Comparison of early mortality between leukapheresis and non-leukapheresis in adult acute myeloid leukemia patients with hyperleukocytosis: a systematic review and meta-analysis.

OBJECTIVES: One of the treatment modalities that can be used for hyperleukocytosis is leukapheresis. However, the result of studies showing the benefit of early mortality through the use of leukapheresis versus no leukapheresis is still inconclusive. Hence, we aimed to conduct a systematic review with meta-analysis to determine the effect of leukapheresis on early mortality in AML patients with hyperleukocytosis. METHODS: We conducted a literature search on five databases (PubMed, EBSCOhost, Scopus, Clinicalkey, and JSTOR) up to October 2021 for studies comparing early mortality outcomes between hyperleukocytosis AML patients treated with leukapheresis versus no leukapheresis. Summary odds ratios (OR) and 95% confidence intervals (CI) were calculated using random-effects models. Heterogeneity tests were presented in I2 value and publication bias was analyzed using a funnel plot. RESULTS: Eleven retrospective cohort studies were eligible based on the inclusion and exclusion criteria. Pooled analysis showed that there was no significant difference in early mortality between patients receiving leukapheresis and not receiving leukapheresis in studies using hyperleukocytosis cutoff of 95,000/mm3 or 100,000/mm3 (OR: 1.17; 95% CI: 0.74-1.86; p: 0.50; I2: 0%). Similarly, studies using hyperleukocytosis cutoff of 50,000/mm3 also showed no benefits of early mortality (OR: 0.67; 95% CI: 0.43-1.05; p: 0.08; I2: 0%). Most of the studies used had a moderate risk of bias due to being observational studies. Funnel plot showed an indication of publication bias on studies using hyperleukocytosis cutoff of ≥50,000/mm3. CONCLUSION: The use of leukapheresis does not provide early mortality benefit in adult AML patients with hyperleukocytosis.

Preoperative leukocytosis among female patients predicts poor postoperative outcomes following endovascular aneurysm repair for intact infrarenal abdominal aortic aneurysms.

OBJECTIVES: Elevated white blood cell count (WBC) can be predictive of adverse outcomes following vascular interventions, but the association has not established using multi-institutional data. We evaluated the predictive value of preoperative WBC after endovascular aneurysm repair (EVAR) for nonruptured abdominal aortic aneurysms (AAAs) in a nationally representative surgical database. METHODS: Patients with nonruptured AAA undergoing EVAR were identified in the vascular-targeted National Surgical Quality Improvement Program (NSQIP) database. Baseline characteristics were compared between patients with WBC <10 K/µL and WBC ≥10 K/µL. Multivariable logistic regression analyses were performed to assess the odds of outcomes. The primary outcome was 30-day mortality. Multiple secondary outcomes including length of stay (LOS) > 1 week, 30-day readmission, lower extremity (LE) ischemia, ischemic colitis, myocardial infarction, and others were assessed based on WBC and patient sex. RESULTS: A total of 10,955 patients were included, with a mean WBC 7.7 ± 2.7 K/µL. Patients with WBC ≥10 K/µL were younger (71.8 ± 9.5 years vs 74.1 ± 8.7 years; P < .001) and were more likely to be diabetic, on steroids, smokers, functionally dependent, and presenting emergently (all P ≤ .009). Aneurysm diameter was larger in patients with WBC ≥10 K/µL (5.9 ± 1.5 cm vs 5.7 ± 1.5 cm; P < .001). Patients with WBC ≥10 K/µL had more mortality (2.4% vs 1.3%), LOS >1 week (13.5% vs 6.7%), 30-day readmissions (9.8% vs 7.3%), LE ischemia (2.3% vs 1.4%), ischemic colitis (1.2% vs 0.5%), and myocardial infarction (2.0% vs 1.1%) (all P ≤ .008). Female patients with WBC ≥10 K/µL, compared with male patients with WBC ≥10 K/µL, had more adverse events, including mortality, LOS >1 week, 30-day readmission, and LE ischemia (all P ≤ .025). With each incremental increase in WBC by 1 K/µL, the adjusted odds ratio of adverse outcomes for all patient was higher (mortality: 1.05; 95% confidence interval [CI], 1.00-1.10; readmission: 1.03; 95% CI, 1.00-1.06; LOS >1 week: 1.08; 95% CI, 1.05-1.10; and ischemic colitis: 1.11; 95% CI, 1.05-1.16; all P < .05). The effect was more pronounced in female patients and was statistically significant. CONCLUSIONS: WBC is a predictor of adverse outcomes in patients undergoing EVAR for nonruptured AAA. After adjusting for associated risk factors, the effect of increasing WBC was more prominent for female patients. Preoperative WBC should be used as a prognostic factor to predict adverse outcomes among patients undergoing EVAR.

Description of an Association Between Leukocytosis and Clinical Outcomes in Large Hemispheric Infarctions.

BACKGROUND: Large hemispheric infarctions (LHI) are associated with significant morbidity and mortality. Leukocytosis has been observed to directly correlate with stroke severity but has not been specifically described in the LHI population. We hypothesized that patients with LHI and leukocytosis on admission have worse clinical outcomes. METHODS: Retrospective study of patients admitted to the neurosciences intensive care unit at a tertiary care center with the diagnosis of acute ischemic stroke from Jan 2012 to Dec 2018. Inclusion criteria included admission imaging with stroke size greater than two-thirds of the middle cerebral artery territory, with or without other vascular territory involvement. Patients were excluded if antibiotics were started on admission for presumed infection. White blood cell count was recorded at admission, along with Modified Rankin Scale on admission and discharge, need for mechanical ventilation, tracheostomy, and discharge disposition. Logistic regression was used for association measures. RESULTS: Of the 2,318 patients that were screened, 360 met inclusion criteria. Mean age was 64, median was 63; 51.7% were female. Mean and median NIHSS were 21. Leukocytosis on admission was seen in 139 patients (38.6%), and it was associated with need for mechanical ventilation (p<0.0001, OR 2.54, [1.64-3.95]) and mortality during hospitalization (p<0.0003, OR 2.66, [1.56-4.55]). Results persisted after correction for age and sex in a logistic regression model. CONCLUSIONS: Leukocytosis on admission in patients with LHI significantly correlated with mortality and need for mechanical ventilation. There was a trend towards association with poor outcome at discharge, although not statistically significant. Further research may identify how leukocytosis and other SIRS markers may be used to prognosticate outcomes in this challenging patient population.

Leucocytosis and early organ involvement as risk factors of mortality in adults with dengue fever.

The clinical profile and risk factors for mortality in dengue fever have evolved over the years. The all-cause mortality in admitted dengue patients is around 6%. We aimed to evaluate the recent change in trends of the clinical characteristics and risk factors for in-hospital mortality in adults with dengue fever. This is a retrospective study on adults with confirmed dengue fever admitted in a medical unit of a tertiary care center in North India. Medical records of confirmed dengue fever patients admitted between January 2011, and December 2016 were reviewed. Chi-squared tests with Bonferroni correction for multiple testing were used to identify risk factors for mortality. 232 records were included, of which 66.8% were males. The mean age was 31.6 ± 14 years. There were 17 deaths with an all-cause mortality rate of 7.3% with 76.5% being classified as severe dengue at admission. Among the 17 mortality cases, dyspnea (47%), tachypnea (86.7%), leucocytosis (58.8%), raised urea (80%), and elevated serum creatinine (52.9%) at presentation were significantly associated with mortality (p < 0.001). Shock at any time during the hospital stay (58.8%) was also found to be significantly associated with mortality (p < 0.001). We found that dyspnea, tachypnea, acute kidney injury, and leucocytosis at presentation was significantly associated with in-hospital mortality. Based on our results, we recommend aggressive management of patients with severe dengue and those with mild/moderate disease with the above risk factors.

Leukapheresis for the management of hyperleukocytosis in acute myeloid leukemia-A systematic review and meta-analysis.

BACKGROUND: Up to 20% of patients with acute myeloid leukemia (AML) present with hyperleukocytosis, usually defined as a white blood cell (WBC) count greater than 100 × 109 /L. Given the high early mortality rate, emergent cytoreduction with either leukapheresis, hydroxyurea, or chemotherapy is indicated, but the optimal strategy is unknown. STUDY DESIGN AND METHODS: For this systematic review and meta-analysis we searched MEDLINE and EMBASE via Ovid, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science from inception through March 2020 for multiarm studies comparing early mortality rates of patients with AML treated with leukapheresis and those who were not. The risk ratio (RR) of early death for patients who received leukapheresis vs patients who did not was estimated using a sum of the log-ratio of individual study estimates weighted by sample size. RESULTS: Among 13 two-arm, retrospective studies with 1743 patients (486 leukapheresis and 1257 nonleukapheresis patients), leukapheresis did not improve the primary outcome of early mortality compared to treatment strategies in which leukapheresis was not used (RR, 0.88; 95% confidence interval [CI], 0.69-1.13; P = .321) without statistically significant heterogeneity between studies (Cochran's Q, 18; P = .115; I2 , 33.4%). Patients presenting with clinical leukostasis tended to be more likely to undergo leukapheresis (odds ratio, 2.01; 95% CI, 0.99-4.08; P = .052). CONCLUSION: As we did not find evidence of a short-term mortality benefit and considering the associated complications and logistic burden, our results argue against the routine use of leukapheresis for hyperleukocytosis among patients with AML.

Clinical features in 52 patients with COVID-19 who have increased leukocyte count: a retrospective analysis.

Recent reports have showed that a proportion of patients with Coronavirus Disease 2019 (COVID-19) presented elevated leukocyte count. Clinical data about these patients is scarce. We aimed to evaluate the clinical findings of patients with COVID-19 who have increased leukocyte at admission. We retrospectively collected the clinical data on the 52 patients who have increased leukocyte count at admission from the 619 patients with confirmed COVID-19 who had pneumonia with abnormal features on chest CT scan in Renmin Hospital of Wuhan University in Wuhan, China, from February 3 to March 3, 2020. The mean age of the 52 patients with increased leukocyte count was 64.7 (SD 11.4) years, 32 (61.5%) were men and 47 (90.4%) had fever. Compared with the patients with non-increased leukocyte count, the patients with increased leukocyte count were significantly older (P < 0.01), were more likely to have underlying chronic diseases (P < 0.01), more likely to develop critically illness (P < 0.01), more likely to admit to an ICU (P < 0.01), more likely to receive mechanical ventilation (P < 0.01), had higher rate of death (P < 0.01) and the blood levels of neutrophil count and the serum concentrations of CRP and IL-6 were significantly increased, (P < 0.01). The older patients with COVID-19 who had underlying chronic disorders are more likely to develop leukocytosis. These patients are more likely to develop critical illness, with a high admission to an ICU and a high mortality rate.

Postimplantation Syndrome Is Not Associated with Myocardial Injury after Noncardiac Surgery after Endovascular Aneurysm Repair.

BACKGROUND: Postimplantation syndrome (PIS) is the clinical and biochemical expression of an inflammatory response following endovascular aneurysm repair (EVAR), with a reported incidence ranging from 2% to 100%. Although generally benign, some studies report an association between PIS and postoperative major adverse cardiovascular events (MACEs). Nonetheless, the role of PIS in postoperative myocardial injury after noncardiac surgery (MINS) is unknown. This work aims to evaluate the relationship between PIS and MINS in a subset of EVAR patients, as well as assess the impact of PIS in all-cause mortality. METHODS: All patients undergoing elective standard EVAR between January 2008 and June 2017, and with at least one measurement of contemporary (cTnI) or high sensitivity troponin I (hSTnI) in the first 48h after surgery, were retrospectively analyzed. PIS was defined as the presence of fever and leukocytosis in the postoperative period in the absence of infectious complications. MINS was defined as the value exceeding the 99th percentile of a normal reference population with a coefficient of variation <10%, which was >0.032 ng/mL for cTnI and 0.0114 (female) and 0.027 ng/mL (male) for hSTnI. Patients' demographics, comorbidities, medication, access, and anesthesia were also evaluated. RESULTS: One hundred thirty-three consecutive patients were included (95.5% male; mean age 75.66 ± 7.13 years). Mean follow-up was 46.35 months. Survival rate was 86.5%, 80.5%, and 57.6% at 1, 3, and 5 years of follow-up, with 2 fatalities at 30 days of follow-up. The prevalence of PIS was 11.4%. MACE occurred in 2.3% of the patients, while MINS was reported in 16.5% of the patients. No association was found between PIS and patients' gender, comorbidities, type of anesthesia, or transfusional support. The type of graft used significantly affected the prevalence of PIS, with all cases reported when polyester grafts were used (P = 0.031). MACE occurred in 2.3% of the patients, while MINS was reported in 16.5% of the patients. PIS was found to be significantly associated with postoperative MACE (P = 0.001), but not MINS. Survival analysis revealed no differences between patients with or without PIS regarding 30-day mortality as well as long-term all-cause mortality. American Society of Anesthesiologists score (hazard ratio [HR] 2.157, 95% confidence interval [CI] 1.07-4.33, P = 0.031) and heart failure (HR 2.284, 95% CI 1.25-4.18, P = 0.008) were found to be independently associated with increased long-term all-cause mortality in this cohort of patients. CONCLUSIONS: PIS is a common complication after EVAR, occurring in 11.4% of the patients from this cohort. Graft type seems to significantly affect the risk of PIS, since all reported cases occurred when polyester grafts were used. PIS did not influence 30-day or long-term survival and was found to be significantly associated with postoperative MACE but not MINS, suggesting the involvement of different pathophysiological mechanisms.

Treatment Outcome in Pediatric Acute Lymphoblastic Leukemia With Hyperleukocytosis in the Yeungnam Region of Korea: A Multicenter Retrospective Study.

Acute lymphoblastic leukemia (ALL) with hyperleukocytosis at diagnosis is associated with early morbidity and mortality due to complications of leukostasis. Of 535 pediatric ALL patients (January 2004 to December 2016 from the Yeungnam region of Korea), 72 (13.5%) patients with an initial white blood cell (WBC) count of ≥100×10/L were included in this study, of whom 38 patients had extreme hyperleukocytosis (WBC>200×10/L) at diagnosis. Fourteen patients (19.4%) had ≥1 early respiratory and neurologic complications during induction therapy. Relapse occurred in 8 patients (24.2%) with extreme hyperleukocytosis and in 1 patient (3.0%) with an initial WBC count of 100 to 200×10/L (P=0.012). Estimated 10-year event-free survival rate (EFS) and overall survival rate were 78.3%±8.4% and 82.6%±7.7%, respectively. The 10-year EFS was significantly lower in patients with an initial WBC count of >200×10/L than in those with an initial WBC count of 100 to 200×10/L (65.7%±13.4% vs. 91.2%±7.9%; P=0.011). The 10-year EFS and overall survival rate did not differ significantly between patients with extreme hyperleukocytosis who received hematopoietic stem cell transplantation and those who received chemotherapy. In conclusion, pediatric ALL with hyperleukocytosis can lead to early complications and mortality. Patients with initial extreme hyperleukocytosis showed significantly poorer prognosis than those with WBC counts of 100 to 200×10/L.

High Leukocyte Count and Risk of Poor Outcome After Subarachnoid Hemorrhage: A Meta-Analysis.

BACKGROUND: Subarachnoid hemorrhage is (SAH) is a devastating neurologic emergency often associated with systemic inflammatory response. Many reports have demonstrated an association between elevated inflammatory markers and poor outcome. We performed an observational study and a meta-analysis of the impact of high leukocyte count on outcome after SAH. METHODS: We initially retrospectively analyzed 147 patients with SAH through assessment of medical records database. Poor outcome was defined as modified Rankin Scale score >3. Then, we performed a systematic literature search of PubMed, EMBASE, and the Cochrane Library. Prospective and retrospective studies were included if they assessed impact of leukocytosis on outcome after aneurysmal SAH in adults. We used a random-effect model and quality-effect model, based on the study quality assessment tool, an adapted version of inventory to assess quality of intervention studies. RESULTS: Within our initial observational study, a total of 63 (42.86%) patients had poor treatment outcome. Those patients significantly more often had elevated white blood cell count upon admission (60.32 vs. 40.48%; P = 0.02). A literature search identified 10,119 articles, of which 13 were included into the meta-analysis. Pooled impact of high leukocyte count on outcome was odds ratio 1.42 (95% confidence interval 1.24-1.63) for random-effect model and OR 1.86 (95% confidence interval 1.46-2.36) for the quality-effect model. However, the studies were heterogenous (I = 54%). CONCLUSIONS: Elevated white blood cells is a marker of poor outcome after SAH. Despite the fact that it is unlikely to be causative, it may be treated as a useful risk predictor.

Infectious causes and outcomes in patients presenting with cerebral spinal fluid pleocytosis.

To evaluate the infectious etiologies, clinical features, and outcomes of patients with CNS infections at a tertiary care center. Patients that present with a pleocytosis in the cerebral spinal fluid (CSF), defined as a CSF WBC count > 5 cells/mm3, from July 2015 to June 2016 at a tertiary care hospital were analyzed for this report. Data from patients with confirmed (n = 43) and presumed (n = 51) CNS infections were analyzed. CNS infection was the leading known cause of CSF pleocytosis (n = 43, 18% of all patients with a pleocytosis in the CSF), and HSV-2 was identified as the leading causative pathogen (n = 10) followed by varicella zoster virus (n = 5). Fifty-three percent of patients with a pleocytosis in the CSF did not receive a diagnosis. In the patients that did not receive a diagnosis, CNS infection was presumed to be the cause in 51 patients (21% of patients with CSF pleocytosis). The mean time to diagnosis for patients with confirmed CNS infection was 16 days, but time to diagnosis was highly variable depending on the causative pathogen. There was a significant overlap in CSF parameters and peripheral white blood cell counts in patients diagnosed with a viral, bacterial, or fungal infection. Neuroimaging changes were present in only 44% of CNS infections. The overall mortality was 7% for CNS infections, and 17% of patients with a CNS infection had a severe neurologic deficit at presentation while only 3% had a severe deficit at the last neurologic assessment. This study provides new insights into the infectious causes of disease in a cohort of patients with pleocytosis in the CSF. The study provides new insights into the time to diagnosis and outcomes in patients that present with pleocytosis in the CSF.

Hyperleukocytosis is associated with distinct genetic alterations and is an independent poor-risk factor in de novo acute myeloid leukemia patients.

OBJECTIVES: Acute myeloid leukemia (AML) with hyperleukocytosis (HL) is intuitively thought as a unique group with dismal prognosis. However, comprehensive studies regarding the genetic landscape and clinical outcome in this group of patients are limited. METHODS: A total of 693 newly diagnosed de novo non-M3 AML patients were consecutively enrolled. We compared relevant mutations in 20 genes between AML patients with or without HL and exposed their prognostic implications. RESULTS: Hyperleukocytosis, defined as initial white blood cell counts above 50 000/µL, occurred in 28.9% of AML patients. HL patients had higher incidences of FLT3-ITD, NPM1, DNMT3A, CEBPA, and TET2 mutations. Multivariate analysis demonstrated that HL was an independent poor prognostic factor for overall survival and disease-free survival in total patients, those with intermediate-risk cytogenetics and normal karyotype irrespective of genetic alterations. Intriguingly, HL predicted poor survival in CEBPA double mutated, NPM1 + /FLT3-ITD- and NPM1-/FLT3-ITD- patients. Further, HL patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR) had a significantly longer overall survival and disease-free survival than those without allo-HSCT. CONCLUSIONS: Hyperleukocytosis is an independent poor prognostic factor irrespective of cytogenetics and mutation status. Allo-HSCT in first CR seems to ameliorate the poor prognostic impact of HL.

A hospital based retrospective study of factors influencing therapeutic leukapheresis in patients presenting with hyperleukocytic leukaemia.

Therapeutic leukapheresis is a rapid and effective method to reduce early mortality of patients with hyperleukocytic leukaemia (HLL). However, few studies on factors influencing the efficiency have been reported. In this study, 67 cases who underwent leukapheresis were retrospectively analysed and factors related to the collection efficiency of leukapheresis (CEWBC) were also evaluated. Paired t test showed that there was a significant decrease in statistics of white blood cell (WBC) counts after apheresis. The results of two independent samples nonparametric test suggested that WBC counts, platelet (PLT) counts, haematocrit (HCT), hemoglobin (HGB), serum chlorine (Cl) and globulin (GLB) before leukapheresis correlated with the CEWBC. Multiple linear regression analysis with background stepwise variable selection indicated that only WBC and HCT before leukapheresis had an influence on CEWBC significantly. Kaplan-Meier analysis and Cox regression model indicated that lymphocyte (LY) and mean corpuscular hemoglobin (MCH) pre-apheresis as independent factors significantly affected the prognostic survival of patients with HLL. Moreover, platelets and red blood cell were contaminated in the product of leukapheresis. It is an urgent problem to be solved in order to realise higher efficacy and higher purity of WBC collection to improve the survival of patients with HLL through optimising instruments.

Dexamethasone-induced leukocytosis is associated with poor survival in newly diagnosed glioblastoma.

Despite its well-characterized side effects, dexamethasone is widely used in the pre-, peri- and postoperative neurosurgical setting due to its effective relief of tumor-induced symptoms through the reduction of tumor-associated edema. However, some patients show laboratory-defined dexamethasone induced elevation of white blood cell count, and its impact on glioblastoma progression is unknown. We retrospectively analyzed 113 patients with newly diagnosed glioblastoma to describe the incidence, risk factors and clinical features of dexamethasone-induced leukocytosis in primary glioblastoma patients. We further conducted an immunohistochemical analysis of the granulocyte and lymphocyte tumor-infiltration in the available corresponding histological sections. Patient age was identified to be a risk factor for the development of dexamethasone-induced leukocytosis (p < 0.05). The presence of dexamethasone-induced leukocytosis decreased overall survival (HR 2.25 95% CI [1.15-4.38]; p < 0.001) and progression-free survival (HR 2.23 95% CI [1.09-4.59]; p < 0.01). Furthermore, patients with dexamethasone-induced leukocytosis had significantly reduced CD15 + granulocytic- (p < 0.05) and CD3 + lymphocytic tumour infiltration (p < 0.05). We identified a subgroup of glioblastoma patients that are at particularly high risk for poor outcome upon dexamethasone treatment. Therefore, restrictive dosage or other edema reducing substances should be considered in patients with dexamethasone-induced leukocytosis.

What Factors Are Associated With Early Mortality in Patients Undergoing Femur Surgery for Metastatic Lung Cancer?

BACKGROUND: Pathologic fractures of the femur resulting from metastasis severely increase mortality in patients with nonsmall cell lung cancer (NSCLC). However, factors associated with early mortality after surgery have not been elucidated. QUESTIONS/PURPOSES: The purpose of this study was to identify clinical and laboratory factors available to surgeons before surgery for a metastatic femur in patients with metastatic lung cancer that might be associated with mortality at 1 and 3 months. METHODS: Between 2010 and 2014 we treated 126 patients for pathologic fracture of the femur caused by NSCLC. Of those, complete data sets for the parameters of interest (including clinical factors, laboratory factors, and survivorship) were available in 105 (83%). The factors we considered included sex, age, fracture location, surgical procedure, postoperative complications, blood cell counts, serum biomarkers, genetic alterations of primary cancer, chemotherapeutic agents, preoperative radiation therapy, pleural effusion, bone and internal organ metastasis, performance scores, and medical center where the treatment was performed. Multivariate logistic regression was performed to identify factors associated with mortality at 1 and 3 months. RESULTS: Intertrochanteric location was associated with a higher risk of death (odds ratio [OR], 17.0; 95% confidence interval [CI], 2.65-109.5), lower serum albumin level was associated with an increased risk of death (OR, 0.13; 95% CI, 0.028-0.60), and availability of a suitable chemotherapeutic target agent was associated with a lower risk of death (OR, 0.28; 95% CI, 0.08-0.91) within 3 months of surgery. Undergoing reconstruction with an endoprosthesis was associated with a higher risk of death (OR, 48.3; 95% CI, 1.7-1329) and elevated serum leukocyte count (OR, 1.2; 95% CI, 1.0-1.4) and elevated alanine aminotransferase (ALT) were associated with a higher risk of death (OR, 1.1; 95% CI, 1.0-1.2) within 1 month of surgery. CONCLUSIONS: Although the risk factors for early mortality need to be validated by prospective studies, surgical options need to be reconsidered in patients with femoral metastases from NSCLS showing high ALT or leukocytosis on the preoperative blood test. LEVEL OF EVIDENCE: Level III, prognostic study.

Fatal Pertussis in the Neonatal Mouse Model Is Associated with Pertussis Toxin-Mediated Pathology beyond the Airways.

In infants, Bordetella pertussis can cause severe disease, manifested as pronounced leukocytosis, pulmonary hypertension, and even death. The exact cause of death remains unknown, and no effective therapies for treating fulminant pertussis exist. In this study, a neonatal mouse model of critical pertussis is characterized, and a central role for pertussis toxin (PT) is described. PT promoted colonization, leukocytosis, T cell phenotypic changes, systemic pathology, and death in neonatal but not adult mice. Surprisingly, PT inhibited lung inflammatory pathology in neonates, a result which contrasts dramatically with observed PT-promoted pathology in adult mice. Infection with a PT-deficient strain induced severe pulmonary inflammation but not mortality in neonatal mice, suggesting that death in these mice was not associated with impaired lung function. Dissemination of infection beyond the lungs was also detected in neonatal mice, which may contribute to the observed systemic effects of PT. We propose that it is the systemic activity of pertussis toxin and not pulmonary pathology that promotes mortality in critical pertussis. In addition, we observed transmission of infection between neonatal mice, the first report of B. pertussis transmission in mice. This model will be a valuable tool to investigate causes of pertussis pathogenesis and identify potential therapies for critical pertussis.

Hyperleucocytosis in paediatric acute myeloid leukaemia - the challenge of white blood cell counts above 200 × 109 /l. The NOPHO experience 1984-2014.

Hyperleucocytosis in paediatric acute myeloid leukaemia (AML) is associated with increased morbidity and mortality. We studied hyperleucocytosis in 890 patients with AML aged 0-18 years registered in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) registry, with special focus on very high white blood cell counts (WBC >200 × 10/l). Eighty-six patients (10%) had WBC 100-199 × 109 /l and 57 (6%) had WBC ≥200 × 109 /l. Patients with WBC ≥200 × 109 /l had a high frequency of t(9;11) and a paucity of trisomy 8. Due to the high frequency of deaths within the first 2 weeks (30% vs. 1% for all others), overall survival in this group was inferior to patients with WBC <200 × 109 /l (39% vs. 61%). Main cause of early death was intracranial haemorrhage and leucostasis. Twenty-six per cent of these patients never started antileukaemic protocol therapy. Leukapheresis or exchange transfusion was used in 24% of patients with hyperleucocytosis without impact on survival. Patients with hyperleucocytosis surviving the first week had identical survival as patients with lower WBC. We conclude that death within the first days after diagnosis is the major challenge in patients with high WBC and advocate rapid initiation of intensive chemotherapy.

Snake bite mortality in children: beyond bite to needle time.

OBJECTIVE: To study the clinical characteristics and predictors of mortality from snake bite envenomation in children. DESIGN: Prospective observational study with a one-group cohort design. SETTING: Paediatric intensive care unit of a tertiary care hospital in South India. SUBJECTS: The study cohort consisted of 145 children (55 girls and 90 boys) <12 years of age with snake bite envenomation. METHODS: Demographic and clinical details were recorded in a semistructured pro forma. Children were treated with polyvalent antisnake venom (ASV) as per WHO protocol. Details of treatment, complications and outcomes were recorded. Univariate analysis was done to identify statistical significance, and those variables found to be significant were analysed using binary logistic regression. RESULTS: Russell's viper was the most common offending snake followed by hump-nosed pit viper. Features of haemotoxicity, neurotoxicity and combined haemotoxicity and neurotoxicity occurred in 68 (47%), 39 (26.9%) and 9 (6%) children, respectively. Acute kidney injury (AKI) occurred in 36 (25%) children. The mortality rate was 10.3%. On univariate analysis, nocturnal bites, severe leucocytosis on day 1, AKI, capillary leak syndrome and a need for more than 20 vials of ASV were significantly associated with mortality. On multivariate analysis, only severe leucocytosis on day 1 (OR 35.29; 95% CI 1.37 to 911.89) and AKI (OR 35.05 95% CI 1.74 to 706.93) were found to be independent predictors of mortality. CONCLUSIONS: This study has identified two hitherto unrecognised risk factors-severe leucocytosis on day 1 and capillary leak syndrome. These findings need to be taken into consideration when planning management strategies for snake bite envenomation in children.

Increased Short-Term Mortality in Patients with Spontaneous Intracerebral Hemorrhage and its Association with Admission Glucose Levels and Leukocytosis.

OBJECTIVE: Spontaneous intracerebral hemorrhage (ICH) can be a devastating event. An increased glucose level in patients with ICH is known to be related to poor outcomes, including acute leukocytosis, which is a well-established response to ICH. The purpose of this study was to evaluate the association between admission laboratory factors and 3-month mortality in patients with spontaneous supratentorial ICH. METHODS: We performed a Kaplan-Meier analysis to evaluate the risk factors for 3-month mortality in patients with ICH. We used univariate and multivariate Cox regression analyses to calculate hazard ratios with 95% confidence intervals for short-term mortality based on clinical and laboratory factors. The area under the receiver operating characteristic curve was used to determine the laboratory risk factors that predicted mortality. RESULTS: In total, 538 patients from our hospital admitted with primary spontaneous supratentorial ICH over an 8-year period were enrolled in this study. Higher leukocyte counts (hazard ratio, 1.019; 95% confidence interval, 1.012-1.027; P < 0.001) and glucose levels on admission were associated with higher 3-month mortality. The receiver operating characteristic curve analysis showed that the areas under the curve of ICH volume, glucose, and leukocyte counts were 0.696 (cutoff value, 41.63), 0.687 (cutoff value, 134), and 0.642 (cutoff value, 9.4), respectively. CONCLUSIONS: Higher admission white blood cell counts and glucose levels were associated with higher 3-month mortality in patients with spontaneous ICH. These data show that an altered glucose metabolism and inflammatory state after ICH may be related to early deterioration after an ICH.