Differential Diagnosis of COVID-19: Importance of Measuring Blood Lymphocytes, Serum Electrolytes, and Olfactory and Taste Functions.

Coronavirus disease 2019 (COVID-19) is associated with various symptoms and changes in hematological and biochemical variables. However, clinical features, which can differentiate COVID-19 from non-COVID-19, are not clear. We therefore examined the key clinical features of COVID-19 and non-COVID-19 patients. This study included 60 COVID-19 patients and 100 non-COVID-19 patients, diagnosed by PCR, and no significant differences in the age and sex were seen between the two groups. The frequencies of fatigue, loose stool, diarrhea, nasal obstruction, olfactory dysfunction, taste dysfunction, underlying hyperlipidemia, and the prescription of angiotensin II receptor blocker (ARB) were significantly higher in COVID-19 patients than those in non-COVID-19 patients. The counts of leucocytes, neutrophils, lymphocytes, eosinophils, monocytes, and basophils and the levels of chloride and calcium in blood of COVID-19 patients were significantly lower than those of non-COVID-19 patients. The frequencies of atypical lymphocytes and the levels of lactate dehydrogenase (LDH) and potassium were significantly higher in COVID-19 than those in non-COVID-19. The C-reactive protein (CRP) level in COVID-19 patients was significantly lower than that in non-COVID-19 patients, when we compared CRP levels among patients with elevated CRP. This study is the first to indicate that electrolyte levels and the frequency of atypical lymphocytes in COVID-19 are significantly different from those in non-COVID-19. Fatigue, loose stool, diarrhea, nasal obstruction, olfactory dysfunction, and taste dysfunction were the key symptoms of COVID-19. Furthermore, hyperlipidemia and ARB may be risk factors of COVID-19. In conclusion, leucocytes, leucocyte fractions, CRP, LDH, and electrolytes are useful indicators for COVID-19 diagnosis.

Transient Appearance of Plasmablasts in the Peripheral Blood of Japanese Patients With Severe Fever With Thrombocytopenia Syndrome.

Atypical lymphocytes in the peripheral blood in patients with severe fever with thrombocytopenia syndrome (SFTS) have not been well examined. In this study, we analyzed counts and characteristics of atypical lymphocytes in 7 patients with SFTS. Atypical lymphocytes resembled plasma cells morphologically and appeared in the peripheral blood of all patients 4-8 days after onset of disease. Among these lymphocytes flow cytometry showed a CD19+CD38+CD138-/+ phenotype, and immunohistochemical staining revealed a CD79a+CD38+CD138-/+CD27+ phenotype. From our observations, atypical lymphocytes transiently that appeared in the peripheral blood during the acute phase of SFTS were considered to be plasmablasts.

CD 4+, CD 8+ and CD 19+cell surface antigen and abnormal mitochondria ultrastructure of peripheral blood P-type atypical lymphocytes in patients with schizophrenia.

OBJECTIVE: P-type atypical lymphocytes may play important roles in the aetiology and therapy of schizophrenia. However, there is merely a direct immunological characterisation of it. The aim of this study is to explore the surface antigens of these cells and their comparative ultrastructure in schizophrenia. METHODS: We recruited 25 age-and gender-matched patients with unmedicated schizophrenia, other mental diseases and healthy individuals. Peripheral venous blood was smeared and stained. CD4+, CD8+ and CD19+ cell surface antigen- positive lymphocytes were purified using magnetic beads and prepared for light microscopy and electron microscopy. RESULTS: The percentages of P-type atypical lymphocytes (34.53% ± 9.92%) were significantly higher (p < 0.0001) in schizophrenia than that of other mental diseases (9.79% ± 3.45%). These cells could present CD4+, CD8+ and CD19+ surface antigens. Their relative ultrastructure differed from that of normal lymphocytes, especially in mitochondria, which showed abundant, aggregated and quite irregular mitochondria; for example, slight dilation of the foci, swelling, degeneration, and even cavity. CONCLUSIONS: P-type atypical lymphocytes could be found among CD4+, CD8+, and CD19 + lymphocytes with schizophrenia. Their abnormal ultrastructure of mitochondria implied that energy metabolism might play an important role in the aetiology of schizophrenia.

Tuberculosis-induced aplastic crisis and atypical lymphocyte expansion in advanced myelodysplastic syndrome: A case report and review of literature.

BACKGROUND: Myelodysplastic syndrome (MDS) is caused by malignant proliferation and ineffective hematopoiesis. Oncogenic somatic mutations and increased apoptosis, necroptosis and pyroptosis lead to the accumulation of earlier hematopoietic progenitors and impaired productivity of mature blood cells. An increased percentage of myeloblasts and the presence of unfavorable somatic mutations are signs of leukemic hematopoiesis and indicators of entrance into an advanced stage. Bone marrow cellularity and myeloblasts usually increase with disease progression. However, aplastic crisis occasionally occurs in advanced MDS. CASE SUMMARY: A 72-year-old male patient was definitively diagnosed with MDS with excess blasts-1 (MDS-EB-1) based on an increase in the percentages of myeloblasts and cluster of differentiation (CD)34+ hematopoietic progenitors and the identification of myeloid neoplasm-associated somatic mutations in bone marrow samples. The patient was treated with hypomethylation therapy and was able to maintain a steady disease state for 2 years. In the treatment process, the advanced MDS patient experienced an episode of progressive pancytopenia and bone marrow aplasia. During the aplastic crisis, the bone marrow was infiltrated with sparsely distributed atypical lymphocytes. Surprisingly, the leukemic cells disappeared. Immunological analysis revealed that the atypical lymphocytes expressed a high frequency of CD3, CD5, CD8, CD16, CD56 and CD57, suggesting the activation of autoimmune cytotoxic T-lymphocytes and natural killer (NK)/NKT cells that suppressed both normal and leukemic hematopoiesis. Elevated serum levels of inflammatory cytokines, including interleukin (IL)-6, interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), confirmed the deranged type I immune responses. This morphological and immunological signature led to the diagnosis of severe aplastic anemia secondary to large granule lymphocyte leukemia. Disseminated tuberculosis was suspected upon radiological examinations in the search for an inflammatory niche. Antituberculosis treatment led to reversion of the aplastic crisis, disappearance of the atypical lymphocytes, increased marrow cellularity and 2 mo of hematological remission, providing strong evidence that disseminated tuberculosis was responsible for the development of the aplastic crisis, the regression of leukemic cells and the activation of CD56+ atypical lymphocytes. Reinstitution of hypomethylation therapy in the following 19 mo allowed the patient to maintain a steady disease state. However, the patient transformed the disease phenotype into acute myeloid leukemia and eventually died of disease progression and an overwhelming infectious episode. CONCLUSION: Disseminated tuberculosis can induce CD56+ lymphocyte infiltration in the bone marrow and in turn suppress both normal and leukemic hematopoiesis, resulting in the development of aplastic crisis and leukemic cell regression.

Development of infectious mononucleosis as an unusual manifestation of COVID-19.

It has generally been reported that patients with COVID-19 show a fever, cough, and/or respiratory failure as the most common clinical symptoms but some have unusual symptoms, such as anosmia, diarrhea, and throat pain. We herein report a 26-year-old woman with chief complaints of lymphadenopathy and a fever. First, she underwent a laboratory examination, which showed a high proportion of atypical lymphocytes (19%) and an increase in hepatic enzyme activities, and was then hospitalized with a diagnosis of infectious mononucleosis (IM). However, the blood examination did not show any increase in anti-Epstein-Barr virus VCM-IgM. Subsequently, she developed tonsillar hypertrophy with purulent plugs. An additional examination for infection of other pathogens revealed positivity only for SARS-CoV-2 in a loop-mediated isothermal amplification (LAMP) test. The patient was transferred to the COVID-19-specific isolation ward, and none of the ward staff, patients, or either of the two otolaryngologists who had directly examined this patient showed positive signs for SARS-CoV-2 in a LAMP test. Consequently, this case suggests that even if patients show clinical symptoms and signs of common diseases for otolaryngologists, such as IM, we should keep in mind the possibility of COVID-19 without arbitrarily assuming that IM is caused by Epstein-Barr virus.

Comprehensive evaluation of bronchoalveolar lavage from patients with severe COVID-19 and correlation with clinical outcomes.

Information on bronchoalveolar lavage (BAL) in patients with COVID-19 is limited, and clinical correlation has not been reported. This study investigated the key features of BAL fluids from COVID-19 patients and assessed their clinical significance. A total of 320 BAL samples from 83 COVID-19 patients and 70 non-COVID-19 patients (27 patients with other respiratory viral infections) were evaluated, including cell count/differential, morphology, flow cytometric immunophenotyping, and immunohistochemistry. The findings were correlated with clinical outcomes. Compared to non-COVID-19 patients, BAL from COVID-19 patients was characterized by significant lymphocytosis (p < 0.001), in contrast to peripheral blood lymphopenia commonly observed in COVID-19 patients and the presence of atypical lymphocytes with plasmacytoid/plasmablastic features (p < 0.001). Flow cytometry and immunohistochemistry demonstrated that BAL lymphocytes, including plasmacytoid and plasmablastic cells, were composed predominantly of T cells with a mixture of CD4+ and CD8+ cells. Both populations had increased expression of T-cell activation markers, suggesting important roles of helper and cytotoxic T-cells in the immune response to SARS-CoV-2 infection in the lung. More importantly, BAL lymphocytosis was significantly associated with longer hospital stay (p < 0.05) and longer requirement for mechanical ventilation (p < 0.05), whereas the median atypical (activated) lymphocyte count was associated with shorter hospital stay (p < 0.05), shorter time on mechanical ventilation (p < 0.05) and improved survival. Our results indicate that BAL cellular analysis and morphologic findings provide additional important information for diagnostic and prognostic work-up, and potential new therapeutic strategies for patients with severe COVID-19.

Severe Thrombocytopenia in a Case of Epstein-Barr Virus-Induced Infectious Mononucleosis.

Epstein-Barr virus (EBV) infections have variable presentations ranging from asymptomatic to the triad of fever, pharyngitis, and adenopathy in infectious mononucleosis. Although haematological abnormalities are commonly seen in EBV infections, severe EBV-associated thrombocytopenia is a rare presentation, complicating clinical diagnosis and requiring appropriate management. Here we describe a case of a 14-year-old female with severe thrombocytopenia (platelet count of 5 x109/L) and spontaneous haemorrhage, accompanied by periorbital oedema, an uncommon symptom in EBV-associated infectious mononucleosis. She was treated with intravenous immunoglobulins and a four-day course of methylprednisolone. Treatment resulted in progressive platelet count recovery, and the patient was discharged seven days post-admission with a platelet count of 143 x109/L. The case highlights the need to consider EBV infection as a differential diagnosis in patients presenting with acute severe thrombocytopenia.

Smoldering adult T-cell leukemia complicated with pneumocystis pneumonia: A case report.

Adult T-cell leukemia (ATL) is a tumor of CD4-positive T cells that accompanies an infection by human T-cell lymphotropic virus (HTLV-I). ATL is classified into four types-acute, lymphomatous, chronic, and smoldering. Opportunistic infections are known to occur in patients with acute or lymphomatous type ATL; however, whether patients with chronic or smoldering ATL also have a high risk of opportunistic infections is not yet known. Herein, we report a case of pneumocystis pneumonia in a patient with smoldering ATL. He was a 64-year-old man with primary complaints of cough and dyspnea on exertion. A chest radiograph showed infiltration shadows in the left lung field. He was prescribed antibiotics for pneumonia; however, his symptoms worsened, and he developed hypoxemia. White-blood cell count was 13000/µL, and 7% of atypical lymphocytes were found in the smears of peripheral blood cells. His serum ß-D glucan concentration was increased to 85.9 pg/mL, and his serum tested positive for anti-HTLV-1 antibody. Chest-computed tomography revealed diffuse ground-glass opacities in the bilateral lung fields. Pneumocystis-polymerase chain reaction performed on bronchoalveolar lavage fluid confirmed pneumocystis, but atypical lymphocytes were not detected via transbronchial lung biopsy. Therefore, he was diagnosed with pneumocystis pneumonia associated with smoldering ATL. Sulfamethoxazole-trimethoprim and corticosteroid therapies were administered to treat the pneumocystis pneumonia, and his symptoms and lung shadows improved rapidly. Thus, opportunistic infections, including pneumocystis pneumonia, may be caused by smoldering ATL. In the case of atypical lymphocyte detection in peripheral-blood smears, clinicians should consider the possibility of ATL.

The atypical lymphocyte count: a novel predictive factor for severe thrombocytopenia related to dengue.

BACKGROUND: Early identification of patients at risk of severe dengue disease (DD) is critical to guide its management. We evaluated whether the atypical lymphocyte count (ALC), generated from the Sysmex automated full blood count analyzer, is predictive of severe thrombocytopenia secondary to Dengue infection. METHODS: We prospectively collected data on patients admitted with DD between December 2017 and October 2018. ALC data were extracted from the Sysmex XS500i analyzer from day 1 to day 7 of admission. Clinical data were obtained from patients' medical records. RESULTS: We enrolled 256 patients with DD. A negative correlation between ALC on admission and platelet count on day 5 to day 7 (Spearmen's correlation; day 5:-0.485, day 6:-0.428 and day 7:-0.344) (p=0.001) was observed. Based on receiver operator characteristic curve analysis, we found that an ALC of >0.5x103/L had 90% sensitivity and 70% specificity for severe thrombocytopenia (platelet count <50x109/L) on day 5. The positive and negative predictive values were 74.4 and 91.2%, respectively (power 84.7). CONCLUSIONS: We propose that ALC on admission may be a novel negative predictive factor for severe thrombocytopenia on day 5 to day 7 of DD. Further studies are required to validate our findings and evaluate whether ALC is predictive of other complications of DD.

Combined hematologic parameters to optimize review criteria on XE-5000.

INTRODUCTION: Forty-one consensus review rules are presented to a large number of hematology laboratories worldwide, as suggested by the International Consensus Group for Hematology Review. Research on the review criteria has mainly focused on adjusting the threshold of each parameter to establish optimized criteria with better efficiency based on the consensus group criteria. This study aimed to optimize the review criteria by combining hematologic parameters on a Sysmex XE-5000 hematology analyzer (XE-5000). MATERIAL AND METHODS: A total of 662 nucleated red blood cell (NRBC) and 406 atypical lymphocyte cell (AL) flagged samples were used to establish hematologic parameters associated with NRBC and AL, respectively. Another set of 1423 optimization samples were used to validate the optimized criteria of NRBC and AL by combining associative hematologic parameters. The efficiency of each set of criteria was compared and optimized to obtain better efficiency, an acceptable slide review rate, and a low false-negative rate. RESULTS: In the optimization NRBC set combining triple parameters, compared with the default setting (P < .001), the slide review rate declined from 30.26% to 14.42%, and the efficiency increased from 75.65% to 91.02%. In the optimization AL set combining triple parameters, compared with the default setting (P < .001), the slide review rate declined from 40.60% to 11.80%, and the efficiency increased from 64.02% to 93.00%. CONCLUSIONS: Based on the adjustment of Q-flag values combining associative hematologic parameters, the optimal criteria with a low false-negative rate not only might have a higher efficiency but also may significantly reduce the slide review rate.

Comparison of abnormal cell flagging of the hematology analyzers Sysmex XN and Sysmex XE-5000 in oncohematologic patients.

INTRODUCTION: Hematology analyzers should optimize flagging while minimizing false-negative results and unnecessary microscopic reviews. METHODS: We compared flagging performance of Sysmex XE-5000 and XN analyzers in oncohematologic patients. Differential counts were performed by Cellavision digital system (100 cells) and a hematologist (another 100 cells). RESULTS: First, we included 292 samples (86 with blasts): 28 acute lymphoblastic leukemia, 88 acute myeloid leukemia, 91 myelodysplastic syndromes, 45 chronic myeloproliferative neoplasms, and 40 chronic myelomonocytic leukemia. Sensitivity, specificity and efficiency to detect blasts were 59.3%, 88.3%, and 79.8% for XE-5000 analyzer and 70.9%, 91.3%, and 85.2% for the XN analyzer. Then, we included 111 lymphoid malignancies. In 55 CLL XE-5000 flagged for Abn Lympho/L_Blasts?, XN flagged for Abn Lympho?. In one-third of 19 samples with splenic marginal lymphoma, none of the analyzers flagged. In 5 Sézary syndrome cases, XE-5000 triggered the Abn Lympho/L_Blasts? flag while the flagging in XN was less consistent: Abn Lympho? Blasts? and Atypical Lympho?. In 5 hairy cell leukemias, both analyzers only flagged one sample. In 13 myelomas, XE-5000 generated Atypical Lympho? flag; XN triggered more variable flags. In other lymphoid malignancies, flags were variable. XN analyzer generates less samples with false basophilia. CONCLUSION: XN analyzer has improved blast detection in oncohematologic patients. Operators cannot rely on the blast flag alone but have to consider other flags and hemogram data. In lymphoproliferative disorders, XN analyzer yields less samples with pseudobasophilia. Both analyzers must improve flagging for hairy cell leukemia.

Analysis of atypical lymphocyte and basophilic granulocyte warning information indicated by Sysmex XE-5000 blood cell analyzer / 国际检验医学杂志

Objective To evaluate the performance of the Sysmex XE-5000 analyzer for analyzing atypical lymphocytes ,baso-philic granulocytes and their abnormalities warnings .Methods A total of 197 specimens with both atypical lymphocytes and baso-philic granulocytes warnings and 914 specimens with single warning of atypical lymphocytes indicated by Sysmex-5000 blood cell analyzer were collected and inspected by microscope simultaneously .Results Using microscopic examination as a standard ,baso-philic granulocytes within the normal range ,the coincidence rate of samples with both atypical lymphocytes and basophilic granulo-cytes warnings was 64 .9% ,while the coincidence rate of samples with single warning of atypical lymphocytes was 72 .5% .The for-mer was significantly lower than the latter(P<0 .05) .Conclusion When Sysmex XE-5000 indicates atypical lymphocytes and baso-philic granulocytes simultaneously ,there is interference between each other .It should be combined with microscopic examination in order to reduce the probability of missed diagnosis and misdiagnosis .

A Case of Atypical CD30+ Lymphocytic Hyperplasia Following Tick Bite / 대한피부과학회지

Since the discovery of the CD30 molecule, its expression has been considered a reliable marker for CD30+ lymphomas, including lymphomatoid papulosis, primary cutaneous anaplastic large cell lymphoma and borderline cases. However, CD30+ cells can be observed in Hodgkin's lymphoma, as well as in T-cell and B-cell lymphomas or NK cell lymphomas. Furthermore, it can also be found in reactive inflammatory disorders or in non-lymphoid neoplasms. It is very important to differentiate between lymphomas and reactive inflammatory disorders using a combination of clinical, histological, phenotypic and molecular analyses. We report a case of atypical CD30+ lymphocytic hyperplasia in a 57-year-old man following tick bite.

Appearance Characteristics of the Atypical Lymphocytes in the Blood of the Plasmodium vivax Malarial Patients / 대한혈액학회지

BACKGROUND: Malaria has been new epidemic in Korea since 1993 and most of them have been Plasmodium vivax. Although there were some reports about appearance of atypical lymphocytes in malaria, there was no analytical report about their characteristics. We tried to make a useful reference via statistical analysis of the Korean malaria patients. METHODS: Forty-nine malarial patients and 197 healthy controls were prepared. The atypical lymphocytes were counted via complete blood count (CBC) and microscopic examination of blood smears. Blood concentration and growing-stage differential count of the parasites were measured. Mean differences and correlation between two groups about CBC, and prevalence and mean differences between them about the atypical lymphocytes were analyzed. Correlation between parasitemia and atypical lymphocytes, and correlation between developmental stage of malaria and atypical lymphocytes were analyzed, too. RESULTS: There were differences between the patients and the controls in almost all CBC items except MCH and MCHC. Atypical lymphocytes were appeared in all the malarial cases and only 11.7% of controls. Correlation between RBC and hemoglobin, and atypical lymphocytes showed positive correlation in the cases, and platelet count did negative correlation. Thrombocytopenia or anemia was found in 48 cases (98%). Atypical lymphocytes were more frequently observed in thrombocytopenia or anemia-free cases. There were no correlation between parasitemia, developmental stage of malaria and atypical lymphocytes. CONCLUSION: Atypical lymphocytes were found in all cases. The count of atypical lymphocytes in blood was correlated negatively with hemoglobin and positively with platelet count, but there were no correlation between parasitemia, developmental stage of malaria and atypical lymphocytes.