Dexamethasone Treatment for COVID-19-Related Lung Injury in an Adult with WHIM Syndrome.
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ABSTRACT:
SUBMITTER: Akahane D
PROVIDER: S-EPMC8635474 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), a primary immunodeficiency disorder involving panleukopenia, is caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Myelokathexis is neutropenia caused by neutrophil retention in bone marrow. Patients with WHIM syndrome are often treated with granulocyte colony-stimulating factor (G-CSF), which can increase neutrophil counts but does not affect cytopenias other than neutropenia. In this investigator-initiated, open-label study, three severely affected patients with WHIM syndrome who could not receive G-CSF were treated with low-dose plerixafor, a CXCR4 antagonist, for 19 to 52 months. Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus-associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly. Adverse events were mainly infections attributable to the underlying immunodeficiency. One patient died from complications of elective reconstructive surgery. (Funded by the National Institutes of Health.).
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Project description:Dexamethasone improves the survival of COVID-19 patients in need of supplemental oxygen therapy. Hospitalized COVID-19 patients eligible for dexamethasone therapy were recruited from the general care ward in several centers in Greece and the Netherlands and whole blood transcriptomic analysis was performed before and after starting dexamethasone treatment. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy individuals and COVID-19 patients and stimulated with inactivated SARS-CoV-2 ex vivo in the presence or absence of dexamethasone and their transcriptome was assessed.
2023-07-26 | GSE227585 | GEO
Project description:Low-dose dexamethasone reduces mortality in patients with coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS). We retrospectively analyzed the efficacy of high-dose dexamethasone in patients with COVID-19-related ARDS and evaluated factors affecting the composite outcome (death or invasive mechanical ventilation). From March 4th to April 1st 2020, 98 patients with COVID-19 pneumonia were included. Those who after at least 7 days from symptom onset presented a worsening of the respiratory function or of inflammatory biomarkers were started on intravenous high-dose dexamethasone (20 mg daily for 5 days, followed by 10 mg daily for 5 days). Most patients were males (62%) with a mean age of 69 years. Hypertension and cardiovascular disease (CVD) were prevalent. Following dexamethasone treatment, a significant improvement in PaO2/FiO2 (277.41 [178.5-374.8] mmHg vs. 146.75 [93.62-231.16] mmHg, p < 0.001), PaO2 (88.15 [76.62-112.0] mmHg vs. 65.65 [57.07-81.22] mmHg, p < 0.001), and SpO2 (96 [95-98]% vs. 94 [90-96]%, p < 0.001) was observed. A concomitant decrease in C-reactive protein and ferritin levels was found (132.25 [82.27-186.5] mg/L vs. 7.3 [3.3-24.2] mg/L and 1169 [665-2056] ng/mL vs. 874.0 [569.5-1434] ng/mL, respectively; p < 0.001 for both vs. baseline). CVD was found to increase the risk of the composite outcome (RR 7.64, 95% CI 1.24-47.06, p = 0.028). In hospitalized patients with COVID-19-related ARDS, high-dose dexamethasone rapidly improves the clinical status and decreases inflammatory biomarkers. CVD was found to increase the risk of the composite outcome. These data support the importance of randomized clinical trials with high-dose dexamethasone in COVID-19 patients.
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Project description:BackgroundDexamethasone improves the survival of COVID-19 patients in need of supplemental oxygen therapy. Although its broad immunosuppressive effects are well-described, the immunological mechanisms modulated by dexamethasone in patients hospitalized with COVID-19 remain to be elucidated.ObjectiveWe combined functional immunological assays and an omics-based approach to investigate the in vitro and in vivo effects of dexamethasone in the plasma and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients.MethodsHospitalized COVID-19 patients eligible for dexamethasone therapy were recruited from the general care ward between February and July, 2021. Whole blood transcriptomic and targeted plasma proteomic analyses were performed before and after starting dexamethasone treatment. PBMCs were isolated from healthy individuals and COVID-19 patients and stimulated with inactivated SARS-CoV-2 ex vivo in the presence or absence of dexamethasone and transcriptome and cytokine responses were assessed.ResultsDexamethasone efficiently inhibited SARS-CoV-2-induced in vitro expression of chemokines and cytokines in PBMCs at the transcriptional and protein level. Dexamethasone treatment in COVID-19 patients resulted in down-regulation of genes related to type I and II interferon (IFN) signaling in whole blood immune cells. In addition, dexamethasone attenuated circulating concentrations of secreted interferon-stimulating gene 15 (ISG15) and pro-inflammatory cytokines and chemokines correlating with disease severity and lethal outcomes, such as tumor necrosis factor (TNF), interleukin-6 (IL-6), chemokine ligand 2 (CCL2), C-X-C motif ligand 8 (CXCL8), and C-X-C motif chemokine ligand 10 (CXCL10). In PBMCs from COVID-19 patients that were stimulated ex vivo with multiple pathogens or Toll-like receptor (TLR) ligands, dexamethasone efficiently inhibited cytokine responses.ConclusionWe describe the anti-inflammatory impact of dexamethasone on the pathways contributing to cytokine hyperresponsiveness observed in severe manifestations of COVID-19, including type I/II IFN signaling. Dexamethasone could have adverse effects in COVID-19 patients with mild symptoms by inhibiting IFN responses in early stages of the disease, whereas it exhibits beneficial effects in patients with severe clinical phenotypes by efficiently diminishing cytokine hyperresponsiveness.
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Project description:Chromothripsis is a catastrophic cellular event recently described in cancer in which chromosomes undergo massive deletion and rearrangement. Here, we report a case in which chromothripsis spontaneously cured a patient with WHIM syndrome, an autosomal dominant combined immunodeficiency disease caused by gain-of-function mutation of the chemokine receptor CXCR4. In this patient, deletion of the disease allele, CXCR4(R334X), as well as 163 other genes from one copy of chromosome 2 occurred in a hematopoietic stem cell (HSC) that repopulated the myeloid but not the lymphoid lineage. In competitive mouse bone marrow (BM) transplantation experiments, Cxcr4 haploinsufficiency was sufficient to confer a strong long-term engraftment advantage of donor BM over BM from either wild-type or WHIM syndrome model mice, suggesting a potential mechanism for the patient's cure. Our findings suggest that partial inactivation of CXCR4 may have general utility as a strategy to promote HSC engraftment in transplantation.
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Project description:Cysteine-X-cysteine chemokine receptor 4 (CXCR4) is a broadly expressed and multifunctional G protein-coupled chemokine receptor critical for organogenesis, hematopoiesis, and antimicrobial host defense. In the hematopoietic system, the binding of CXCR4 to its cognate chemokine ligand, CXCL12, mediates leukocyte trafficking, distribution, survival, activation, and proliferation. Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare, autosomal dominant, combined immunodeficiency disorder caused by mutations in the C-terminus of CXCR4 that prevent receptor downregulation and therefore result in pathologically increased signaling. The "M" in the acronym WHIM refers to myelokathexis, the retention of neutrophils in the bone marrow resulting in neutropenia, which explains in part the increased susceptibility to bacterial infection. However, WHIM patients also present with B and T lymphopenia, which may explain the susceptibility to human papillomavirus (HPV), the cause of warts. The impact of WHIM mutations on lymphocytes and adaptive immunity has received less attention than myelokathexis and is the focus of this review.
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Project description:SARS-CoV-2, the virus responsible for COVID-19, causes widespread damage in the lungs in the setting of an overzealous immune response whose origin remains unclear. We present a scalable, propagable, personalized, cost-effective adult stem cell-derived human lung organoid model that is complete with both proximal and distal airway epithelia. Monolayers derived from adult lung organoids (ALOs), primary airway cells, or hiPSC-derived alveolar type-II (AT2) pneumocytes were infected with SARS-CoV-2 to create in vitro lung models of COVID-19. Infected ALO-monolayers best recapitulated the transcriptomic signatures in diverse cohorts of COVID-19 patient-derived respiratory samples. The airway (proximal) cells were critical for sustained viral infection, whereas distal alveolar differentiation (AT2→AT1) was critical for mounting the overzealous host immune response in fatal disease; ALO monolayers with well-mixed proximodistal airway components recapitulated both. Findings validate a human lung model of COVID-19 , which can be immediately utilized to investigate COVID-19 pathogenesis and vet new therapies and vaccines.
2021-01-20 | GSE165200 | GEO
Project description:Since the initial description in 2019, the novel coronavirus SARS-Cov-2 infection (COVID-19) pandemic has swept the globe. The most severe form of the disease presents with fever and shortness of breath, which rapidly deteriorates to respiratory failure and acute lung injury (ALI). COVID-19 also presents with a severe coagulopathy with a high rate of venous thromboembiolism. In addition, autopsy studies have revealed co-localized thrombosis and inflammation, which is the signature of thromboinflammation, within the pulmonary capillary vasculature. While the majority of published data is on adult patients, there are parallels to pediatric patients. In our experience as a COVID-19 epicenter, children and young adults do develop both the coagulopathy and the ALI of COVID-19. This review will discuss COVID-19 ALI from a hematological perspective with discussion of the distinct aspects of coagulation that are apparent in COVID-19. Current and potential interventions targeting the multiple thromboinflammatory mechanisms will be discussed.
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Project description:The kidney is not typically the main target of severe acute respiratory syndrome coronavirus 2, but surprisingly, acute kidney injury (AKI) may occur in 4-23% of cases, whereas the dialysis management of AKI from coronavirus 2019 has not gained much attention. The severity of the pandemic has resulted in significant shortages in medical supplies, including respirators, ventilators and personal protective equipment. Peritoneal dialysis (PD) remains available and has been used in clinical practice for AKI for >70 years; however, it has been used on only a limited basis and therefore experience and knowledge of its use has gradually vanished, leaving a considerable gap. The turning point came in 2007, with a series of sequential publications providing solid evidence that PD is a viable option. As there was an availability constraint and a capacity limit of equipment/supplies in many countries, hemodialysis and convective therapies became alternatives. However, even these therapies are not available in many countries and their capacity is being pushed to the limit in many cities. Evidence-based PD experience lends support for the use of PD now.
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Project description:ObjectiveWe aimed to analyze clinical outcomes from patients with severe COVID-19 pneumonia that received either baricitinib plus dexamethasone or dexamethasone monotherapy.MethodologyWe performed a retrospective comparative study. Data from hospitalized patients with severe COVID-19 pneumonia (saturation <93%, bilateral pulmonary infiltrates) that were treated with baricitinib plus dexamethasone or dexamethasone were collected. Our primary objective was to compare overall mortality and secondly to compare progression to mechanical ventilation and over infection rates.ResultsA total of 793 patients were assessed for inclusion criteria, 596 were excluded and 197 were analyzed for primary outcome: 123 in the baricitinib plus dexamethasone group and 74 in the dexamethasone monotherapy group. The mean age was 59.9 years (SD ± 14.5) and 62.1% (123/197) were male. 42.9% (85/197) of the cases required ICU admission and 25.8% (51/197) underwent invasive mechanical ventilation (IMV). Overall thirty-day mortality was 27.9% (55/197); Mortality was significantly lower in the baricitinib plus dexamethasone group compared to the dexamethasone monotherapy group (20.3% vs 40.5%, P = <.05). There was no difference in hospital acquired infections between both groups.ConclusionThirty-day mortality was significantly lower in patients with COVID-19 pneumonia treated with baricitinib plus dexamethasone versus dexamethasone monotherapy. No difference was observed in progression to invasive mechanical ventilation and hospital acquired infections.
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