0.195). The median follow-up time was 29 months. The median duration of response in RCD and BCD group was 35 months and 30 months, respectively. The 3-year progression-free rate of RCD group was significantly higher than that of the BCD group (87.5% vs 39.2%,p=0.045). The 3-year overall survival rate was 100% with RCD group versus 70% with BCD group (100% vs 70%, p=0.127)The most common adverse events of any grade with RCD and BCD were hematological toxicity. 3 patients in the RCD group had grade 3 or higher granulocytopenia.4 patients in the BCD group occurred grade 3 or higher hypocytosis. Other adverse event in the RCD group included pneumonia (40%), non-infectious fever (26.7%), hyperglycemia (13.3%) and rash (6.7%).The most common non-hematological adverse event in BCD group were peripheral neuropathy (40%), pneumonia (26.7%), herpes zoster (13.3%) and ventosity(6.7%). Events of non-infectious fever occurred more frequently in the RCD group (26.7% vs 0%, p=0.032). However, peripheral neuropathy was more common in the BCD group (40% vs 6.7%, p=0.031). There was no serious non-hematological grade 3 or higher adverse events occurred in the both groups. Conclusion: The RCD and BCD regimens have similar overall response in newly diagnosed WM. RCD regimen has higher good response rate and longer PFS time compared to BCD regimen. Both regimens have good tolerance. Disclosures No relevant conflicts of interest to declare.

Engraftment Syndrome in the Setting of Autologous Stem Cell Transplantation for Multiple Myeloma-a Single Institution Review of over 600 Patients

Engraftment Syndrome in the Setting of Autologous Stem Cell Transplantation for Multiple Myeloma-a Single Institution Review of over 600 Patients

The Efficacy of Risk Score System Establishment and Methylprednisolone Stratification Treatment for Pre-Engraftment Syndrome after Unrelated Cord Blood Transplantation: A Retrospective (development) and a Prospective (validation) Study

Introduction Pre-engraftment syndrome (PES) is a common immune reaction prior to neutrophil engraftment after unrelated cord blood transplantation (UCBT), with a unique clinical manifestation of non-infectious fever and skin rash. The reported incidence of PES ranges from 20% to 78%. Although many researchers believe that PES is associated with a high incidence of acute graft-versus-host disease (GVHD) but not with transplant-related mortality (TRM) , relapse, or overall survival (OS), they did not stratify the risk factors of PES, and how to carry out different doses of methylprednisolone (MP) stratified intervention therapy still remains unknown. Method s First, 136 hematological malignancy patients treated with UCBT from April 2000 to February 2012 in our transplantation center were retrospectively analysis. Among them, 92 patients occurred PES. High-risk factors for 180-day TRM in PES patients were established by univariate and multivariate analysis. Then, from January 2013 to August 2016, 221 PES patients were scored according to the risk scoring system and stratified treated with different doses of MP. Finally, in order to validate the efficacy of MP stratification treatment, we conducted a prospective, open label and non-randomized clinical trial including 240 PES patients who underwent UCBT from September 2016 to December 2018. This trial is registered at www.chictr.org.cn as ChiCTR-ONC-16009013. Results The cumulative incidence of neutrophil and platelet engraftment was significantly higher in PES group than non-PES group (97.8% vs 70.5%, P&lt;0.001; 75.0% vs 54.5%, P=0.05). In 92 PES patients, multivariate analysis showed that failed MP treatment, multiple clinical symptoms and early onset of PES were independent high risk factors affecting180-day TRM. One high risk factor was scored as 1. The 92 PES patients were divided into PES-0, PES-1,PES-2 and PES-3, and the higher the score, the higher the TRM (17.7% vs 21.9% vs 62.5% vs 100%,respectively; P&lt;0.001), and the lower the OS (68.3% vs 56.2% vs 25.0% vs 0%, respectively; P&lt;0.001). Then, from January 2013 to August 2016, 221 PES patients were scored as PES-0, PES-1 and PES-2 according to the following two high risk factors (multiple clinical symptoms and early onset of PES) and stratified treated with different doses of MP (0.5mg/kg/d for PES-0, 1mg/kg/d for PES-1 and 2mg/kg/d for PES-2). Compared to the previous PES patients with the same risk score, the 180-day TRM of PES-1 and PES-2 patients was significantly reduced and the OS, disease free survival (DFS), and GVHD-free and Relapse-free survival (GRFS) were significantly increased after stratified treatment. The results in the prospective trial were similar to the retrospective study. In addition, although stratified therapy could significantly improve the prognosis of PES-2 patients cohort, the cumulative incidence of acute GVHD and GRFS are still the worst compared with other risk score patients. Therefore, how to improve the outcomes of PES-2 patients remains to be further studied. Conclusion s PES after UCBT is benefit for engraftment, but should be graded according the risk scoring system. Different doses of MP stratified intervention therapy can significantly improve the prognosis of severe PES patients. The risk scoring system of PES after UCBT and MP stratification treatment are worthy of clinical application. But the cumulative incidence of acute GVHD and GRFS in severe PES patients still need to be ameliorated in the further study. Disclosures No relevant conflicts of interest to declare.

Prediction of endoscopic third ventriculostomy (ETV) success with preoperative third ventricle floor bowing (TVFB): a supplement to ETV success score.

Preoperative judgement of which children is likely to benefit from endoscopic third ventriculostomy (ETV) is still the most difficult challenge. This study aimed to compare the efficiency of third ventricular floor bowing (TVFB) and ETV success score (ETVSS) in selecting ETV candidates and achieve a better preoperative patient selection method for ETV based on our institutional experience. Children (≤ 16years old) with newly diagnosed hydrocephalus treated with ETV between January 2013 and June 2018 were included in this prospective study. Patients with TVFB will receive ETV procedure in the pediatric subgroup of our department. ETVSS was calculated in every patient. The ETVSS predicted ETV success rate and the actual ETV success rate in our institution were compared and further analyzed. One hundred twenty-nine children with TVFB were enrolled in our study. The mean age at ETV was 5.84 ± 5.17years (range, 0.04-16). Brain tumors, aqueductal stenosis, and inflammatory are the most common hydrocephalus etiologies. The most common complication was noninfectious fever (3.1%). During the average follow-up of 19.5 ± 14.95months, twenty-five patients had depicted ETV failure. The actual ETV success rate (81%) in our study was higher than the success rate (69%) predicted by ETVSS. TVFB is a pragmatic, efficient, and simple model to predict the ETV outcome. We suggest that for hydrocephalic patients with preoperative third ventricular floor bowing, ETV should be the first-treatment choice regardless of the ETV success score. And for patients without such sign, ETVSS should be applied to select ETV candidates.

1112. Improving Urine Culturing Practices in a Neurocritical Care Unit through a Multidisciplinary Algorithm-Based Approach

BackgroundAsymptomatic bacteriuria is common in hospitalized patients with urinary catheters. Inappropriate urine culturing as part of reflexive response to fever contributes to unnecessary and excessive antibiotic use, selection for resistant organisms, increased risk for Clostridium difficile infections, and false elevation in catheter-associated urinary tract infection (CAUTI) rates. This project aimed to implement an evidence-based urine culture algorithm in a 33-bed neurocritical care unit, a unit with a historically elevated CAUTI rate due to a high prevalence of noninfectious fever.MethodsA multidisciplinary quality improvement project was initiated in August 2018 by the Infection Prevention, Quality and Safety, Neurocritical Care, Trauma, and Neurosurgery teams of an urban academic health center. The group implemented a urine culture algorithm that was adapted from the Infectious Diseases Society of America (IDSA) guidelines that clearly highlighted appropriate indications for sending urine cultures. The team agreed to utilize a urinalysis with reflex to culture as the preferred method to evaluate for CAUTI. The algorithm was implemented in September 2018. Outcomes were compared for pre-implementation (March-August 2018) and post-implementation (September 2018–February 2019).ResultsThe NHSN CAUTI rate decreased from 4.52/1,000 Foley days to 1.27/1,000 Foley days (P-value 0.037) as a result of the intervention. The number of urine cultures ordered decreased by 82% after implementation. No cases of bacteremia or mortality secondary to a urinary source were identified during the project. Total days of antibiotic therapy for the unit was similar between the pre- and post-implementation time periods (P = 0.631).ConclusionImplementation of a urine culture algorithm in a neurocritical care unit resulted in reduced CAUTI rate with less financial and operational waste in unnecessary orders and treatment, without resulting in adverse events to patients as a result of missed diagnosis.Disclosures All authors: No reported disclosures.

Fever Burden in Patients With Subarachnoid Hemorrhage and the Increased Use of Antibiotics

Background: Fever occurs in the majority of subarachnoid hemorrhage (SAH) patients. Nearly 50% of SAH patients have noninfectious fevers. Data are lacking describing the effects of fever burden in the SAH patient population. Methods: This was a single-center, retrospective observational cohort study in patients more or equal to 18 years of age with a diagnosis of nontraumatic SAH admitted to an ICU between January 1, 2010 and September 1, 2015. Exclusion criteria were SAH secondary to trauma or admission for more than 48 hours. Temperature measurements, demographic data, and other pertinent information were collected from Day 0 to Day 13. Daily fever burden was calculated for each patient by calculating an area under the curve. Results: A total of 194 subjects were included. The mean study period maximum temperature (Tmax) for all 194 patients was 40.8 ± 0.83°C. The mean overall fever burden for all 194 patients was 89.2 ± 99.59°C h more than 37°C. The overall fever burden peaked on day 5 and declined thereafter. Fever burden, Tmax, and length of stay in the hospital were all significantly associated with receipt of antibiotics. Only Tmax was associated with poor outcome. The 31 patients who had fever but no identified cause of infection received 1000 doses of antibiotics or 32.25 doses per patient. Conclusion: Fever is common in SAH patients and is associated with antibiotic use, infection, vasospasm, and poor outcome. Some SAH patients may receive antibiotics unnecessarily for noninfectious fever. Clinicians should consider using site-specific parameters related to infection rather than systemic symptoms such as fever to evaluate infection in SAH patients.

Maternal Noninfectious Fever Enhances Cell Proliferation and Microglial Activation in the Neonatal Rat Dentate Gyrus.

Fever and increased maternal interleukin-6 (IL-6) plasma levels in labor are associated with an increased risk of adverse events in offspring, including neonatal seizures, cerebral palsy, and low intelligence scores at school age. However, the neural changes in the neonate that might mediate the adverse effects of maternal noninfectious fever are not fully characterized. This study was designed to test the hypothesis that induced maternal noninfectious fever alters neonatal neural progenitor cell proliferation and enhances microglial activation in the rat dentate gyrus of the hippocampus. Systemic vehicle or IL-6 was given 3 times to near-term pregnant rats (n = 7/group) every 90 minutes, and maternal core temperature was recorded. Neonatal brains were processed and analyzed for dentate gyrus cell proliferation (using Ki-67, n = 10/group, and glial fibrillary acidic protein, n = 6/group) and resident microglia activation (using ionized calcium-binding adaptor protein-1 [Iba-1], n = 6/group). In separate studies, the authors assessed microglia proliferation using Ki-67/Iba-1 costaining (n = 5/group). Compared to controls, exposure to IL-6 resulted in significant maternal temperature increase [mean temperature difference 0.558°C (95% CI, 0.417-0.698; P < .0001)]. Following maternal IL-6, Ki-67 cell proliferation in the dentate gyrus was 55 % higher in neonates whose mother received IL-6 (38.8 ± 9.2) compared with those that received vehicle (25.1 ± 7.8); mean difference 13.7 (95% CI, 5.68-21.71); (P = .0021). Glial fibrillary acidic protein cell proliferation was 40% higher in the neonatal dentate gyrus whose mother received IL-6 when compared to controls (713 ± 85.52 vs 500 ± 115); mean difference 212 (95% CI, 82.2-343.4); (P = .004). Resident microglial activation was 90% higher in the dentate gyrus of neonates whose mother received IL-6 when compared to controls (71.8 ± 9.3 vs 37.8 ± 5.95); mean Iba-1 in stained cells was significantly different between IL-6 and vehicle groups 34 (95% CI, 23.94-44.05); (P < .0001). Proliferating microglia, determined by the colocalization of Ki-67 and Iba-1, were not different in the vehicle (8.8 % ± 3.19 %) and the IL-6 (5.6% ± 2.3%) groups (mean difference 3.2% (95% CI, -0.8-7.25) (P = .1063). IL-6 is sufficient to induce maternal systemic temperature increases in near-term pregnant rats as well as neuronal, glial, and neuroinflammatory changes in the dentate gyrus of the neonatal hippocampus. These alterations might disrupt fetal neurodevelopment during a vulnerable period.

Engraftment Syndrome: A Retrospective Analysis of the Experience at a Tertiary Care Institute

Engraftment syndrome (ES) is a clinical syndrome that occurs in the early neutrophil recovery phase following hematopoietic stem cell transplant (HSCT). Although also described for allogenic HSCT, it is basically diagnosed in the context of autologous HSCT. We retrospectively reviewed 171 consecutive HSCTs performed between January 2013 and January 2015 in our Bone Marrow Transplant (BMT) unit and analyzed all cases of noninfectious fever and strong clinical features suggestive of ES in the peri-engraftment period for up to 7 days. We observed the incidence of ES to be 12.3% (16/130) in the autologous and 4.8% (2/41) in the allogeneic cohort. Among plasma cell disorders, which constitute 50% of our study population, the incidence of ES was 19.7%. Among the ES cases of autologous transplants, 81.2% (13/16) patients satisfied the Maiolino criteria (MC) and 87.5% (14/16) patients the Spitzer diagnostic criteria (SC). A total of 68.7% (11/16) patients satisfied both MC and SC, and two patients (12.5%) did not satisfy either (MC- SC-). There was no significant difference in days of hospitalization and usage of supportive care between ES and non-ES patients, and there was no mortality due to ES. On univariate analysis, female patients (p < 0.013) and those with diagnosis of a plasma cell disorder (p < 0.03) had higher risk of ES. In conclusion, the incidence of ES in our study population is consistent with that of many others, but severity evaluation needs exploration in larger cohorts with pragmatically modified diagnostic criteria.

Neonatal Inhibition of Connexin 36 Ameliorates Fetal Brain Injury Induced by Maternal Noninfectious Fever in Mice

Prenatal fever could result in brain function impairments in the offspring. The present study investigated the effect of interleukin-6 (IL-6)-induced maternal fever on the offspring and the involvement of connexin 36 in this process. Pregnant C57BL/6J mice were injected with IL-6 on gestational day 15. The levels of iNOS and COX-2 were measured as an index of neuroinflammation in the brain of newborn pups. Offspring were treated with the connexin 36 (Cx36) inhibitor mefloquine at postnatal day (P)1–P3 or at P40–P42. Rotarod, grip traction, and foot fault tests were carried out to evaluate the motor behavior of adult offspring. Injection of IL-6 led to an elevation of the core temperature in the pregnant dams. Offspring of these dams showed significantly increased COX-2 and iNOS mRNA expression and protein levels in the whole-brain samples and significantly increased Cx36 in the cerebellum. Moreover, offspring of these dams showed motor deficits at an adult age. Neonatal administration of the Cx36 inhibitor mefloquine could prevent these motor deficits. Maternal fever during pregnancy induced by IL-6 injection could lead to neuroinflammation and motor deficits in the offspring. Neonatal inhibition of Cx36 could ameliorate the motor deficits in the offspring, indicating an involvement of Cx36 in the IL-6-induced maternal fever.

Noninfectious Causes of Fever in 128 Patients with Systemic Lupus Erythematosus

This study aimed to explore the clinical characteristics of noninfectious fever in patients with systemic lupus erythematosus (SLE) and the underlying causes through multivariate analysis. Clinical data of 128 patients with SLE who were admitted to Affiliated Hospital of Nanjing University of TCM, Nanjing 210029, P.R. China from January 2015 to December 2017 were retrospectively analyzed. The following factors were closely associated with fever: patient age, treatment history, SLEDAI score, enlarged liver, spleen and lymph nodes, low hemoglobin, leukopenia, CRP, complement C3, albumin, anti-dsDNA antibody, glucocorticoids, and cyclophosphamide. Multivariate logistic regression analysis showed that factors, such as enlarged liver, spleen and lymph nodes, digestive system involvement, low hemoglobin, leukopenia, CRP, decreased albumin, anti-dsDNA antibody, glucocorticoids and cyclophosphamide, were closely associated with noninfectious fever in SLE. Noninfectious fever is a common clinical manifestation of SLE. Factors, such as enlarged liver, spleen and lymph nodes, digestive system involvement, low hemoglobin, leukopenia, CRP, decreased albumin, anti-dsDNA antibody, glucocorticoids, and cyclophosphamide, were independent risk factors for noninfectious fever in SLE.

Evaluation of Corticosteroids for Engraftment Syndrome (ES) Prophylaxis in Patients Undergoing Autologous Hematopoietic Cell Transplantation (AHCT) with High-Dose Melphalan (MEL)

Background ES is a potential complication following AHCT. First-line treatment typically involves corticosteroids (CS). In 2002, due to historically high ES incidence resulting in prolonged hospitalizations requiring CS treatment, our institution adopted the practice of administering prophylactic CS in patients undergoing AHCT. Due to lack of contemporary evidence supporting ES prophylaxis as well as potential intolerance of prophylactic CS noted in our patient population, a pilot was instituted to remove prophylactic CS from MEL conditioning regimen for multiple myeloma (MM) or amyloidosis. Objectives The primary objective was to evaluate the impact of prophylactic CS on the incidence of ES. Secondary objectives included hospital length of stay (LOS), duration of intravenous (IV) opioid administration during hospitalization, and incidence of infection, fever, or 30-day readmission due to any cause. Methods Beginning December 2016, CS for ES prophylaxis were removed from our standard of care in patients receiving MEL. Prior to this pilot, patients received methylprednisolone 40 mg IV daily from day +5 to day +15 or hospital discharge (whichever occurred sooner). We retrospectively reviewed the charts of patients receiving MEL from June 1 to December 15 of 2016 (CS group) and December 16, 2016 to June 30, 2017 (CS-free group). ES was defined as noninfectious fever >38°C and new documented rash at the time of engraftment (between day +7 to +11). Results A total of 76 patients were reviewed (CS group, n = 40; CS-free group, n = 36). Baseline characteristics were similar between groups in terms of median age (63 vs. 63 years, p = .65), sex (62.5% vs. 56% male, p = .54), and median CD34+ cell dose (6.36 vs. 6.43 × 106 cells/kg, p = .75). There was no difference in the incidence of documented ES between the CS and CS-free groups (2.5% vs. 0%, p = 1.00). There were no significant differences in median hospital LOS (14 vs. 14 days, p = .67), incidence of infection (17.5% vs. 22.2%, p = .61), incidence of fever (25% vs. 25%, p = .81), and 30-day readmission rate (17.5% vs. 11.1%, p = .43) in CS vs. CS-free groups, respectively. Patients in the CS group received significantly more days of IV opioid administration (median 4.5 vs. 4.0, p = .01). A greater proportion of patients received treatment with CS for suspected ES in the CS-free group compared to the CS group (8.3% vs. 2.5%, p = .34), possibly due to the strict conditions required for our definition of ES or the preemptive use of CS. Conclusions These results suggest a low overall incidence of ES in MM or amyloidosis patients undergoing AHCT using MEL. The use of prophylactic CS did not have a significant impact on incidence of ES which could be attributed to the pre-specified definition of ES. A preemptive strategy of using CS in patients with suspected ES may be sufficient in ameliorating symptoms associated with this syndrome.

Rates of Engraftment Syndrome after Autologous Stem Cell Transplantation in Patients with Immunoglobulin Light Chain Amyloidosis

Background Engraftment syndrome (ES) is a complication of autologous hematopoietic stem cell transplantation (auto-HCT), often characterized by non-infectious fever, rash, diarrhea, hepatic or renal dysfunction and non-cardiogenic pulmonary edema at the time of neutrophil recovery. Based on our experience observing increased incidence of ES in recent years, we conducted single center study and evaluated incidence of ES in patients (pts) with light chain amyloidosis (AL). Methods We reviewed data of 72 AL pts who underwent auto-HCT at our center between 1999 and 2017. We reviewed data regarding incidence of ES, feature of ES and evaluated it effects on outcome post auto-HCT. Engraftment syndrome was defined according to Maiolino criteria (Bone Marrow Transplant 2003; 31(5):393-7). Results Baseline characteristics are summarized in the figure 1. The median age of pts at auto-HCT was 58 years (range, 30-75). Twenty-two (31%) pts developed ES, two patients died before neutrophil engraftment. Most common symptoms observed with ES were fever (77%), diarrhea (73%), rash (68%), weight gain (56%), non-cardiogenic pulmonary edema (23%), and acute kidney injury (9%), as shown in figure 2. All patients with ES were treated with steroids. One patient with ES required hemodialysis and management in intensive care unit. In univariate analysis, age (p= 0.23), AL stage (p= 0.24), number of organs involved (p= 0.30), cytoreductive therapy prior to auto-HCT (p= 0.5), method of stem cell mobilization (G vs P+G; p= 0.16) and dose of melphalan used (p= 0.19) were not predictive of ES, as shown in figure 3. Similarly, day 100 post auto-HCT hematological response (19.5% vs 14%, p= 0.7), best organ response (23% vs 36%, p= 0.24) and median length of hospital stay after auto-HCT (20 vs 19 days, p= 0.5) were not significantly different between patients who did not or develop ES, respectively. Overall survival censored at day 180 post auto-HCT to focus on short term outcome, 100% and 80% were alive with or without ES, respectively (p= 0.3; Fig. 3). Conclusion In this single center series, we report a relatively high rate of ES among recipients of auto-HCT for AL compared with previous reports in AL (8%) (Irazabel MV et al. AJH 2012;87[1]:51–54) or with auto-HCT for MM at our center (21%) (Cornell, RF et al. Biol Blood Marrow Transplant. 2013;19[9]:1368-73). Although higher morbidity (ICU stay/ peri engraftment weight change) appeared to be associated with ES, statistically significant predictors or sequelae could not be identified. A larger series with multicenter collaboration is needed to better identify the risk factors associated with ES in AL pts.

Diagnosis of Light Chain Amyloidosis Is the Primary Risk Factor for Engraftment Syndrome after Autologous Stem Cell Transplant in a Contemporary Cohort

Engraftment syndrome (ES) after autologous stem cell transplant (ASCT) is characterized by non-infectious fevers, skin rash, hypoxia, acute kidney injury (AKI) among other signs and is defined by the Spitzer or Maiolino criteria. It is a significant cause of morbidity and rarely mortality; risk factors and etiology are poorly understood. We sought to perform an analysis of risk factors and outcomes in patients with ES in a contemporary cohort. We performed a retrospective analysis of consecutive patients with lymphoma or plasma cell dyscrasia who received their first ASCT between 01/2012 and 06/2018. ES was defined according to the Spitzer criteria. Chi-square or Fisher's exact test is used to compare categorical variables and t-test is used for continuous variables. Logistic regression was performed for binary outcomes. Kaplan Meier estimator and cox model were used to explore associations between predictors and time-to-event outcomes. Stepwise regression was used for variable selection. We included 188 patients in this analysis. Median follow up was 28 months. Leading primary diagnosis was myeloma (n=73, 38.3%), followed by NHL (n=53, 28.2%), Amyloidosis (n=31, 16.5%), Hodgkin lymphoma (n=24, 12.8%), and POEMS (n=5, 2.7%). Seventeen patients developed ES (n=17, 9.0%) and 13 patients were treated with corticosteroids. Complete resolution was seen in 16 patients, 1 patient with ES died shortly after engraftment. Two patients treated with corticosteroids had relapse of ES and required a second course of corticosteroids, one of whom required a third course. ES was associated with the primary diagnosis (p=0.0014) and age (p=0.033) but was not associated with gender (p=0.20), use of plerixafor (p=0.68), TNC cell dose (p=0.82), CD34 cell dose (p=0.66), and graft volume (p=0.91). Patients with ES had a higher rate of steady state mobilization which approached significance (94.1% vs 74.3%, p=0.053). Logistic regression analysis confirmed diagnosis of amyloidosis as the primary risk factor for ES (OR of 7.62, p=0.0002). ES had no impact on OS (p=0.91, fig 1) or PFS (p=0.79, fig 2). 1-year survival rate was 98.1% in patients without ES and 94.1% in patients with ES whereas 1-year PFS rates were 87.1% and 78.1% respectively according to Kaplan Meier estimates. ES remains common in a contemporary cohort of ASCT recipients. Use of plerixafor, which has been increasingly common, did not impact incidence. Primary diagnosis of amyloidosis was the most important risk factor. While one mortality was attributed to ES, ES had no impact on OS or PFS in the overall cohort.

Pre-Engraftment Syndrome (PES) Is Frequent in Double Unit Cord Blood Transplantation (dCBT) Recipients and Is Potentiated By the Addition of Haplo-Identical CD34+ Cells

Introduction PES is common after dCBT. Manifestations have been described but severity & risk factors are not fully established. Methods We analyzed the incidence, manifestations, severity & risk factors of PES in adult dCBT recipients transplanted 8/2012-12/2017 for hematologic malignancies/ severe aplastic anemia with Cy 50/ Flu 150/ Thio 5-10/ TBI 400 & CSA/ MMF. Standard PES therapy was IV methylprednisolone (IV MP) 1 mg/kg/day x 3 days. Results 133 1st allograft dCBT recipients (median 49 years, range 21-65) were analyzed. Patients (pts) most commonly had acute leukemia (n = 98, 74%). The median TNC cell doses were 2.4 × 107/kg/unit (range 1.2-6.0). The median unit-recipient HLA-match was 5/8 (range 3-7); the median unit-unit HLA-match was 4/8 (range 0-8). 71 (53%) pts also received haploidentical CD34+ cells. 96% of pts engrafted with CB. Overall, 98 pts developed non-infectious sustained fevers ≥ 38.5°C consistent with PES for a cumulative incidence of 74% (95%CI: 65-80) by 21 days post-dCBT (Table). The median onset was 10 days (range 6-21) post-dCBT with a median temperature at onset of 38.9°C degrees (range 38-39.8). Nearly all (94, 95%) of PES pts required IV MP therapy. PES associated rash within the 1st 72 hrs only occurred in a minority of pts (incidence 24%; 95%CI: 17-32). Weight gain > 5% from the baseline 24 hrs prior to PES onset (incidence 18%; 95%CI: 12-25) was correlated with the development of hypoxia requiring oxygen (incidence 20%; 95%CI: 14-28). Incidence of PES associated renal impairment (gr 2-3 AKI) was low overall at 2% (95%CI: 0-8). No pt had hypotension. Concurrent bacteremias were treated in 2 pts but clinical manifestations/ therapy response was consistent with PES. Median time to MP therapy was 1 day (range 0-12). Therapy response was rapid (median 1 day, range 1-9). The median MP duration was 3 days (range 3-14). 7/94 (7%) PES pts [7/133, 5% of entire cohort) required ICU care; this correlated with delayed therapy [median MP start 4 days (range 0-5)]. 30 (32%) pts required a 2nd MP course. Addition of haploidentical cells was associated with a higher PES incidence & severity as measured by weight gain & hypoxia (Table). There was no association with age, disease (acute leukemia vs other), dominant unit-recipient or unit-unit HLA-match or total TNC infused dose (split at median). Conclusions PES is common after dCBT. It should be promptly treated with IV MP without waiting for results of infectious work-up as delay can be associated with severe capillary leak syndrome & multi-organ failure. The worse manifestations in haplo-dCBT recipients supports PES being mediated by GVG/ GVH reactions & an associated cytokine storm. This is highly relevant to CBT platforms that involve infusion of multiple donors including 3rd-party products. We are now investigating day -1 tocilizumab 8 mg/kg in dCBT recipients with the aim to abrogate PES & acute GVHD (Politikos et al, ASBMT 2019).

Evaluation of T Cell and Monocyte Immune Subsets in the Stem Cell Product of Patients Developing Engraftment Syndrome Following Autologous Stem Cell Transplantation for Multiple Myeloma and Lymphoma

BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is now standard of care for newly diagnosed patients with multiple myeloma (MM) and is used for some forms of non-Hodgkin lymphoma, providing improved outcomes. ASCT has been associated with a high incidence of engraftment syndrome (ES), which clinically presents as skin rashes, diarrhea, non-infectious fevers, and capillary leak syndrome in the peri-engraftment period. ES can be a severe and potentially lethal complication in patients who do not respond to corticosteroid therapy. RATIONALE: Prior to stem cell collection, MM and lymphoma patients are typically exposed to chemotherapy and immunomodulatory agents in order to reduce the cancer cell burden and other drugs to mobilize stem cells. It has been hypothesized that these agents may be involved with ES development in that they can disrupt the balance of immune regulatory and effector cell subsets. OBJECTIVE: To analyze T cell activation/memory and Treg cell compartments as well as classical, intermediate, and non-classical monocytes in the autologous apheresis product of MM and lymphoma patients undergoing ASCT. STUDY DESIGN: Samples were collected under IRB approval from 28 patients undergoing ASCT for the treatment of MM (n=21) or lymphoma (n=7) at the time of peripheral blood stem cell collection (the apheresis product); Peripheral blood mononuclear cells (PBMC) were isolated by sucrose gradient centrifugation and frozen until needed for phenotyping by multi-parametric flow cytometry. MM patients were conditioned for ASCT with melphalan alone (n=14) or in combination with bortezomib (n=7); lymphoma patients received conditioning with BEAM (carmustine, etoposide, cytarabine, and melphalan) chemotherapy. RESULTS: Of the 28 patients undergoing ASCT, 10 (35.7%) developed ES within the first four weeks post-transplantation. We analyzed by flow cytometric phenotyping the following immune cell subsets: overall CD4/CD8 T cells, CD4/CD8 naive and memory cells, HLA-DR expression on memory T Cells, memory CD4 Tregs, as well as overall classical, intermediate, and non-classical monocytes. The absolute numbers (PBMC conc. (cell/ml of blood) x (% of cells in PBMC/100) and percentage population (# of events in population gate/# of total PBMC events x 100) data were transformed with log and square root functions, respectively. All data were tested for normality with a Shapiro-Wilks online test and p-values were obtained by performing an unpaired Student T-test. From our analysis of the apheresis product, the main cell compartments that were significantly increased in the ES+ group were the % CD8+ T cells [5.41 mean ± 0.51 s.e. vs. 3.34 ± 0.36 (ES-), p=0.003] and naive CD8+ T cells [3.76 ± 0.56 vs. 1.61 ± 0.18 (ES-), p In the monocyte compartment, the main subset that was significantly increased was the non-classical CD16+CD14low cells in the ES+ group [0.40 ± 0.08 vs. 0.25 ± 0.03 (ES-), p=0.02]. In addition, the % of CD25+ and CD163+ non-classical and intermediate monocytes were favorably increased in the ES+ group (non-classical monocytes, CD25+ [0.14 ± 0.03 vs. 0.07 ± 0.02 (ES-), p=0.03] and CD163+ [0.33 ± 0.06 vs. 0.18 ± 0.02 (ES-), p=0.03]; and for intermediate monocytes, CD25+ [0.44 ± 0.1 vs. 0.22 ± 0.04 (ES-), p=0.02] and CD163+ (p=0.02). No major differences were observed between ES+ and ES- groups for CD64 and PDL-1 expression. CONCLUSIONS: The development of ES correlated with the observation of a significant increase of naive and activated CD8 T cells in the autologous apheresis product. In contrast, no significant differences were found between the ES+ and ES- groups in the CD4 T cell or memory Treg subsets, suggesting that they do not contribute to the etiology of the syndrome. Moreover, an increased presence of non-classical monocytes with higher expression of both CD163 and CD25 was found, suggesting increased potential for both M2 and M1 activity. Further investigation is needed to determine the implications of these findings for the development of ES. Disclosures Siegel:Merck: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Novartis: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Biran:BMS: Research Funding; Merck: Research Funding; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Feldman:Johnson and Johnson: Speakers Bureau; KITE: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; Pharmacyclics: Speakers Bureau; Janssen: Speakers Bureau; Portola: Research Funding; Celgene: Speakers Bureau. Skarbnik:Gilead Sciences: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

Elevated IL-1Ra Levels in the Stem Cell Product Is Associated with the Development of Engraftment Syndrome Following Autologous Stem Cell Transplantation for the Treatment of Multiple Myeloma and Lymphoma

Engraftment syndrome (ES) is a frequently occurring complication in patients receiving autologous stem cell transplantation (ASCT) for the treatment of multiple myeloma and various types of non-Hodgkin lymphomas. This clinical entity presents as skin rashes, diarrhea, non-infectious fevers and capillary leak syndrome in the peri-engraftment period coinciding with neutrophil recovery. The etiology and risk factors contributing to the development of ES remain unclear. The goal of the present study was to analyze the cytokine composition of the grafted mobilized peripheral blood stem cell product as well as serum cytokine levels in patients undergoing ASCT for the treatment of multiple myeloma and lymphoma. Cytokines were analyzed in the apheresis stem cell product, as well as patient plasma 1-2 days pre-transplant, 12 days post-transplant, and 2-4 months post-transplant using the Luminex xMAP multiplex cytokine platform. The concentrations of 29 cytokines from 38 patients were analyzed. Seventeen of these patients were diagnosed with engraftment syndrome using the Spitzer criteria. Patients who developed ES were shown to have significantly elevated levels of IL-1 receptor antagonist (IL-1Ra) in the apheresis product as compared to patients that did not develop ES (31,033 vs. 6015 pg/ml; p=0.028). IL-1Ra levels were not significantly different at other time points. IL-1Ra competes with IL-1α and IL-1β for binding to the IL-1 receptor thus acting as an antagonist to this proinflammatory cytokine. The gene encoding IL-1Ra has a tandem repeat sequence resulting in polymorphic alleles in the population with varying number of repeats. The allele containing 2 repeats, IL1RN*2, has been associated with various inflammatory diseases including Sjogren's syndrome, ulcerative colitis, Crohn disease, psoriasis, multiple sclerosis, and SLE. We performed PCR on the DNA isolated from the PBMCs of these patients to determine if patients with elevated IL-1Ra possessed the IL1RN*2 allele. Results did not find any correlation between IL-1RN*2 allele and elevated IL-1Ra levels in the apheresis samples. In addition, levels of the chemokine IFN-gamma-induced protein 10 (IP-10/CXCL10) were found to be significantly higher in patients diagnosed with ES at both the day 12 post-transplant (1089 vs. 689 pg/ml; p=0.022) and 2-4 month post-transplant time points (1768 vs. 922 pg/ml; p<0.01), and trending higher in the apheresis product (6132 vs. 2655 pg/ml; p=0.126). IP-10, which plays a role in leukocyte homing to inflamed tissues, has been identified as a major biological marker of disease severity in several inflammatory conditions. The only other cytokine that exhibited a significant difference at any time point was the increased level of IL-12p40 in the apheresis product of those developing ES (412 vs. 74 pg/ml; p=0.026). Characterizing these and other differences in graft product composition and changes that occur during hematopoietic reconstitution may aid in prediction or early identification of ES and may lead to early intervention treatment for this common and potentially serious complication of ASCT. DisclosuresSiegel:Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria. Biran:Takeda: Consultancy, Speakers Bureau; Merck: Research Funding; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; BMS: Research Funding. Vesole:Amgen: Speakers Bureau; Takeda: Speakers Bureau. Feldman:Janssen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; KITE: Speakers Bureau; Portola: Research Funding. Skarbnik:Novartis: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.