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The Journal of Clinical Investigation Oct 2023BACKGROUNDWarts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUNDWarts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function CXCR4 mutations. Myelokathexis is a kind of neutropenia caused by neutrophil retention in bone marrow and in WHIM syndrome is associated with lymphopenia and monocytopenia. The CXCR4 antagonist plerixafor mobilizes leukocytes to the blood; however, its safety and efficacy in WHIM syndrome are undefined.METHODSIn this investigator-initiated, single-center, quadruple-masked phase III crossover trial, we compared the total infection severity score (TISS) as the primary endpoint in an intent-to-treat manner in 19 patients with WHIM who each received 12 months treatment with plerixafor and 12 months treatment with granulocyte CSF (G-CSF, the standard of care for severe congenital neutropenia). The treatment order was randomized for each patient.RESULTSPlerixafor was nonsuperior to G-CSF for TISS (P = 0.54). In exploratory endpoints, plerixafor was noninferior to G-CSF for maintaining neutrophil counts of more than 500 cells/μL (P = 0.023) and was superior to G-CSF for maintaining lymphocyte counts above 1,000 cells/μL (P < 0.0001). Complete regression of a subset of large wart areas occurred on plerixafor in 5 of 7 patients with major wart burdens at baseline. Transient rash occurred on plerixafor, and bone pain was more common on G-CSF. There were no significant differences in drug preference or quality of life or the incidence of drug failure or serious adverse events.CONCLUSIONPlerixafor was not superior to G-CSF in patients with WHIM for TISS, the primary endpoint. Together with wart regression and hematologic improvement, the infection severity results support continued study of plerixafor as a potential treatment for WHIM syndrome.TRIAL REGISTRATIONClinicaltrials.gov NCT02231879.FUNDINGThis study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases.
Topics: Humans; Immunologic Deficiency Syndromes; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Cross-Over Studies; Quality of Life; Heterocyclic Compounds; Primary Immunodeficiency Diseases; Warts; Receptors, CXCR4
PubMed: 37561579
DOI: 10.1172/JCI164918 -
Scientific Reports Oct 2022Monocytopenia is a common finding in patients with myelodysplastic syndrome (MDS), but although monocytes may exhibit prognostic significance in MDS due to their role in...
Monocytopenia is a common finding in patients with myelodysplastic syndrome (MDS), but although monocytes may exhibit prognostic significance in MDS due to their role in innate immunity, they have not been incorporated in any prognostic scoring system for MDS. In this study, we analyzed national registry data from 1719 adults with MDS. Monocytopenia was present in 29.5% of the patients and was correlated with the presence of excess blasts and higher revised international prognostic scoring system categories. Univariate analysis showed that monocytopenia was prognostic of a lower overall survival [(OS), 32.0 versus 65.0 months, p < 0.001], while it retained its prognostic significance in a multivariate model comprising anemia, neutropenia and thrombocytopenia [hazard ratio (HR) for OS, 1.320, p < 0.001]. Moreover, it was prognostic of a lower leukemia free survival (LFS) both in univariate analysis and in a multivariate model comprising cytopenias, bone marrow blasts, and cytogenetic risk (HR for LFS 1.27, p = 0.031). The findings regarding OS and LFR were exclusive or more pronounced in lower risk patients, respectively. Moreover, monocytopenia could divide the low and intermediate risk groups of IPSS-R in prognostically distinct subgroups. Our results redefine the prognostic role of monocytes in MDS and set the basis for further studies to validate our results and expand our knowledge on the prognostic significance of monocytopenia in MDS.
Topics: Adult; Humans; Prognosis; Myelodysplastic Syndromes; Bone Marrow; Proportional Hazards Models; Thrombocytopenia; Neutropenia
PubMed: 36289284
DOI: 10.1038/s41598-022-21933-7 -
EMBO Molecular Medicine Oct 2020Early in the COVID-19 pandemic, type 2 diabetes (T2D) was marked as a risk factor for severe disease and mortality. Inflammation is central to the aetiology of both... (Observational Study)
Observational Study
Early in the COVID-19 pandemic, type 2 diabetes (T2D) was marked as a risk factor for severe disease and mortality. Inflammation is central to the aetiology of both conditions where variations in immune responses can mitigate or aggravate disease course. Identifying at-risk groups based on immunoinflammatory signatures is valuable in directing personalised care and developing potential targets for precision therapy. This observational study characterised immunophenotypic variation associated with COVID-19 severity in T2D. Broad-spectrum immunophenotyping quantified 15 leucocyte populations in peripheral circulation from a cohort of 45 hospitalised COVID-19 patients with and without T2D. Lymphocytopenia and specific loss of cytotoxic CD8 lymphocytes were associated with severe COVID-19 and requirement for intensive care in both non-diabetic and T2D patients. A morphological anomaly of increased monocyte size and monocytopenia restricted to classical CD14 CD16 monocytes was specifically associated with severe COVID-19 in patients with T2D requiring intensive care. Increased expression of inflammatory markers reminiscent of the type 1 interferon pathway (IL6, IL8, CCL2, INFB1) underlaid the immunophenotype associated with T2D. These immunophenotypic and hyperinflammatory changes may contribute to increased voracity of COVID-19 in T2D. These findings allow precise identification of T2D patients with severe COVID-19 as well as provide evidence that the type 1 interferon pathway may be an actionable therapeutic target for future studies.
Topics: Aged; COVID-19; Chemokine CCL2; Diabetes Mellitus, Type 2; Female; Humans; Immunophenotyping; Inflammation; Interleukin-6; Leukocytes, Mononuclear; Lipopolysaccharide Receptors; Lymphopenia; Male; Middle Aged; Monocytes; Risk Factors; SARS-CoV-2; Severity of Illness Index
PubMed: 32816392
DOI: 10.15252/emmm.202013038 -
Therapeutics and Clinical Risk... 2021Chemotherapy-induced febrile neutropenia is a common and serious oncological emergency which carries a substantial mortality and morbidity. The main objective of this...
OBJECTIVE
Chemotherapy-induced febrile neutropenia is a common and serious oncological emergency which carries a substantial mortality and morbidity. The main objective of this study is to evaluate the usage of absolute monocyte count (AMC) at presentation as a prognostic factor for patients with chemotherapy-induced febrile neutropenia who were subsequently treated with granulocyte colony-stimulating factor (G-CSF).
STUDY DESIGN
The electronic medical records of our center were used retrospectively to identify patients diagnosed with unprecedented chemotherapy-induced febrile neutropenia treated with G-CSF between January 2010 to December 2020 and diagnosed with solid and hematological malignancies. Patient's demographics, disease characteristics and laboratory investigations were extracted. Disease progression measures were statistically compared between the study groups in the short-term period of follow-up (six days) including absolute neutrophil count (ANC), ANC difference compared to the baseline readings, hospitalization period, and mortality.
RESULTS
A total of 80 patients were identified and categorized into two groups namely monocytopenia (n = 34) and non-monocytopenia (n = 46) with an AMC cutoff point of 0.1×10 cells/L. The monocytopenia group exhibited a worse prognosis with lower ANC values and slower improvement illustrated by the low ANC difference values at all follow up points (value ≤ 0.05) apart from day 5. A statistically significant lower hospitalization period was also observed in the non-monocytopenia group (value = 0.006). Linear regression analysis evaluated the association between AMC values at admission and ANC values at admission along with subsequent days of follow up which were found to be statistically significant (value ≤ 0.05). Receiver operating characteristic curves suggest a satisfactory predictability of ANC changes by AMC values at admission, days1, 2, 3, 4 and 6.
CONCLUSION
Monocytopenia holds a worse prognosis in chemotherapy-induced febrile neutropenia patients treated with G-CSF. In addition, AMC values at presentation represents a potential risk factor that can predict short-term changes regarding ANC measures.
PubMed: 34522100
DOI: 10.2147/TCRM.S318370 -
Blood Sep 2011The syndrome of monocytopenia, B-cell and NK-cell lymphopenia, and mycobacterial, fungal, and viral infections is associated with myelodysplasia, cytogenetic...
The syndrome of monocytopenia, B-cell and NK-cell lymphopenia, and mycobacterial, fungal, and viral infections is associated with myelodysplasia, cytogenetic abnormalities, pulmonary alveolar proteinosis, and myeloid leukemias. Both autosomal dominant and sporadic cases occur. We identified 12 distinct mutations in GATA2 affecting 20 patients and relatives with this syndrome, including recurrent missense mutations affecting the zinc finger-2 domain (R398W and T354M), suggesting dominant interference of gene function. Four discrete insertion/deletion mutations leading to frame shifts and premature termination implicate haploinsufficiency as a possible mechanism of action as well. These mutations were found in hematopoietic and somatic tissues, and several were identified in families, indicating germline transmission. Thus, GATA2 joins RUNX1 and CEBPA not only as a familial leukemia gene but also as a cause of a complex congenital immunodeficiency that evolves over decades and combines predisposition to infection and myeloid malignancy.
Topics: GATA2 Transcription Factor; Genes, Dominant; Genetic Predisposition to Disease; Humans; Monocytes; Mutation; Mycobacterium; Mycobacterium Infections; Syndrome
PubMed: 21670465
DOI: 10.1182/blood-2011-05-356352 -
Cells Jun 2021Cell death mechanisms are crucial to maintain an appropriate environment for the functionality of healthy cells. However, during viral infections, dysregulation of these... (Review)
Review
Cell death mechanisms are crucial to maintain an appropriate environment for the functionality of healthy cells. However, during viral infections, dysregulation of these processes can be present and can participate in the pathogenetic mechanisms of the disease. In this review, we describe some features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and some immunopathogenic mechanisms characterizing the present coronavirus disease (COVID-19). Lymphopenia and monocytopenia are important contributors to COVID-19 immunopathogenesis. The fine mechanisms underlying these phenomena are still unknown, and several hypotheses have been raised, some of which assign a role to cell death as far as the reduction of specific types of immune cells is concerned. Thus, we discuss three major pathways such as apoptosis, necroptosis, and pyroptosis, and suggest that all of them likely occur simultaneously in COVID-19 patients. We describe that SARS-CoV-2 can have both a direct and an indirect role in inducing cell death. Indeed, on the one hand, cell death can be caused by the virus entry into cells, on the other, the excessive concentration of cytokines and chemokines, a process that is known as a COVID-19-related cytokine storm, exerts deleterious effects on circulating immune cells. However, the overall knowledge of these mechanisms is still scarce and further studies are needed to delineate new therapeutic strategies.
Topics: Apoptosis; COVID-19; Cell Death; Cytokine Release Syndrome; Cytokines; Humans; Necroptosis; SARS-CoV-2; Virus Internalization
PubMed: 34201847
DOI: 10.3390/cells10071585 -
Microorganisms May 2023Unusual viral skin infections might be the first clinical manifestation in children with an inborn error of immunity (IEI). We performed a prospective study from 1...
Unusual viral skin infections might be the first clinical manifestation in children with an inborn error of immunity (IEI). We performed a prospective study from 1 October 2017 to 30 September 2021, at the Department of Pediatric Infectious Diseases and Clinical Immunity of Ibn Rochd University Hospital-Casablanca. During this period, on 591 patients newly diagnosed with a probable IEI, eight of them (1.3%), from six independent families, had isolated or syndromic unusual viral skin infections, which were either profuse, chronic or recurrent infections, and resistant to any treatment. The median age of disease onset was nine years old and all patients were born from a first-degree consanguineous marriage. By combining clinical, immunological and genetic investigations, we identified GATA2 deficiency in one patient with recalcitrant profuse verrucous lesions and monocytopenia (1/8) and STK4 deficiency in two families with HPV lesions, either flat or common warts, and lymphopenia (2/8), as previously reported. We also identified COPA deficiency in twin sisters with chronic profuse Molluscum contagiosum lesions, pulmonary diseases and microcytic hypochromic anemia (2/8). Finally, we also found one patient with chronic profuse MC lesions and hyper IgE syndrome, (1/8) and two patients with either recalcitrant profuse verrucous lesions or recurrent post-herpetic erythema multiforme and a combined immunodeficiency (2/8) with no genetic defect identified yet. Raising clinicians awareness that infectious skin diseases might be the consequence of an inborn error of immunity would allow for optimized diagnosis, prevention and treatment of patients and their families.
PubMed: 37317175
DOI: 10.3390/microorganisms11051202 -
BMC Hematology 2014We have previously shown that lymphopenia and monocytopenia at 2-3 months post-allogeneic haematopoietic cell transplant (HCT) is associated with poor survival in...
Impact of clinical factors and allograft leukocyte content on post-transplant lymphopenia, monocytopenia, and survival in patients undergoing allogeneic peripheral blood haematopoietic cell transplant.
BACKGROUND
We have previously shown that lymphopenia and monocytopenia at 2-3 months post-allogeneic haematopoietic cell transplant (HCT) is associated with poor survival in recipients of both myeloablative and reduced intensity conditioning regimens. It is not known whether the graft leukocyte content has a role in early lymphocyte and monocyte recovery following allogeneic T-cell replete peripheral blood HCT.
METHODS
Haematologic recovery data, including absolute lymphocyte and monocyte counts (ALC and AMC, respectively) at day +15, +30, +60, and +100, and outcomes data were pooled from two prior independent cohorts, and parameters were correlated with leukocyte graft content in those individuals receiving peripheral blood progenitor cell grafts. 216 consecutive patients from 2001-2010 were included in the analysis.
RESULTS
Neither infused allograft lymphocyte, monocyte, granulocyte, nor CD34+ cell number per kilogram recipient body weight correlated with haematologic recovery parameters or overall survival in this cohort. Prognostic factors for overall survival based on multivariate analysis were as expected from the results of the previous independent cohorts and included severity of chronic GVHD (p < 0.001), development of post-transplant relapse (p = 0.001), day +60 AMC > 0.3 x 10(9) cells/L (p = 0.0015), and day +100 ALC > 0.3 x 10(9) cells/L (p < 0.001). Low monocyte and lymphocyte counts at the day +60 and day +100 time points were significantly associated with acute GVHD and/or CMV viraemia.
CONCLUSIONS
This study suggests that graft cell count does not influence post-transplant monocyte and lymphocyte recovery following T-cell replete allogeneic peripheral blood HCT. Post-transplant complications such as acute GVHD and/or CMV viraemia negatively influenced monocyte and lymphocyte recovery, and hence the survival. Further studies aimed at understanding the mechanisms behind sustained lymphopenia and monocytopenia post-transplant are needed.
PubMed: 25221674
DOI: 10.1186/2052-1839-14-14 -
Blood Feb 2010We identified 18 patients with the distinct clinical phenotype of susceptibility to disseminated nontuberculous mycobacterial infections, viral infections, especially...
We identified 18 patients with the distinct clinical phenotype of susceptibility to disseminated nontuberculous mycobacterial infections, viral infections, especially with human papillomaviruses, and fungal infections, primarily histoplasmosis, and molds. This syndrome typically had its onset in adulthood (age range, 7-60 years; mean, 31.1 years; median, 32 years) and was characterized by profound circulating monocytopenia (mean, 13.3 cells/microL; median, 14.5 cells/microL), B lymphocytopenia (mean, 9.4 cells/microL; median, 4 cells/microL), and NK lymphocytopenia (mean, 16 cells/microL; median, 5.5 cells/microL). T lymphocytes were variably affected. Despite these peripheral cytopenias, all patients had macrophages and plasma cells at sites of inflammation and normal immunoglobulin levels. Ten of these patients developed 1 or more of the following malignancies: 9 myelodysplasia/leukemia, 1 vulvar carcinoma and metastatic melanoma, 1 cervical carcinoma, 1 Bowen disease of the vulva, and 1 multiple Epstein-Barr virus(+) leiomyosarcoma. Five patients developed pulmonary alveolar proteinosis without mutations in the granulocyte-macrophage colony-stimulating factor receptor or anti-granulocyte-macrophage colony-stimulating factor autoantibodies. Among these 18 patients, 5 families had 2 generations affected, suggesting autosomal dominant transmission as well as sporadic cases. This novel clinical syndrome links susceptibility to mycobacterial, viral, and fungal infections with malignancy and can be transmitted in an autosomal dominant pattern.
Topics: Adolescent; Adult; Child; Female; Fungi; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Humans; Leukocyte Count; Leukopenia; Male; Middle Aged; Mycobacterium; Mycobacterium Infections; Mycoses; Myelodysplastic Syndromes; Neoplasms; Papillomaviridae; Papillomavirus Infections; Pedigree
PubMed: 20040766
DOI: 10.1182/blood-2009-03-208629 -
Haematologica Aug 2011A novel, genetic immunodeficiency syndrome has been recently described, herein termed "MonoMAC". It is characterized by severe circulating monocytopenia, NK- and... (Clinical Trial)
Clinical Trial
A novel, genetic immunodeficiency syndrome has been recently described, herein termed "MonoMAC". It is characterized by severe circulating monocytopenia, NK- and B-lymphocytopenia, severe infections with M. avium complex (MAC), and risk of progression to myelodysplasia/acute myelogenous leukemia. Detailed bone marrow analyses performed on 18 patients further define this disorder. The majority of patients had hypocellular marrows with reticulin fibrosis and multilineage dysplasia affecting the myeloid (72%), erythroid (83%) and megakaryocytic (100%) lineages. Cytogenetic abnormalities were present in 10 of 17 (59%). Despite B-lymphocytopenia, plasma cells were present but were abnormal (e.g. CD56(+)) in nearly half of cases. Increased T-cell large granular lymphocyte populations were present in 28% of patients. Chromosomal breakage studies, cell cycle checkpoint functions, and sequencing of TERT and K-RAS genes revealed no abnormalities. MonoMAC appears to be a unique, inherited syndrome of bone marrow failure. We describe distinctive bone marrow features to help in its recognition and diagnosis. (Clinicaltrials.gov identifiers: NCT00018044, NCT00923364, NCT01212055).
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Cytogenetic Analysis; Disease Progression; Female; Genomic Instability; Humans; Immunologic Deficiency Syndromes; Immunophenotyping; Leukemia, Myeloid, Acute; Leukopenia; Lymphocytes; Male; Middle Aged; Monocytes; Mutation; Myelodysplastic Syndromes; Primary Myelofibrosis; Risk; Young Adult
PubMed: 21508125
DOI: 10.3324/haematol.2011.041152