Performance evaluation of the digital morphology analyser Sysmex DI-60 for white blood cell differentials in abnormal samples.

Sysmex DI-60 enumerates and classifies leukocytes. Limited research has evaluated the performance of Sysmex DI-60 in abnormal samples, and most focused on leukopenic samples. We evaluate the efficacy of DI-60 in determining white blood cell (WBC) differentials in normal and abnormal samples in different WBC count. Peripheral blood smears (n = 166) were categorised into normal control and disease groups, and further divided into moderate and severe leucocytosis, mild leucocytosis, normal, mild leukopenia, and moderate and severe leukopenia groups based on WBC count. DI-60 preclassification and verification and manual counting results were assessed using Bland-Altman and Passing-Bablok regression analyses. The Kappa test compared the concordance in the abnormal cell detection between DI-60 and manual counting. DI-60 exhibited notable overall sensitivity and specificity for all cells, except basophils. The correlation between the DI-60 preclassification and manual counting was high for segmented neutrophils, band neutrophils, lymphocytes, and blasts, and improved for all cell classes after verification. The mean difference between DI-60 and manual counting for all cell classes was significantly high in moderate and severe leucocytosis (WBC > 30.0 × 109/L) and moderate and severe leukopenia (WBC < 1.5 × 109/L) groups. For blast cells, immature granulocytes, and atypical lymphocytes, the DI-60 verification results were similar to the manual counting results. Plasma cells showed poor agreement. In conclusion, DI-60 demonstrates consistent and reliable analysis of WBC differentials within the range of 1.5-30.0 × 109. Manual counting was indispensable in examining moderate and severe leucocytosis samples, moderate and severe leukopenia samples, and in enumerating of monocytes and plasma cells.

Clinical features of histiocytic necrotizing lymphadenitis in children.

Due to its nonspecific clinical characteristics, histiocytic necrotizing lymphadenitis (HNL) is often misdiagnosed as a suppurative cervical lymphadenitis and lymphoma. Thus, this study aimed to investigate the clinical characteristics of HNL in pediatric patients. We retrospectively identified 61 patients with histopathologically confirmed HNL. Clinical and laboratory data, including age, sex, clinical manifestations, laboratory investigations, histological discoveries, treatment, and outcomes, were collected from the medical records to determine associations with extracervical lymph node (LN) involvement. The mean age of patients was 9.7 ± 2.8 years (range, 1.5-14.0 years), and the male-to-female ratio was 2.2:1. The most common systemic symptom was fever in all patients. The median pre-admission and total durations of fever were 13.0 (interquartile range [IQR]: 9.0-22.5 days) and 22.0 days (IQR: 17.0-33.0 days), respectively. Patients with temporary fever (< 2 weeks) had a higher peak temperature and were more likely to undergo LN biopsy after admission than those with a prolonged fever (≥ 2 weeks). Multivariate analysis revealed that peak temperature ≥ 40 °C was significantly associated with a longer fever duration (P = 0.023). Laboratory values showed leukopenia (68.9%), which presented more frequently in solitary cervical LNs than in extracervical LNs (82.4% vs. 52.9%, p = 0.027) in patients with prolonged fever. CONCLUSIONS: HNL is often misdiagnosed in older children with persistent fever and lymphadenopathy, leading to unnecessary diagnostic tests and evaluations, inappropriate antibiotic administration, and mismanagement. A multidisciplinary team, including primary care providers, rheumatologists, and pathologists, can improve patient outcomes by increasing their awareness of this rare condition. WHAT IS KNOWN: • Histiocytic necrotizing lymphadenitis (HNL) is characterized by fever, leukopenia, and neck lymphadenopathy with unknown etiology. • The lack of neutrophils or eosinophils in the histology, immunohistochemistry results help distinguish HNL from infectious causes. Although HNL is a self-limiting disease, antibiotics and steroid treatments were used inappropriately. WHAT IS NEW: • A fever peak ≥ 40 °C was associated with a longer fever duration in HNL patients. Leukopenia presented more frequently in solitary cervical lymph node (LNs) than in extracervical LNs inpatients with prolonged fever. • Steroids are not recommended as a routine treatment, however, in some severe or relapsing cases with persistent symptoms, prednisolone (5 mg twice a day for 2 days) or other steroids (an equivalent dose of prednisolone) responded favorably.

Sarcopenia and dosimetric parameters in relation to treatment-related leukopenia and survival in anal cancer.

BACKGROUND: Treatment-related white blood cell (WBC) toxicity has been associated with an inferior prognosis in different malignancies, including anal cancer. The aim of the present study was to investigate predictors of WBC grade ≥ 3 (G3+) toxicity during chemoradiotherapy (CRT) of anal cancer. METHODS: Consecutive patients with locally advanced (T2 ≥ 4 cm-T4 or N+) anal cancer scheduled for two cycles of concomitant 5-fluorouracil and mitomycin C chemotherapy were selected from an institutional database (n = 106). All received intensity modulated radiotherapy (IMRT; mean dose primary tumor 59.5 Gy; mean dose elective lymph nodes 45.1 Gy). Clinical data were extracted from medical records. The highest-grade WBC toxicity was recorded according to CTCAE version 5.0. Pelvic bone marrow (PBM) was retrospectively contoured and dose-volume histograms were generated. The planning CT was used to measure sarcopenia. Dosimetric, anthropometric, and clinical variables were tested for associations with WBC G3+ toxicity using the Mann-Whitney test and logistic regression. Cox proportional hazard regression was used to assess predictors for overall survival (OS) and anal cancer specific survival (ACSS). RESULTS: WBC G3+ was seen in 50.9% of the patients, and 38.7% were sarcopenic. None of the dosimetric parameters showed an association with WBC G3+ toxicity. The most significant predictor of WBC G3+ toxicity was sarcopenia (adjusted OR 4.0; P = 0.002). Sarcopenia was also associated with an inferior OS (adjusted HR 3.9; P = 0.01), but not ACSS (P = 0.07). Sensitivity analysis did not suggest that the inferior prognosis for sarcopenic patients was a consequence of reduced doses of chemotherapy or a prolonged radiation treatment time. Patients who experienced WBC G3+ toxicity had an inferior OS and ACSS, even after adjustment for sarcopenia. CONCLUSIONS: Sarcopenia was associated with increased risks of both WBC G3+ toxicity and death following CRT for locally advanced anal cancer. In this study, radiation dose to PBM was not associated with WBC G3+ toxicity. However, PBM was not used as an organ at risk for radiotherapy planning purposes and doses to PBM were high, which may have obscured any dose-response relationships.

Polymorphism of FGD4 and myelosuppression in patients with esophageal squamous cell carcinoma.

Background: Chemotherapy-related adverse events may restrain taxane/cisplatin administration as a regimen for patients with esophageal squamous cell carcinoma. Genetic polymorphisms may contribute to adverse event susceptibility. Method & results: The authors genotyped ten SNPs from five genes (rs1045642, rs2032582 and rs3213619 of ABCB1; rs2231137 and rs2231142 of ABCG2; rs246221 of ABCC1; rs3740066 of ABCC2; and rs10771973, rs12296975 and rs1239829 of FGD4) in 219 patients with esophageal squamous cell carcinoma treated with taxane/cisplatin. Patients with severe toxicities were compared with those with minor or no adverse events by unconditional logistic regression models and semi-Bayesian shrinkage. After adjustment for age and sex, with the null prior, FGD4 rs1239829 was statistically significantly related to grade 3-4 leukopenia (odds ratio [95% CI] in dominant model = 1.77 [1.04-3.03]). Conclusion: The minor allele of FGD4 rs1239829 was related to grade 3-4 leukopenia in patients with esophageal squamous cell carcinoma treated with taxane/cisplatin, with unclear biological mechanism.

Lay abstract Taxane/cisplatin is the main chemotherapy regimen in patients with esophageal squamous cell carcinoma in China. Many patients suffer from neurotoxicity or bone marrow suppression, such as decreased white blood cells. Higher-grade adverse events, in particular, usually result in chemotherapy dose reduction or treatment termination. Researchers explored the associations between genetics and chemotherapy toxicity and found that the genetic variant (SNP rs1239829) of the gene FGD4 was related to serious white blood cell decline in patients with esophageal squamous cell carcinoma who were treated with the taxane/cisplatin regimen.

Bacterial virulence plays a crucial role in MRSA sepsis.

Bacterial sepsis is a major global cause of death. However, the pathophysiology of sepsis has remained poorly understood. In industrialized nations, Staphylococcus aureus represents the pathogen most commonly associated with mortality due to sepsis. Because of the alarming spread of antibiotic resistance, anti-virulence strategies are often proposed to treat staphylococcal sepsis. However, we do not yet completely understand if and how bacterial virulence contributes to sepsis, which is vital for a thorough assessment of such strategies. We here examined the role of virulence and quorum-sensing regulation in mouse and rabbit models of sepsis caused by methicillin-resistant S. aureus (MRSA). We determined that leukopenia was a predictor of disease outcome during an early critical stage of sepsis. Furthermore, in device-associated infection as the most frequent type of staphylococcal blood infection, quorum-sensing deficiency resulted in significantly higher mortality. Our findings give important guidance regarding anti-virulence drug development strategies for the treatment of staphylococcal sepsis. Moreover, they considerably add to our understanding of how bacterial sepsis develops by revealing a critical early stage of infection during which the battle between bacteria and leukocytes determines sepsis outcome. While sepsis has traditionally been attributed mainly to host factors, our study highlights a key role of the invading pathogen and its virulence mechanisms.

Coadministration of liposomal methylglyoxal increases the activity of amphotericin B against Candida albicans in leukopoenic mice.

In this study, we investigated the therapeutic efficacy of a combination of liposomal amphotericin B (Lip-Amp B) and Methylglyoxal (Lip-MG) against Candida albicans in the leukopoenic mice. The antifungal efficacy of Lip-Amp B or Lip-MG or a combination of Lip-Amp B and Lip-MG was evaluated by the analysis of the survival rate and the fungal load in the treated mice. The immune-stimulatory effect of Lip-MG on macrophages was evaluated by analysing the secretion of proinflammatory cytokines. C. albicans infected mice treated at the doses of 1 and 2 mg/kg of Lip-Amp B showed 20% and 50% survival rates, respectively. Whereas the mice treated with free Amp B at the same doses died within 40 days of treatment. Interestingly, C. albicans infected mice treated with a combination of Lip-Amp B and Lip-MG had 70% survival rate on day 40 postinfection. Moreover, treatment of macrophages with Lip-MG increased their fungicidal activity and the secretion of proinflammatory cytokines, including TNF-α and IL-1ß. These findings suggested that co-treatment with Lip-Amp B and Lip-MG had a synergistic effect and could be effective against C. albicans in immunocompromised subjects.

A novel SLC37A4 missense mutation in GSD-Ib without hepatomegaly causes enhanced leukocytes endoplasmic reticulum stress and apoptosis.

BACKGROUND: Glycogen storage disease (GSD) type Ib is an autosomal recessive disease caused by defects of glucose-6-phosphate transporter (G6PT), encoded by the SLC37A4 gene. To date, over 100 mutations have been revealed in the SLC37A4 gene. GSD-Ib patients manifest a metabolic phenotype of impaired blood glucose homeostasis and also carry the additional complications of neutropenia and myeloid dysfunction. METHODS: Here, we present two daughters with an initial diagnosis of gout in a Chinese consanguineous family. Whole-exome sequencing was performed to identify the mutations. The mechanism of leukocytopenia was investigated. RESULTS: Whole-exome sequencing analysis of the proband identified a novel homozygous p.P119L mutation in SLC37A4, leading to a diagnosis of GSD-Ib. We found that the potential pathogenic p.P119L mutation leads to an unusual phenotype characterized by gout at onset, and GSD-Ib arising from this variant also manifests multiple metabolic abnormalities, leukocytopenia, and anemia, but no hepatomegaly. The leukocytes from the proband showed increased mRNA levels of sXBP-1, BIP, and CHOP genes in the unfolded protein response pathway, and enhanced Bax mRNA and caspase-3 activity, which might contribute to leukocytopenia. CONCLUSION: Our findings broaden the variation spectrum of SLC37A4 and suggest no strict genotype-phenotype correlations in GSD-Ib patients.

Hematological Manifestations among Patients with Rheumatic Diseases.

BACKGROUND: Rheumatic diseases have many hematological manifestations. Blood dyscrasias and other hematological abnormalities are sometimes the first sign of rheumatic disease. In addition, novel antirheumatic biological agents may cause cytopenias. SUMMARY: The aim of this review was to discuss cytopenias caused by systemic lupus erythematosus and antirheumatic drugs, Felty's syndrome in rheumatoid arthritis, and autoimmune hemolytic anemia, thrombosis, and thrombotic microangiopathies related to rheumatological conditions such as catastrophic antiphospholipid syndrome and scleroderma renal crisis. Key Message: The differential diagnosis of various hematological disorders should include rheumatic autoimmune diseases among other causes of blood cell and hemostasis abnormalities. It is crucial that hematologists be aware of these presentations so that they are diagnosed and treated in a timely manner.

Leukocytospermia in late adolescents: possible clinical interpretations.

BACKGROUND: No data are currently available on the implication of amicrobial leukocytospermia in male adolescents. Therefore, the primary aim of this study was to evaluate the prevalence of amicrobial leukocytospermia among non-smoker late adolescents who were exposed to other risky lifestyles for the andrological health. The main andrological clinical features of adolescents with leukocytospermia were also reported. METHODS: This is a cross-sectional study carried out in 80 boys. Each adolescent underwent a physical examination, and to the assessment of sperm conventional parameters, seminal leukocytes concentration and immature germ cell evaluation. A possible correlation between seminal leukocytes and immature germ cells and testicular volume (TV) was tested. RESULTS: The adolescents enrolled in this study had 18.0 ± 0.4 (range 18.1-18.9) years. Unprotected sexual intercourse was referred by 38% of them. Sexual dysfunctions were found in 25% and isolated hypoactive sexual desire in 12.5% of boys. Low TV and penile length in flaccidity were found in 44% and 30% of them, respectively. Only 41% had normozoospermia at the sperm analysis, whereas 19% had isolated oligozoospermia, 15% oligo-asthenozoospermia, and 25% oligo-astheno-teratozoospermia. Leukocytospermia occurred in 25% (20 out of 80) of adolescents. No seminal infection was detected in 19% (15 out of 80) of them. Adolescents with leukocytospermia had lower progressive sperm motility, percentage of normal forms, TV, and a higher percentage of immature germ cells compared to those without leukocytospermia. Semen leukocyte concentration correlated negatively with TV and positively with the percentage of immature germ cells in the ejaculate. CONCLUSION: Leukocytospermia, increased immature germ cell number, and low TV identify a distinct phenotype suggestive of testicular tubulopathy. Primary prevention of male infertility and the counselling for andrological risky lifestyles is mandatory and should be started as early as possible.

Ziyuglycoside II alleviates cyclophosphamide-induced leukopenia in mice via regulation of HSPC proliferation and differentiation.

Ziyuglycoside II (ZGS II) is a major bioactive ingredient of Sanguisorbae officinalis L., which has been widely used for managing myelosuppression or leukopenia induced by chemotherapy or radiotherapy. In the current study, we investigated the pro-hematopoietic effects and underlying mechanisms of ZGS II in cyclophosphamide-induced leukopenia in mice. The results showed that ZGS II significantly increased the number of total white blood cells and neutrophils in the peripheral blood. Flow cytometry analysis also showed a significant increase in the number of nucleated cells and hematopoietic stem and progenitor cells (HSPCs) including ST-HSCs, MPPs, and GMPs, and enhanced HSPC proliferation in ZGS II treated mice. The RNA-sequencing analysis demonstrated that ZGS II effectively regulated cell differentiation, immune system processes, and hematopoietic system-related pathways related to extracellular matrix (ECM)-receptor interaction, focal adhesion, hematopoietic cell lineage, cytokine-cytokine receptor interaction, the NOD-like receptor signaling pathway, and the osteoclast differentiation pathway. Moreover, ZGS II treatment altered the differentially expressed genes (DEGs) with known functions in HSPC differentiation and mobilization (Cxcl12, Col1a2, and Sparc) and the surface markers of neutrophilic precursors or neutrophils (Ngp and CD177). Collectively, these data suggest that ZGS II protected against chemotherapy-induced leukopenia by regulating HSPC proliferation and differentiation.

Efficacy of combination-chemotherapy with pirarubicin, ifosfamide, and etoposide for soft tissue sarcoma: a single-institution retrospective analysis.

BACKGROUND: The standard chemotherapy regimens for soft tissue sarcoma are doxorubicin-based. This retrospective study aimed to assess the efficacy and safety of pirarubicin, ifosfamide, and etoposide combination therapy for patients with this disease. METHODS: Between 2008 and 2017, 25 patients with soft tissue sarcoma were treated with pirarubicin (30 mg/m2, 2 days), ifosfamide (2 g/m2, 5 days), and etoposide (100 mg/m2, 3 days) every 3 weeks. The primary endpoint was overall response, and the secondary endpoint was adverse events of this regimen. RESULTS: Responses to this regimen according to RECIST criteria were partial response (n = 9, 36%), stable disease (n = 9, 36%) and progressive disease (n = 7, 28%). During the treatment phase, frequent grade 3 or worse adverse events were hematological toxicities including white blood cell decreases (96%), febrile neutropenia (68%), anemia (68%), and platelet count decreases (48%). No long-term adverse events were reported during the study period. CONCLUSION: This regimen was comparable to previously published doxorubicin-based combination chemotherapy in terms of response rate. Although there were no long-lasting adverse events, based on our results, severe hematological toxicity should be considered.

Sulfated polymannuroguluronate TGC161 ameliorates leukopenia by inhibiting CD4+ T cell apoptosis.

Polysaccharides have aroused considerable interest due to their diverse biological activities and low toxicity. In this study, we evaluated the effect of marine polysaccharide sulfated polymannuroguluronate (TGC161) on the leukopenia induced by chemotherapy. It is found that TGC161 ameliorates the leukopenia. Besides, TGC161 would promote CD4+ T cell differentiation and maturation in the thymus, but does not have a significant effect on precursor cells in bone marrow. Furthermore, TGC161 inhibits CD4+ T cell apoptosis in vitro. Collectively, our findings offer a natural and harmless polysaccharide to ameliorate leukopenia.

Glucocorticoid-induced eosinopenia results from CXCR4-dependent bone marrow migration.

Glucocorticoids are considered first-line therapy in a variety of eosinophilic disorders. They lead to a transient, profound decrease in circulating human eosinophils within hours of administration. The phenomenon of glucocorticoid-induced eosinopenia has been the basis for the use of glucocorticoids in eosinophilic disorders, and it has intrigued clinicians for 7 decades, yet its mechanism remains unexplained. To investigate, we first studied the response of circulating eosinophils to in vivo glucocorticoid administration in 3 species and found that the response in rhesus macaques, but not in mice, closely resembled that in humans. We then developed an isolation technique to purify rhesus macaque eosinophils from peripheral blood and performed live tracking of zirconium-89-oxine-labeled eosinophils by serial positron emission tomography/computed tomography imaging, before and after administration of glucocorticoids. Glucocorticoids induced rapid bone marrow homing of eosinophils. The kinetics of glucocorticoid-induced eosinopenia and bone marrow migration were consistent with those of the induction of the glucocorticoid-responsive chemokine receptor CXCR4, and selective blockade of CXCR4 reduced or eliminated the early glucocorticoid-induced reduction in blood eosinophils. Our results indicate that glucocorticoid-induced eosinopenia results from CXCR4-dependent migration of eosinophils to the bone marrow. These findings provide insight into the mechanism of action of glucocorticoids in eosinophilic disorders, with implications for the study of glucocorticoid resistance and the development of more targeted therapies. The human study was registered at ClinicalTrials.gov as #NCT02798523.

Cirrhosis in Wilson Disease is characterized by Impaired Hepatic Synthesis, Leukopenia and Thrombocytopenia.

Background: Patients with Wilson disease (WD) progress to cirrhosis at an early age but have good prognoses. This study aimed to delineate hepatic features in WD patients with or without cirrhosis. Methods: Medical data were retrospectively collected from 27 July 2015 to 27 June 2018. WD patients were divided into two groups based on whether or not they progressed to cirrhosis. Liver function, portal hypertension features and hematocytopenia rates were compared between groups. Results: The study enrolled 119 WD patients with cirrhosis and 53 WD patients without cirrhosis. There were no differences between groups for liver enzyme levels or incidence rates of Kayser-Fleischer ring (all P > 0.05). Ascites and hepatic encephalopathy were nearly absent in both groups, and almost all patients were Child-Pugh group A. However, WD-associated cirrhotic patients had a higher prothrombin time (beta = 0.908, P = 0.004) and international normalized ratio (beta = 0.089, P = 0.040), wider portal vein diameter (beta = 1.330, P < 0.001), and an increased risk of splenomegaly/splenectomy (odds ratio [OR] = 4.36, 95% confidence interval [CI]: 2.15-8.84, P < 0.001). Moreover, WD-associated cirrhotic patients have significantly increased risks of leukopenia (OR = 2.30, 95% CI: 1.00-5.25, P = 0.049) and thrombocytopenia (OR = 6.89, 95% CI: 2.01-23.59, P = 0.002). Conclusions: Despite presenting good outcomes, mild hepatocyte injury, and good hepatic metabolic function, WD-associated cirrhotic patients show more serious impairment of hepatic synthetic function, wider portal vein diameter, and higher risk of splenomegaly due to portal hypertension.

Abnormal DNA methylation patterns in patients with infection­caused leukocytopenia based on methylation microarrays.

The present study aimed to investigate the association between gene methylation and leukocytopenia from the perspective of gene regulation. A total of 30 patients confirmed as having post­infection leukocytopenia at People's Hospital of Xinjiang Uygur Autonomous Region between January 2016 and June 2017 were successively recruited as the leukocytopenia group; 30 patients with post­infection leukocytosis were enrolled as the leukocytosis group. In addition, 30 healthy volunteers who received a health examination at the hospital during the same period were included as the normal control group. In each group, four individuals were randomly selected for whole genome methylation screening. After selection of key methylation sites, the remaining samples in each group were used for verification using matrix­assisted laser desorption/ionization­time of flight mass spectrometry. The levels of serum complement factors C3 and C5 in the leukocytopenia group were significantly lower than those in the other two groups (P<0.05). According to whole­genome DNA methylation detection, 66 and 27 methylation loci may be associated with leukocytopenia and leukocytosis, respectively. Most of these abnormal loci are located on chromosomes 2, 6, 7, 1, 17 and 11. The rates of WW domain containing E3 ubiquitin protein ligase 2 gene methylation at cytosine­phosphate­guanine (CpG)_1, CpG_5/6 and CpG_7 in the leukocytopenia group were higher than in the other two groups (P<0.05); the rate of AKT2 CpG_1 methylation was higher in the leukocytopenia group than in the other two groups (P<0.05); the rate of calcium­binding atopy­related autoantigen 1 gene CpG_2 methylation was higher in the leukocytosis group than in the normal control group (P<0.05); and the rate of NADPH oxidase 5 gene CpG_3 methylation was higher in the leukocytosis group than in the normal control group (P<0.05). Chemotactic factor secretion and cell migration abnormalities, ubiquitination modification disorders and reduced oxidative burst may participate in infection­complicated leukocytopenia. The results of this study shed new light on the molecular biological mechanisms of infection­complicated leukocytopenia and provide novel avenues for diagnosis and treatment.

Flow Cytometric, Morphologic, and Laboratory Comparative Study in Patients With Leukocytosis and Cytopenia.

OBJECTIVES: We wanted to evaluate the effectiveness of flow cytometry immunophenotyping (FCI) as a screening test for patients with leukocytosis and cytopenia. METHODS: We identified 320 patients during August 2016 to December 2016 and evaluated FCI and morphology of peripheral blood smears (PBSs). RESULTS: The most common indications for FCI included history of hematologic malignancy (HHM, n = 126), leukocytosis (n = 80), and cytopenia (n = 53). Positive FCI rate was low with a range of 4.4% to 12.5% in patients with absolute neutrophilia regardless of HHM, if cases with circulating blasts were excluded. Patients with absolute lymphocytosis had a 93% positive FCI rate. Patients with HHM and pancytopenia showed a higher incidence of positive FCI findings than patients without HHM and with isolated cytopenia. PBS morphology correlated strongly with FCI (P = .0001). CONCLUSION: PBS evaluation is an accurate and cost-effective screening test. FCI for patients with mature neutrophilia and isolated cytopenia has a very low yield.

Myelosuppression and acute hematological complications of sulfur mustard exposure in victims of chemical terrorism.

Sulfur mustard (SM) is a vesicant chemical warfare agent. Recent studies reported alleged use of SM by non-state actors in Syria and Iraq. It has been shown that SM induced immunological and hematological complications. The aim of this study was to determine acute toxic effects of SM exposure on hematological parameters. Blood samples from a group of Syrian exposed to SM in 2016 were taken daily during the follow-up of the patients in intensive care unit. Initial leukocytosis was observed in all patients (100%) on the first 48 h after exposure. Following leukocytosis, isolated lymphopenia was observed in all patients (100%) between 2nd and 4th days. A decrease in hemoglobin level was noted in five patients (62.5%) between 4th and 5th days. Thrombocytopenia was observed in 75% of patients between 4th and 6th days for mild cases and between 9th and 11th days for severe cases. Three patients (37.5%) developed distinct leucopenia/neutropenia on 11th and 12th days. It was observed that human exposure to high dose of SM has direct toxic effect on hematological cells and bone marrow. New strategies on treatment of SM-induced myelosuppression could reduce the effects of hematological complications and could increase the survival rate in these patients.

Association between the c.415C > T, c.52G > A, and 36_37insGGAGTC polymorphisms of NUDT 15 and thiopurine-induced leukopenia, thiopurine intolerance, and severe hair loss: an updated meta-analysis.

PURPOSE: As a common immunosuppressive and anticancer drug, thiopurine has achieved remarkable clinical success. However, higher inter-individual dose variability and unpredictable toxicity still challenge its use in clinical practices. Some studies indicate that NUDT 15 polymorphisms are associated with this variation, but specific correlation remains controversial. This meta-analysis assessed the association between three polymorphisms of NUDT 15 and thiopurine-induced toxicities. METHODS: Three databases were electronically searched: PubMed, Embase, and Web of Science. Only case-control studies and cohort studies were eligible. The overall pooled ORs and corresponding 95% CIs were used to represent the results. FINDINGS: We included 16 studies that focus on NUDT 15 c.415C > T, c.52G > A, and 36_37insGGAGTC polymorphisms in patients treated with thiopurine. Significant associations between NUDT 15 c.415C > T polymorphism and leukopenia were found in all genetic models (TC/TT vs CC, OR: 7.64, 95% CI: (6.19, 9.44), P<0.00001; TT vs CC/TC, OR: 29.66, 95% CI: (12.31, 71.46), P<0.00001; TT vs CC, OR: 45.60, 95% CI: (18.84, 110.37), P<0.00001; TC vs CC, OR: 6.41, 95% CI: (5.19, 7.94), P<0.00001; TT vs TC, OR: 6.38, 95% CI: (2.59, 15.72), P<0.00001), early/late leukopenia (in recessive and co-dominant model), leukopenia (grade 3-4), and severe hair loss in all genetic models. Besides, c.52G > A and 36_37insGGAGTC polymorphisms were also significantly associated with leukopenia. No significant association between NUDT 15 c.415C > T polymorphism and early/late leukopenia in the Chinese population was determined in the co-dominant model (TC vs CC). IMPLICATIONS: NUDT 15 c.415C > T polymorphism could increase the risk of leukopenia, early/late leukopenia, leukopenia (grade 3-4), and severe hair loss. Meanwhile, c.52G > A and c.36_37insGGAGTC mutations also probably increase the risk of leukopenia. Preemptive tests for NUDT 15 polymorphisms are highly recommended to individualize the treatment of thiopurine for a better outcome with less toxicity.

Eosinopenia as a marker of diagnosis and prognostic to distinguish bacterial from aseptic meningitis in pediatrics.

Procalcitonin (PCT) has proven its efficacy to distinguish bacterial from aseptic meningitis in children. Nevertheless, its use in routine is limited by its cost and availability, especially in low- and middle-income countries. It is now acknowledged that eosinopenia is a marker of infection and/or severity of the systemic inflammatory response. Although no study ever demonstrated that eosinopenia could differentiate bacterial from viral infection, we decided to conduct a study concerning meningitis in children. This bicentric and retrospective study was conducted between January 2012 and October 2018, in children hospitalized for meningitis. The white blood cell was systematically gathered at the admission to evaluate the eosinophil count. Characteristic data were compared between 2 groups: documented bacterial meningitis (DBP) and aseptic meningitis which includes documented viral meningitis (DVM) and non-documented meningitis (ND). Among 190 patients admitted for meningitis, 151 were analyzed, including DBM (n = 45), DVM (n = 73), and ND (n = 33) meningitis. Groups were comparable. Mean age was 33 ± 48 months with a sex ratio of 1.6. Mean of eosinophil count was 15 ± 34/mm3 in the DBM group versus 132 ± 167/mm3 for the aseptic meningitis group (p < 0.0001). Best threshold for the diagnosis of bacterial meningitis was an eosinophil count < 5/mm3 with a sensitivity of 80% and specificity of 73% and a likelihood ratio of 2.9. Eosinopenia seems to be a reliable and non-invasive marker of bacterial meningitis in pediatrics. The absence of extra cost makes it very interesting in low- and middle-income countries or when usual biomarkers such as PCT are unavailable.