Coronavirus disease 2019 (COVID-19) related cytopenia: A protocol for systematic review and meta-analysis.

BACKGROUND: In December 2019, the novel coronavirus pneumonia was detected in Wuhan and named COVID-19. It is an international outbreak of the respiratory illness caused by severe acute respiratory syndrome coronavirus 2. Recent papers pointed out the cytopenia in COVID-19 patients including lymphopenia, neutrophilia, thrombocytopenia and lower level of hemoglobin had prognostic significance. This systemic review and meta-analysis summaries the latest evidence from available data and determine the hematological abnormality caused by severe acute respiratory syndrome coronavirus 2 and potential efficacy on the outcomes in patients with COVID-19. METHODS: This protocol for a systematic reviews and meta-analysis will be performed according to the preferred reporting items for systematic reviews and meta-analysis protocols 2015 guidelines. The database of Cochrane Library, PUBMED, EMBASE, Medline, Web of Science, Google Scholar, CNKI, WanFang, as well as gray literatures from the inception to present will be comprehensively and systematically searched without limitations of regions or language. The main study outcomes will be the mortality of COVID-19 patients. The meta-analysis was performed by RevMan V.5.3 program and Stata V.12.0 software after 2 reviewers independently selected literature, data extraction, bias risk evaluation and study quality assessment. Any disagreement will be resolved by consensus to the third researcher. RESULTS: This systematic review and meta-analysis may help provide clarify on the effect of cytopenia in patients with COVID-19. The result will be published at a peer-reviewed journal. CONCLUSIONS: This proposed study will evaluate the existing evidence on the effectiveness of cytopenia in COVID-19 patients. ETHIC AND DISSEMINATION: The content of this article does not involve moral approval or ethical review because no individual data will be collected. PROSPERO REGISTRATION: CRD42020187524.

Regulatory mechanisms of B cell responses and the implication in B cell-related diseases.

Terminally differentiated B cell, the plasma cell, is the sole cell type capable of producing antibodies in our body. Over the past 30 years, the identification of many key molecules controlling B cell activation and differentiation has elucidated the molecular pathways for generating antibody-producing plasma cells. Several types of regulation modulating the functions of the important key molecules in B cell activation and differentiation add other layers of complexity in shaping B cell responses following antigen exposure in the absence or presence of T cell help. Further understanding of the mechanisms contributing to the proper activation and differentiation of B cells into antibody-secreting plasma cells may enable us to develop new strategies for managing antibody humoral responses during health and disease. Herein, we reviewed the effect of different types of regulation, including transcriptional regulation, post-transcriptional regulation and epigenetic regulation, on B cell activation, and on mounting memory B cell and antibody responses. We also discussed the link between the dysregulation of the abovementioned regulatory mechanisms and B cell-related disorders.

Decreased soluble RAGE in neutrophilic asthma is correlated with disease severity and RAGE G82S variants.

The advanced glycosylation end product-specific receptor (RAGE) has been demonstrated to be an important mediator of asthma pathogenesis. The soluble isoform of RAGE (sRAGE) acts as a 'decoy' to sequester RAGE ligands, and thus prevents their binding to the receptor. A number of reports have linked deficiency of sRAGE to the severity and outcomes of various human diseases, and association with RAGE G82S variants. However, whether sRAGE levels are increased or decreased in asthmatic patients is unclear. The aim of the present study was to determine plasma sRAGE levels in different asthma phenotypes and associations of plasma sRAGE levels with RAGE G82S variants. A total of 85 neutrophilic and 109 non­neutrophilic newly diagnosed asthmatic patients, and 118 healthy controls, were recruited. Plasma sRAGE levels were measured by ELISA analysis. RAGE G82S genotypes were detected using the Sanger sequencing method. Plasma sRAGE levels were decreased in neutrophilic asthmatics (443.67±208.9 pg/ml) and increased in non­neutrophilic asthmatics (677.63±300.75 pg/ml) compared with healthy controls (550.02±300.83 pg/ml) (P<0.001). Plasma sRAGE levels were positively correlated with FEV1% predicted (FEV1% Pre) (rp=0.258; P=0.023) in neutrophilic asthmatics. The frequency of G82S genotypes was significantly different between neutrophilic and non­neutrophilic asthmatics (P=0.009). Neutrophilic asthmatics with genotypes A/G or A/A (389.83±150.37 and 264.59±161.74 pg/ml, respectively) had significantly decreased sRAGE levels compared with the G/G genotype (498.64±235.37 pg/ml) (P=0.022). Those with the A/G and A/A genotype (60.14±22.36%) displayed a trend toward lower FEV1% Pre compared with those with the G/G genotype (64.51±27.37%). No significant difference in sRAGE levels or an association with FEV1% Pre was observed between the different genotypes in non­neutrophilic asthmatics. In conclusion, the results of the present study indicated that plasma sRAGE levels are altered in different asthma inflammatory phenotypes. Plasma sRAGE may be a biomarker of asthma severity and may be associated with G82S gene variants in neutrophilic asthmatics.

The Significance of Pretreatment Thrombocytosis and Its Association With Neutrophilia in Patients With Surgically Treated Endometrial Cancer.

OBJECTIVE: The aim of this study was to investigate the prognostic significance of a pretreatment thrombocytosis and its association with neutrophilia in patients with surgically treated endometrial cancer. METHODS: The baseline characteristics and outcome data of 508 patients with surgically treated endometrial cancer between January 2000 and December 2010 were collected and retrospectively reviewed. The patients were separated into 4 groups according to their platelet counts and the neutrophil counts, and the progression-free and overall survival rates of the 4 groups were compared. A Cox proportional hazards regression model was used to explore the independent prognostic factors. RESULTS: Pretreatment thrombocytosis was found to be associated with advanced stage (P = 0.0186), nonendometrioid histology (P = 0.0139), a deeper myometrial invasion (P = 0.0103), lymphovascular space involvement (P = 0.0404), cervical involvement (P = 0.004), positive peritoneal cytology (P = 0.0198), lymph node metastasis (P = 0.0301), and more frequent treatment failure (P = 0.0006). Multivariate analysis demonstrated that an older age (hazard ratio [HR], 2.54; 95% confidence interval [CI], 1.46-4.51; P = 0.0009), advanced clinical stage (HR, 5.27; 95% CI, 2.94-9.86; P < 0.0001), lymphovascular space involvement (HR, 3.37; 95% CI, 1.74-7.07; P = 0.0002), and pretreatment thrombocytosis (HR, 4.99; 95% CI, 2.47-9.39; P < 0.0001) were significant predictors of survival. When examined according to clinical stage, pretreatment thrombocytosis was prognostically significant only in patients with stage III-IV disease. The neutrophil count in patients who display thrombocytosis was significantly greater than that observed in patients without thrombocytosis (median, 6702 vs 4406/µL; P < 0.0001). Moreover, patients who displayed both thrombocytosis and neutrophilia had significantly shorter survival than that in those with either thrombocytosis or neutrophilia alone. CONCLUSIONS: Presence of thrombocytosis at the time of the initial diagnosis is an independent predictor of shorter survival in patients with advanced-stage (stages III-IV) endometrial cancer. Moreover, pretreatment thrombocytosis and concurrent neutrophilia are an independent predictor of shorter survival regardless of clinical stage.

The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation.

Neutrophils are the first line of cellular defense in response to infections and inflammatory injuries. However, neutrophil activation and accumulation into tissues trigger tissue damage due to release of a plethora of toxic oxidants and proteases, a cause of acute lung injury (ALI). Despite its clinical importance, the molecular regulation of neutrophil migration is poorly understood. The small GTPase Rap1b is generally viewed as a positive regulator of immune cell functions by controlling bidirectional integrin signaling. However, we found that Rap1b-deficient mice exhibited enhanced neutrophil recruitment to inflamed lungs and enhanced susceptibility to endotoxin shock. Unexpectedly, Rap1b deficiency promoted the transcellular route of diapedesis through endothelial cell. Increased transcellular migration of Rap1b-deficient neutrophils in vitro was selectively mediated by enhanced PI3K-Akt activation and invadopodia-like protrusions. Akt inhibition in vivo suppressed excessive Rap1b-deficient neutrophil migration and associated endotoxin shock. The inhibitory action of Rap1b on PI3K signaling may be mediated by activation of phosphatase SHP-1. Thus, this study reveals an unexpected role for Rap1b as a key suppressor of neutrophil migration and lung inflammation.

Age-related differences in the neutrophil response to pulmonary pseudomonas infection.

BACKGROUND: Pseudomonas aeruginosa pneumonia is more common and more lethal in the elderly. The immunologic underpinnings of this increased incidence and mortality have not been evaluated, however are assumed to be a complication of age-associated immune dysfunction. METHODS: Young (10-12week old) and aged (18-20month old) BALB/c mice were subjected to intratracheal infection of P. aeruginosa. Animals were sacrificed 24h after inoculation. The lungs were collected for analysis of lung pathology, chemokine levels, neutrophil counts, and myeloperoxidase activity. RESULTS: Pulmonary levels of the neutrophil chemokine KC are significantly higher in aged mice relative to young following P. aeruginosa infection. Despite this, neutrophil counts are higher in young mice compared to aged mice after infection. Furthermore, the neutrophils are predominantly found in the air space of young infected mice. This correlated with increased myeloperoxidase activity from bronchoalveolar lavage specimens of young mice relative to aged mice after infection. CONCLUSIONS: Neutrophil migration into the lungs is impaired in aged mice 24h after intratracheal infection despite elevated chemokine levels, suggesting that immunosenescence is impairing neutrophil migration.

Intraluminal crawling versus interstitial neutrophil migration during inflammation.

Site-directed trafficking of polymorphonuclear neutrophils (PMN) to their target regions within the tissue is an important prerequisite for efficient host defense during the acute inflammatory response. This process requires intraluminal crawling of PMN on the activated endothelial cells to their extravasation sites. Upon transendothelial diapedesis, PMN migrate in the interstitial tissue to sites of inflammation. These crucial steps within the recruitment cascade are defined as intraluminal crawling and interstitial migration. In this review, we will focus on the molecular mechanisms that control and fine-tune these migratory processes and discuss the role of adhesion molecules of the ß2 integrin (CD11/CD18) family for these cellular functions.

Disorders of neutrophil function: an overview.

Primary disorders of neutrophil function result from impairment in neutrophil responses that are critical for host defense. This chapter summarizes inherited disorders of neutrophils that cause defects in neutrophil adhesion, migration, and oxidative killing. These include leukocyte adhesion deficiencies, actin defects, and other disorders of chemotaxis; hyperimmunoglobulin E syndrome; Chédiak-Higashi syndrome; neutrophil specific granule deficiency; chronic granulomatous disease; and myeloperoxidase deficiency. Diagnostic tests and treatment approaches are also summarized for each neutrophil disorder.

Diagnostic assays for chronic granulomatous disease and other neutrophil disorders.

Inasmuch as neutrophils are the primary cellular defense against bacterial and fungal infections, disorders that affect these white cells typically predispose individuals to severe and recurrent infections. Therefore, diagnosis of such disorders is an important first step in directing long-term treatment/care for the patient. Herein, we describe methods to identify chronic granulomatous disease (CGD), leukocyte adhesion deficiency (LAD), and neutropenia. The assays are relatively simple to perform, cost-effective, and can be performed with equipment available in most laboratories.

Erythromelalgia: a case report and literature review.

OBJECTIVE: Erythromelalgia is a rare condition, of uncertain etiology, characterized by episodic erythema, intense burning pain and warmth of the hands and/or feet, and when chronic, associated with significant disability. The diagnosis is based on a thorough history and physical exam during a painful episode along with diagnostic testing to exclude other causes. This paper describes the unique syndrome of erythromelalgia through a case report and literature review. DESIGN: Case presentation and literature review. PATIENTS: A 44-year-old male with erythromelalgia. CONCLUSIONS: Despite multiple treatment options, erythromelalgia is a challenging disease to effectively manage. Early recognition and treatment may offer patients the best probability of achieving remission or significant improvement.

Infections in patients with inherited defects in phagocytic function.

Patients with defects in phagocytic function are predisposed to intracellular microorganisms and typically have early dissemination of the infection. Recognition of the underlying disorder and aggressive antimicrobial therapy has been beneficial for the patients. Improved understanding of the pathophysiology has also affected patient management by allowing specific, targeted immunomodulatory intervention. The disorders described in this review are not common but have had a significant impact on our understanding of the role of phagocytic cells in host defense. Conversely, understanding the role of the neutrophil and macrophage in infection has benefited not just the patients described in this review but also other patients with similar disease processes.

A practical approach to neutrophil disorders.

This review discusses disorders of altered neutrophil number and function and provide a basic framework for patient evaluation and management. The sections begin with neutropenia, neutrophilia and neutrophil dysfunction with a general screening approach to differentiate common, more benign syndromes from rare, often more serious disorders. Also included is a detailed discussion of some specific primary neutrophil syndromes at the end of each section. Focus is placed on specific disorders that are clinically common or particularly instructive.

Long-term follow-up of periodontitis in a patient with Chédiak-Higashi syndrome. A case report.

Chediak-Higashi syndrome (CHS) is an extremely rare hereditary disease characterized by leukocyte dysfunction. We report on a 21-year-old woman who presented at the age 9 years with CHS and serious periodontal tissue destruction around erupted teeth. The patient had received systemic, radiographic, immunological, microbial, and clinical periodontal examinations since childhood. The chemotactic activity of neutrophils in the Boyden chamber assay was 22% of the control, and leukocyte bactericidal activity was one-third of the control. Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, and Prevotella intermedia were isolated from periodontal pockets. Periodontal treatment including oral hygiene was provided, followed by professional tooth cleaning from the age of 12 to 21 years. However, the mobility of teeth and the inflammation of periodontal tissue progressed. This CHS patient presented with periodontal disease of extremely early onset, which was resistant to periodontal treatment.

Monocyte dysfunction in patients with multiple myeloma and lymphoplasmacytic disorders is related to serum paraprotein levels.

We have investigated monocyte function in 30 patients with lymphoplasmacytic disorders and in 21 age and sex matched normal controls. Marked abnormalities of all facets of monocyte function were demonstrated in six patients with multiple myeloma (MM) and a single patient with Waldenström's macroglobulinaemia (WM) plus significant paraproteinaemia. Serious infection occurred in three of these patients. An inverse relationship between the level of the serum paraprotein and impairment of monocyte phagocytosis plus killing of Candida albicans was observed. Crossover studies suggested that these abnormal findings were constitutive and not reversed by removal of the serum paraprotein. The data suggest that monocyte function is constitutively abnormal in patients with MM and can be further, but reversibly, inhibited by high paraprotein levels. Further research is required to confirm these findings, ascertain whether monocyte function can be normalized using chemotherapy or growth factors, and if so, whether their tumouricidal functions could be harnessed in the treatment of this currently incurable condition.