Clinical associations with a polygenic predisposition to benign lower white blood cell counts.

Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGSWBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGSWBC [95%CI, 0.30-0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69-0.88], p = 4.0 × 10-5) or immunosuppressant (n = 354, HR = 0.61 [0.38-0.99], p = 0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n = 1,466, HR = 0.62 [0.44-0.87], p = 0.006). Collectively, these findings suggest that there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.

Increased Serum Interleukin 10 Levels Are Associated with Increased Disease Activity and Increased Risk of Anti-SS-A/Ro Antibody Positivity in Patients with Systemic Lupus Erythematosus.

Interleukin 10 (IL-10) plays a role in inflammation and cell-type responses. The anti-SS-A/Ro antibody contributes to leucopenia, and cutaneous and neonatal lupus. OBJECTIVES: To evaluate the association between serum IL-10 levels and autoantibodies, disease activity and organ involvement in systemic lupus erythematosus (SLE) patients. PATIENTS AND METHODS: We studied 200 SLE patients and 50 controls. We analyzed organ involvement, disease activity, serum IL-10 and interleukin-6 (IL-6) levels, and antinuclear and antiphospholipid antibody profiles. RESULTS: Serum IL-10 and IL-6 levels were higher in SLE patients than in controls (all p < 0.00001). Serum IL-10 levels were positively correlated with IL-6 (p < 0.00001), CRP (p < 0.00001), fibrinogen (p = 0.003), and ESR (p < 0.00001), and negatively correlated with hemoglobin (p = 0.0004) and lymphocytes (p = 0.01). Serum IL-6 levels were positively correlated with CRP (p < 0.00001), fibrinogen (p = 0.001), and ESR (p < 0.00001); and negatively correlated with hemoglobin (p = 0.008) and lymphocytes (p = 0.03). Elevated serum IL-10 levels were associated with an increased risk of anti-SS-A/Ro antibody positivity (p = 0.03). Elevated serum IL-6 levels were associated with an increased risk of heart (p = 0.007) and lung (p = 0.04) involvement. CONCLUSIONS: In SLE patients, increased serum IL-10 levels were associated with increased disease activity and risk of anti-SS-A/Ro antibody positivity.

Clinical Implications of Hematologic and Hemostatic Abnormalities in Children With COVID-19.

Leukopenia, thrombocytopenia, elevated D-dimer, and prolonged prothrombin time are considered poor prognostic factors in adults with acute Coronavirus Disease 2019. The prognostic significance of these abnormalities among pediatric patients remains underreported in the literature. This retrospective cohort study evaluates the prognostic implications of hematologic and hemostatic derangements in patients younger than 22-years-of-age who were admitted to a tertiary-care referral institution for management of acute Coronavirus Disease 2019 infection. Leukopenia and thrombocytopenia were identified as independent prognostic factors of disease severity. Although the majority of children, with available results, had elevated D-dimer or prolonged prothrombin time upon initial presentation, these markers were not found to be associated with the development of severe clinical complications.

Increased DNA-incorporated thiopurine metabolite as a possible mechanism for leukocytopenia through cell apoptosis in inflammatory bowel disease patients with NUDT15 mutation.

BACKGROUND AND AIMS: Polymorphisms in the nucleotide diphosphate-linked moiety X-type motif 15 (NUDT15) gene are associated with thiopurine-induced leukopenia in patients with inflammatory bowel disease (IBD). NUDT15-associated subcellular thiopurine metabolism has not been investigated in primary lymphocytes. We hypothesized that NUDT15 mutation increases DNA-incorporated deoxythioguanosine (dTG) and induces apoptosis in lymphocytes. METHODS: DNA-incorporated dTG in peripheral blood mononuclear cells (PBMCs) and 6-thioguanine nucleotides (6-TGN) in red blood cells were measured in patients with IBD undergoing thiopurine treatment. The association of a single nucleotide polymorphism for NUDT15 (rs116855232) with dTGPBMC was examined. The pro-apoptotic effect of DNA-incorporated dTG was examined ex vivo in association with NUDT15 genotypes by co-culturing patient-derived peripheral CD4+ T lymphocytes with 6-thioguanine (6-TG). RESULTS: dTGPBMC was significantly higher in NUDT15 variants than in non-variants. dTGPBMC, but not 6-TGNRBC, negatively correlated with peripheral lymphocyte counts (r = - 0.31 and - 0.12, p = 0.012 and 0.173, respectively). DNA-incorporated dTG significantly accumulated to a greater extent in lymphocytes from NUDT15 variants when co-cultured with 6-TG ex vivo than in those from non-variants and was associated with decreased proliferation and increased apoptosis. CONCLUSION: Increased DNA-incorporated dTG may be responsible for thiopurine-induced leukocytopenia through cell apoptosis in IBD patients with NUDT15 mutation.

Hematological indices and abnormalities among patients with uncomplicated falciparum malaria in Kosti city of the White Nile state, Sudan: a comparative study.

BACKGROUND: Hematological abnormalities are common features in falciparum malaria but vary among different populations across countries. Therefore, we compared hematological indices and abnormalities between Plasmodium falciparum-infected patients and malaria-negative subjects in Kosti city of the White Nile State, Sudan. METHODS: A comparative, cross-sectional study was conducted at the Clinical Laboratory Unit of Kosti Teaching Hospital from June to December 2018. A total of 392 participants (192 P. falciparum-infected patients and 200 malaria-negative subjects) were recruited in the study. Hematological indices of hemoglobin (Hb), red blood cells (RBCs), white blood cells (WBCs) and platelets were measured, and their median values were statistically compared. RESULTS: The majority of P. falciparum-infected patients (67.6%) showed a low-level parasitemia. The median values of Hb concentration, RBC count, mean corpuscular volume (MCV), mean corpuscular Hb (MCH) and mean corpuscular Hb concentration (MCHC) were significantly lower in P. falciparum-infected patients, while the median red cell distribution width (RDW) was significantly higher in the patients compared to malaria-negative subjects. Anemia, low MCV, low MCH, low MCHC and high RDW were significantly associated with falciparum malaria, but parasitemia level was not significantly associated with anemia severity. The median total WBC count was non-significantly higher in P. falciparum-infected patients, with neutropenia being significantly associated with falciparum malaria. The median platelet count was significantly lower in P. falciparum-infected patients, with thrombocytopenia being significantly associated with falciparum malaria. CONCLUSIONS: Falciparum malaria among patients in Kosti city of the White Nile State, Sudan is predominantly of low-level parasitemia. It is significantly associated with anemia, low MCV, low MCH, low MCHC, high RDW, thrombocytopenia and neutropenia. However, parasitemia level is not a significant predictor of anemia severity. On the other hand, leucopenia is not useful to predict falciparum malaria. Further large-scale studies in community and healthcare settings and inclusion of patients with complicated or severe malaria and those with high parasite densities are recommended.

Effect of the coronavirus pandemic on tumor markers.

The new type of coronavirus could cause severe acute respiratory syndrome and injuries in other systems as well. Multiple organ damage can occur rapidly in patients infected with coronavirus disease 2019 (COVID-19). Previous studies have shown that many laboratory biomarkers were not within the normal ranges in COVID-19 patients. We aimed to summarize laboratory parameters and the tumor markers in COVID-19 patients. This is a retrospective cohort study conducted on 53 women between the ages of 19-85 years infected with COVID-19 at a training and research hospital between May 2020 and August 2020. Of the 53 women, 16 (30.2%) had leukopenia. The mean C-reactive protein level was 18.42 ± 59.33 mg/L. The mean procalcitonin level was 0.1 ± 0.21 µg/L. The liver function tests were within normal limits. The mean creatinine level was 0.58 ± 0.37 mg/dl. Elevated levels of α-fetoprotein (AFP) in 1 patient, elevated levels of carcinoembryonic antigen (CEA) in 2 patients, elevated levels of cancer antigen 125 (CA125) in 4 patients, elevated levels of CA19-9 in 2 patients, and elevated levels of CA15-3 in 2 patients were detected. One of 4 patients who were taken to the intensive care unit had elevated levels of AFP. In addition, 2 of 4 patients who were taken to the intensive care unit had elevated levels of CA125 and CA15-3. Except for AFP, levels of all tumor markers of the patient who died were high. We found that COVID-19 had no effect on tumor markers (CA125, CA19-9, CA15-3, AFP, and CEA).

Long-term immunosuppression and multiple transplants predispose systemic lupus erythematosus patients with cytopenias to hematologic malignancies.

ABSTRACT: Cytopenias in systemic lupus erythematosus (SLE) require clinical and laboratory workup and bone marrow (BM) examination to determine the cause and for appropriate patient management. Common causes include an increase in SLE activity, immune-mediated hemolysis, iron deficiency, antiphospholipid antibody syndrome, infection, or the effect of medications. We retrospectively evaluated the clinical and laboratory findings of patients with SLE and cytopenias who had undergone BM studies to determine the indicators of malignancy.We retrospectively reviewed medical records of patients with SLE who presented with cytopenias for their disease course, medications, laboratory parameters and documented the spectrum of morphological changes in BM including CD34 expression.Twenty patients with SLE had undergone BM biopsy for evaluation of cytopenias. 14/20 (70%) of the patients had reactive BM, and the rest had hematologic malignancies involving the BM. Of these 14 patients, 8 had hypocellular marrow with loss of precursor cells (low CD34), 4 had left shift in myeloid lineage, 3 had serous atrophy, and 1had multilineage dysplasia. The 6 patients with hematologic malignancies included 2 with diffuse large B cell lymphoma, and one each of natural killer/T cell lymphoma, post-transplant lymphoproliferative disorder, Hodgkin lymphoma, and myelodysplastic syndrome evolving to acute myelogenous leukemia. The presence of autoantibodies, SLE activity, and lupus nephritis were comparable in patients with and without neoplasia. However, the duration of the use of multiple immunosuppressants, years since renal transplant (22 vs 10), multiple transplants, and the presence of other autoimmune diseases were greater in those with neoplasia. Two of the 14 patients with non-neoplastic BM and 1 with the neoplastic BM had nonhematological malignancy.Clinical and laboratory findings, the number of transplants, and the use of immunosuppressive agents can guide physicians to identify patients with a higher risk of developing hematologic malignancy. BM findings of cytopenia in SLE are often due to increased disease activity causing global cell death and dysmaturation. SLE patients presenting with cytopenias, with a history of long-term exposure to immunosuppressive drugs, should be regularly screened for hematologic and nonhematologic malignancies.

Coronavirus disease 2019 and dengue: two case reports.

BACKGROUND: The pandemic of this century has overwhelmed the healthcare systems of affected countries, and all resources have been diverted to coronavirus disease 2019. At the onset, coronavirus disease 2019 can present as any other acute febrile undifferentiated illness. In tropical regions, clinicians are increasingly challenged to differentiate these febrile illnesses without the use of diagnostics. With this pandemic, many of these tropical diseases are neglected and go underreported. Dengue is holoendemic in the Maldives, and dengue viruses circulate throughout the year. Reports about coinfections with dengue virus and severe acute respiratory syndrome coronavirus 2 are scarce, and the outcome and the dynamics of the disease may be altered in the presence of coinfection. We have described the clinical manifestation and serial laboratory profile, and highlighted the atypical findings uncommon in dengue infection. CASE PRESENTATION: Case 1 was a 39-year old Asian male, presented on day 6 of dengue infection with warning signs. Reverse transcription polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 that was done as per hospital protocol was found to be positive. Case 2 was a 38-year old Asian male, was admitted on day 5 of illness with symptoms of acute respiratory infection with positive reverse transcription polymerase chain reaction for severe acute respiratory syndrome coronavirus 2. Evaluation of progressive leukopenia and thrombocytopenia showed positive dengue serology. CONCLUSION: Clinicians must be conscientious when working on the differential diagnosis of possible tropical diseases in cases of coronavirus disease 2019, specifically, when patients develop hemoconcentration, thrombocytopenia, and transaminitis with elevated expression of aspartate higher than alanine transaminase, which is frequently observed in dengue infection. Caution must be taken during the administration of intravenous fluids when treating patients with coronavirus disease 2019 and dengue coinfection, as coronavirus disease 2019 patients are more prone to develop pulmonary edema. Timely diagnosis and appropriate management are essential to avoid the devastating complications of severe forms of dengue infection. It is important to repeat and reconfirm the dengue serology in coronavirus disease 2019 patients to avoid false positivity. Diligence and care must be taken not to neglect other endemic tropical diseases in the region during the present pandemic.

Relationship between leukocyte, neutrophil, lymphocyte, platelet counts, and neutrophil to lymphocyte ratio and polymerase chain reaction positivity.

BACKGROUND: Exposure to viral or bacterial pathogens increases the number of neutrophils with a relative decrease in lymphocytes, leading to elevated neutrophil to lymphocyte ratio (NLR). This study aimed to investigate whether differences in NLR among real-time polymerase chain reaction (PCR)-positive and -negative patients presenting with a prediagnosis of COVID-19 pneumonia could be useful in the differential diagnosis. METHODS: The study included 174 patients admitted because of suspected COVID-19 infection between March and April 2020. Patients were divided into two groups: PCR-negative and PCR-positive. Hemogram, NLR, urea, creatinine, aspartate aminotransferase, alanine aminotransferase, bilirubin, ferritin, D-dimer, C-reactive protein, procalcitonin, troponin, and coagulation parameters were analyzed. RESULTS: On comparison of laboratory parameters between both groups at presentation, PCR-positive patients were significantly more likely to have leukopenia (p < 0.001), thrombocytopenia (p = 0.006), neutropenia (p < 0.001), lymphopenia (p = 0.001), and increased NLR (p = 0.003). Furthermore, PCR-positive patients showed significant elevations of ferritin (p = 0.012) and procalcitonin (p = 0.038) and significant lower potassium levels (p = 0.05). CONCLUSION: COVID-19 pneumonia has become a major global health problem. Early diagnosis and treatment of these patients are crucial, as COVID-19 pneumonia shows a rapid progression in most cases. Thus, leukopenia, thrombocytopenia, elevated NLR, and elevated ferritin may be useful as supplementary diagnostic tests in these patients, which may allow early initiation of treatment and may contribute to preventing progression in patients with abnormal results.

Evaluation of eosinopenia as a diagnostic and prognostic indicator in COVID-19 infection.

INTRODUCTION: Eosinopenia has been observed during infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. This study evaluated the role of eosinopenia as a diagnostic and prognostic indicator in COVID-19 infection. METHODS: Information on 429 patients with confirmed COVID-19, admitted to Apollo Hospitals, Chennai, India between 04 June 2020 to 15 August 2020, was retrospectively collected through electronic records and analysed. RESULTS: 79.25% of the patients included in the study had eosinopenia on admission. The median eosinophil count in COVID-19-positive patients was 0.015 × 109 /L, and in negative patients, it was 0.249 × 109 /L. Eighteen per cent of the positive patients presented with 0 eosinophil count. Eosinopenia for early diagnosis of COVID-19 had a sensitivity of 80.68% and specificity of 100% with an accuracy of 85.24. Role of eosinopenia in prognostication of COVID-19 was found to be insignificant. There was no statistically significant difference between the median eosinophil counts in survivors and nonsurvivors. Eosinophil trends during the course of disease were found to be similar between survivors and nonsurvivors. CONCLUSIONS: Eosinopenia on admission is a reliable and convenient early diagnostic marker for COVID-19 infection, helping in early identification, triaging and isolation of the patients till nucleic acid test results are available. Role of eosinopenia as a prognostic indicator is insignificant.

Intervention of standardized ethanol leaf extract of Annickia polycarpa, (DC.) Setten and Maas ex I.M. Turner. (Annonaceae), in Plasmodium berghei infested mice produced anti-malaria action and normalized gross hematological indices.

ETHNOPHARMACOLOGICAL RELEVANCE: Malaria is a global public health burden due to large number of annual infections and casualties caused by its hematological complications. The bark of Annickia polycarpa is an effective anti-malaria agent in African traditional medicine. However, there is no standardization parameters for A. polycarpa. The anti-malaria properties of its leaf are also not known. AIM OF THE STUDY: To standardize the ethanol leaf extract of A. polycarpa (APLE) and investigate its anti-malaria properties and the effect of its treatment on hematological indices in Plasmodium berghei infected mice in the Rane's test. MATERIALS AND METHODS: Malaria was induced by inoculating female ICR mice with 1.0 × 107P. berghei-infected RBCs in 0.2 mL (i.p.) of blood. Treatment was commenced 3 days later with APLE 50, 200, 400 mg/kg p.o., Quinine 30 mg/kg i.m. (Standard drug) or sterile water (Negative control) once daily per group for 4 successive days. Anti-malarial activity and gross malaria indices such as hyperparasitemia, mean change in body weight and mean survival time (MST) were determined for each group. Changes in white blood cells (WBCs), red blood cells (RBCs), platelets (PLT) counts, hemoglobin (HGB) concentration, hematocrit (HCT) and mean corpuscular volume (MCV) were also measured in the healthy mice before infection as baseline and on day 3 and 8 after inoculation using complete blood count. Standardization was achieved by UHPLC-MS chemical fingerprint analysis and quantitative phytochemical tests. RESULTS: APLE, standardized to its total alkaloids, phenolics and saponin contents, produced significant (P < 0.05) dose-dependent clearance of mean hyperparasitemia of 22.78 ± 0.93% with the minimum parasitemia level of 2.01 ± 0.25% achieved at 400 mg/kg p.o. on day 8. Quinine 30 mg/kg i.m. achieved a minimum parasitemia level of 6.15 ± 0.92%. Moreover, APLE (50-400 mg/kg p.o.) evoked very significant anti-malaria activity of 89.22-95.50%. Anti-malaria activity of Quinine 30 mg/kg i.m. was 86.22%. APLE also inverse dose-dependently promotes weight gain with the effect being significant (P < 0.05) at 50 mg/kg p.o. Moreover, APLE dose-dependently increased the MST of malaria infested mice with 100% survival at 400 mg/kg p.o. Quinine 30 mg/kg i.m. also produce 100% survival rate but did not promote (P > 0.05) weight gain. Hematological studies revealed the development of leukocytopenia, erythrocytosis, microcytic anemia and thrombocytopenia in the malaria infected mice which were reverted with the treatment of APLE 50-400 mg/kg p.o. or Quinine 30 mg/kg i.m. but persisted in the negative control. The UHPLC-MS fingerprint analysis of APLE led to identification of one oxoaporphine and two aporphine alkaloids (1-3). Alkaloids 1 and 3 are being reported in this plant for the first time. CONCLUSION: These results indicate that APLE possessed significant anti-malaria, immunomodulatory, erythropoietic and hematinic actions against malaria infection. APLE also has the ability to revoke deleterious physiological alteration produced by malaria and hence, promote clinical cure. These properties of APLE are due to its constituents especially, aporphine and oxoaporphine alkaloids.

Amelioration of cyclophosphamide-induced myelosuppression during treatment to rats with breast cancer through low-intensity pulsed ultrasound.

To investigate the alleviating effects of low-intensity pulsed ultrasound (LIPUS) on myelosuppression of Sprague-Dawley rats with breast cancer induced by cyclophosphamide (CTX). Breast cancer in rats was triggered by intragastric gavage with 7,12-dimethylbenz[a]anthracene (150 mg/kg). Then, the rats with breast cancer were randomly allocated to the LIPUS group (n=50) and the control group (n=50). The LIPUS group was injected intraperitoneally with CTX (50 mg/kg) for 4 consecutive days and underwent LIPUS treatment at femoral metaphysis 20 min per day from the first day of injection for 7 consecutive days. The control group was injected with CTX (50 mg/kg) and treated with LIPUS without energy output. Blood, enzyme-linked immunosorbent assay (ELISA), real-time quantitative polymerase chain reaction, Hematoxylin and Eosin (H&E) staining, and scanning electron microscopy were applied to detect the changes. The results indicated that LIPUS significantly promoted the proliferation of bone marrow nucleated cells, white blood cells (WBCs), IgA, IgG, and IgM in the peripheral blood (P<0.05) without the damage to liver and kidney function simultaneously. The mechanisms may result from the LIPUS alleviation effect on bone marrow hematopoietic function through regulating cytokines such as LIPUS can increase the expression of granulocyte colony-stimulating factor (G-CSF), stem cell factor, transforming growth factor-ß, and intercellular cell adhesion molecule-1, meanwhile LIPUS will decrease the expression of interleukin-6, tumor necrosis factor-α, and vascular cell adhesion molecule-1. LIPUS has potential to be a new adjuvant therapy method in clinic for ameliorating chemotherapy-induced myelosuppression.

Clinical Characteristics and Blood Test Results in COVID-19 Patients.

OBJECTIVE: An outbreak of pneumonia named COVID-19 caused by a novel coronavirus in Wuhan is rapidly spreading worldwide. The objective of the present study was to clarify further the clinical characteristics and blood parameters in COVID-19 patients. MATERIALS AND METHODS: Twenty-three suspected patients and 64 patients with laboratory-confirmed SARS-Cov-2 infection were admitted to a designated hospital. Epidemiological, clinical, laboratory, and treatment data were collected and analyzed. RESULTS: Of the 64 patients studied, 47 (73.4%) had been exposed to a confirmed source of COVID-19 transmission. On admission, the most common symptoms were fever (75%) and cough (76.6%). Twenty-eight (43.8%) COVID-19 patients showed leukopenia, 10 (15.6%) showed lymphopenia, 47 (73.4%) and 41 (64.1%) had elevated high-sensitivity C-reactive protein (hsCRP) and erythrocyte sedimentation rate (ESR), respectively, and 30 (46.9%) had increased fibrinogen concentration. After the treatment, the counts of white blood cells and platelets, and the level of prealbumin increased significantly, while aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and hsCRP decreased. COVID-19 patients with the hospital stay longer than 12 days had higher body mass index (BMI) and increased levels of AST, LDH, fibrinogen, hsCRP, and ESR. CONCLUSIONS: Results of blood tests have potential clinical value in COVID-19 patients.

Reduction in total leukocytes in malaria patients compared to febrile controls: A systematic review and meta-analysis.

BACKGROUND: Leukocyte alterations are a common hematological alteration among malaria patients. OBJECTIVES: This systematic review and meta-analysis aimed to provide data and evidence comparing alterations in total leukocyte counts in malaria patients compared to febrile/healthy subjects at baseline before treatment. A systematic review was conducted by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for reporting systematic reviews and meta-analyses. DATA SOURCES: Web of Science (ISI), Scopus, and Medline. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: All published articles reporting a total leukocyte count of patients infected with malaria, non-malaria (febrile or healthy group) at baseline before treatment before August 27, 2019, were retrieved, and data were extracted by two main reviewers independently. STUDY APPRAISAL AND SYNTHESIS METHODS: We used a forest plot, heterogeneity test (Cochran's Q), and the degree of heterogeneity (I2) to test whether the included studies were heterogeneous. The quality of the included studies was determined by a quality assessment guide based on the quality assessment tool developed by the Newcastle-Ottawa Scale (NOS). Cochran's Q (Chi-square) and Moran's I2 were used to evaluate heterogeneity. Meta-regression using STATA software was conducted to find the source of heterogeneity. A funnel plot with Egger's test was used to examine the significance of publication bias among the included studies. The mean differences were estimated using a random-effects model. RESULTS: Out of the 2,261 articles screened, 29 articles were included in this systematic review and meta-analysis. The heterogeneity test indicated that there was heterogeneity among the included studies with no publication bias. The meta-analysis demonstrated that the total leukocyte count was significantly lower in patients with malaria (n = 4,619) than in those without malaria (n = 10,056) (Z = 4.0, P-value < 0.00001, mean difference = -1.38, 95% CI = -2.06-(-0.71)). Leukocyte differential alterations, low lymphocyte counts (P-value <0.0001, mean difference = -1.03, 95% CI = -1.53-(-0.53)) and a high NL ratio were found in the malaria group (n = 1,579) compared to the non-malaria group (n = 4,991) (P-value <0.0001, mean difference = 0.6, 95% CI = 0.32-0.88). The subgroup analysis indicated that there was a significantly lower total leukocyte count in the malaria group (n = 3,545) than in the febrile group (n = 8,947) (Z = 1.33, P-value < 0.0001, mean difference = -1.76, 95% CI = -2.56-(-0.96)), but no significant difference was found between the malaria group (n = 1,232) and the healthy group (n = 1,679) (P-value > 0.05). LIMITATIONS: As the specific diagnoses in the febrile groups were not reported in the included studies so that the results of the present study need to be carefully interpreted. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: This systematic review demonstrated that the total leukocyte count was affected by malarial infection at baseline despite the heterogeneity of the included studies. Future work must aim to understand the treatment-related total leukocyte reduction during follow-up or post-treatment outcomes in malaria-endemic settings.

Value of leukocytosis and elevated C-reactive protein in predicting severe coronavirus 2019 (COVID-19): A systematic review and meta-analysis.

BACKGROUND: Since December 2019, coronavirus 2019 (COVID-19) has spread worldwide. Identifying poor prognostic factors is helpful for risk stratification. In this meta-analysis, we investigated the association between severe COVID-19 and a change in white blood cell (WBC) count, an elevation of C-reactive protein (CRP), and fever. Moreover, we aimed to evaluate the diagnostic accuracy of leukocytosis and an elevation of CRP. METHODS: We performed a systematic search of PubMed, EMBASE, Scopus, and the Cochrane Library through April 20th, 2020. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. A sensitivity analysis was conducted according to the study size (>200 or <200) and median age (>55 or <55). Meta-regression analyses were conducted to examine possible sources of heterogeneity. We calculated the diagnostic accuracy of leukocytosis and CRP. RESULTS: Eighteen studies with 3278 patients were selected. Fever, leukocytosis, and elevated CRP were associated with poor outcomes (OR (95% CI) 1.63 (1.06-2.51), 4.51 (2.53-8.04), and 11.97 (4.97-28.8), respectively). Leukopenia was associated with a better prognosis (OR 0.56, 95% CI 0.40-0.78). Sensitivity analyses showed similar tendencies. Meta-regression analysis for leukocytosis indicated that age, dyspnea, and hypertension contributed to heterogeneity. The pooled area under the leukocytosis and CRP curves were 0.70 (0.64-0.76) and 0.89 (0.80-0.99), respectively. CONCLUSION: In patients with COVID-19, fever, leukocytosis, and an elevated CRP were associated with severe outcomes. Leukocytosis and CRP on arrival may predict poor outcomes.

Adjustment of azathioprine dose should be based on a lower 6-TGN target level to avoid leucopenia in NUDT15 intermediate metabolisers.

BACKGROUND: The association between NUDT15 polymorphisms and thiopurine-induced leucopenia is well known. AIM: To investigate the association between NUDT15 polymorphisms and time-to-leucopenia in paediatric patients with inflammatory bowel disease (IBD) receiving azathioprine and to determine the relationship between NUDT15 polymorphisms and 6-thioguanine nucleotide (6-TGN) levels. METHODS: This retrospective observational study included Korean paediatric patients with IBD who were treated with azathioprine and underwent NUDT15 and TPMT genotyping. Azathioprine doses were adjusted by regular thiopurine metabolite monitoring. Factors associated with time-to-leucopenia and the relationship between NUDT15 polymorphisms and 6-TGN levels were analysed. RESULTS: Among the 167 patients included, leucopenia was observed in 16% (19/119), 44% (20/45) and 100% (3/3) of the NUDT15 normal, intermediate and poor metabolisers respectively (P < 0.001). NUDT15 polymorphism was significantly associated with time-to-leucopenia (HR = 5.26, 95% CI = 2.74-10.09, P < 0.001). There was a positive association between 6-TGN levels and leucopenia among the NUDT15 intermediate/TPMT normal metabolisers (median 361.3 vs 263.8 pmol/8 × 108 RBC, P = 0.013). The most accurate 6-TGN cut-off level associated with leucopenia was 308.2 pmol/8 × 108 RBC (AUC = 0.742, 95% CI = 0.569-0.915, sensitivity 80.0%, specificity 72.7%, P < 0.001) in this subgroup. When the specificity was set to <15%, the 6-TGN cut-off level was 167.1 pmol/8 × 108 RBC (sensitivity 93.3%, specificity 13.6%). CONCLUSIONS: NUDT15 polymorphisms were associated with time-to-leucopenia during azathioprine treatment in Korean paediatric patients with IBD. In order to reduce the development of thiopurine-induced leucopenia (<15%) in NUDT15 intermediate metabolisers, adjustment of azathioprine doses should be based on a lower 6-TGN target level (<167.1 pmol/8 × 108 RBC).

Clinical Presentation of COVID-19: A Systematic Review Focusing on Upper Airway Symptoms.

AIM: Pharyngodynia, nasal congestion, rhinorrhea, smell, and taste dysfunctions could be the presenting symptoms of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2. The aim was to perform a systematic review of current evidences on clinical presentation of COVID-19, focusing on upper airway symptoms in order to help otolaryngologists identifying suspected cases. METHODS: We searched PubMed and Web of Science electronic databases. RESULTS: We included 5 retrospective clinical studies for a total of 1556 hospitalized patients with COVID-19, 57.5% were male and mean age was 49.1 years. Pooled data revealed that pharyngodynia was present in 12.4% of patients, nasal congestion in 3.7%, and rhinorrhea was rare. No reports on COVID-19 and olfactory/gustative disorders matched inclusion criteria but preliminary evidences suggested they could be present. Common symptoms were fever (85.6%), cough (68.7%), and fatigue (39.4%). Frequent comorbidities were hypertension (17.4%), diabetes (3.8%), and coronary heart disease (3.8%); 83% of patients had alterations on chest computed tomography that were bilateral in 89.5% of cases. Ground-glass opacity was the most common finding (50%). Lymphopenia (77.2%) and leucopenia (30.1%) were common. Critical cases with complications were 9%, intensive care unit admission was required in 7.3%, invasive ventilation in 3.4%, and mortality was 2.4%. CONCLUSION: Otolaryngologists should know that pharyngodynia, nasal congestion, olfactory, and gustative disorders could be the presenting symptoms of COVID-19. Clinical presentation together with radiological and laboratory findings could help to identify suspected cases.

Leukocyte nadir as a predictive factor for efficacy of adjuvant chemotherapy in breast cancer. Results from the prospective trial SBG 2000-1.

Background: Retrospective studies have suggested that chemotherapy-induced leukopenia is associated with improved recurrence-free or overall survival. The SBG 2000-1 trial was designed to verify the favorable prognosis associated with chemotherapy-induced leukopenia in early breast cancer. Patients not experiencing chemotherapy-induced leukopenia were randomized into standard dosed or individually escalated chemotherapy doses based on the grade of leukopenia after a first standard dose.Patients and methods: 1452 women in Sweden and Denmark with operable node-positive or high-risk node-negative breast cancer aged 18-60 years were recruited to participate in this trial. Participants received a first FEC cycle at standard doses (600/60/600 mg/m2). Patients (n = 1052) with nadir leukopenia grade 0-2 after the first cycle were randomized between either 6 standard FEC or 6 tailored FEC courses with doses of epirubicin and cyclophosphamide escalated during courses 2 and 3 and thereafter aimed at achieving grade 3 leukopenia. Patients with nadir leukopenia grade 3-4 after the first course continued treatment with standard FEC. Results of the randomized comparison has been published previously. The present study focuses on chemotherapy-induced leukopenia as a covariable with outcome in randomized and non-randomized patients. The prognostic value of leukopenia after course 3, was studied in a Cox model adjusted for cumulative doses of epirubicin and cyclophosphamide. The association of chemotherapy-induced leukopenia with prognosis was a preplanned secondary endpoint for this trial.Results: The eight-year distant disease-free survival was 73%, 77%, 78% and 83% for patients with leucocyte nadir grade 0, 1, 2 and 3-4, respectively. Higher degree of leukopenia was highly significantly associated to improved distant disease-free survival (HR 0.84, 95% CI 0.74-0.96, p = .008) and overall survival (HR 0.87 (0.76-0.99, p = .032).Conclusion: This prospective study confirms that chemotherapy-induced leukopenia is a covariable with outcome in primary breast cancer, even after adjustment for chemotherapy doses.

Evaluation of the HemoCue WBC DIFF in leukopenic patient samples.

BACKGROUND: White blood cell (WBC) counts are used to monitor bone marrow function and to screen for infections. The HemoCue WBC DIFF Point-Of-Care (POC) instrument classifies WBCs through cell image recognition. To evaluate its suitability for monitoring cancer patients, we examined its performance in samples from patient with leukopenia and in samples containing nRBC. METHODS: Sysmex samples with WBCs 0.05-3.40 × 109 /L were examined on the HemoCue WBC DIFF, and the correlations between the instruments were assessed by Deming regression for total WBC, neutrophils, and lymphocytes. The theoretical CV% (CVt), calculated from number of cells counted by the HemoCue WBC DIFF, was used to determine the statistical error of the WBC counts. The interference of nRBC was also evaluated. RESULTS: The counting variation was primarily the source of statistical error in the lower counts with an imprecision between 3.8-9.2% for total WBC (0.56-2.29 ×109 /L), 8.7-14.3% for neutrophils (0.36-1.33 ×109 /L) and 9.8-15.1% for lymphocytes (0.35-0.89 ×109 /L). The correlation coefficient was between 0.658 and 0.986-poorest for lymphocytes. The total WBC count on the HemoCue WBC DIFF was significantly increased in nRBC samples due to lymphocyte count overestimation, and not by other WBCs. CONCLUSIONS: The HemoCue WBC DIFF provided reliable and accurate counts of total WBC, neutrophil, and lymphocyte in leukopenic samples. Until POC instruments that can perform an accurate complete blood count are available, the HemoCue WBC DIFF can be used to assist physicians in making decisions in situations of postchemotherapy leukopenia and neutropenia.