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The emergence of SARS-CoV-2 has precipitated a global pandemic with substantial long-term health implications, including the condition known as post-acute sequelae of SARS-CoV-2 infection (PASC), commonly referred to as Long COVID. PASC is marked by persistent symptoms such as fatigue, neurological issues, and autonomic dysfunction that persist for months beyond the acute phase of COVID-19. This review examines the potential role of herpesvirus reactivation, specifically Epstein-Barr virus (EBV) and cytomegalovirus (CMV), in the pathogenesis of PASC. Elevated antibody titers and specific T cell responses suggest recent herpesvirus reactivation in some PASC patients, although viremia is not consistently detected. SARS-CoV-2 exhibits endothelial trophism, directly affecting the vascular endothelium and contributing to microvascular pathologies. These pathologies are significant in PASC, where microvascular dysfunction may underlie various chronic symptoms. Similarly, herpesviruses like CMV also exhibit endothelial trophism, which may exacerbate endothelial damage when reactivated. Evidence suggests that EBV and CMV reactivation could indirectly contribute to the immune dysregulation, immunosenescence, and autoimmune responses observed in PASC. Additionally, EBV may play a role in the genesis of neurological symptoms through creating mitochondrial dysfunction, though direct confirmation remains elusive. The reviewed evidence suggests that while herpesviruses may not play a direct role in the pathogenesis of PASC, their potential indirect effects, especially in the context of endothelial involvement, warrant further investigation.
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Introduction: Acquired Hemophilia A (AHA) is a rare autoimmune disorder characterized by the emergence of inhibitors that specifically target coagulation Factor VIII, frequently resulting in severe bleeding episodes. Methods: We conducted a retrospective analysis of the medical records of a 68-year-old male patient who presented with adalimumab-induced AHA. Results: The patient received adalimumab, a tumor necrosis factor inhibitor antibody, as part of his treatment for rheumatoid arthritis. The patient's clinical journey, characterized by intense bleeding and coagulopathy, was effectively managed with the application of recombinant Factor VIIa (rFVIIa) and the CyDRi protocol. Discussion: The case emphasizes the importance of prompt coagulation assessment in patients with bleeding symptoms receiving disease-modifying therapy for rheumatoid arthritis that includes adalimumab therapy, considering the rare yet life-threatening nature of AHA. Additionally, this report provides an extensive review of the existing literature on drug-induced AHA, with a special emphasis on cases linked to immunomodulatory medications. Through this two-pronged approach, our report aims to enhance understanding and awareness of this severe complication among healthcare providers, promoting timely diagnosis and intervention.
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Adalimumab , Hemofilia A , Humanos , Hemofilia A/tratamiento farmacológico , Hemofilia A/inducido químicamente , Masculino , Anciano , Adalimumab/efectos adversos , Adalimumab/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Factor VIIa/uso terapéutico , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversos , Rituximab/uso terapéutico , Rituximab/efectos adversos , Estudios Retrospectivos , Proteínas Recombinantes/uso terapéuticoRESUMEN
Baricitinib is considered a first-line treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected adult patients with an associated cytokine storm syndrome (CSS). Our objective was to compare rates of secondary infections and long-term outcomes of elderly and non-elderly patients who received baricitinib for COVID-19. We conducted a single-centre observational study between November 2020 and September 2023, focusing on hospitalized adult SARS-CoV-2 patients with CSS, categorized as elderly (≥ 65 years) and non-elderly (< 65 years). Enrolment, severity stratification, and diagnosis of infectious complications followed predefined criteria. Outcomes of all-cause mortality and rates of non-severe and severe secondary infections were assessed at 1-year post-treatment initiation. Kaplan-Meier analysis was performed for survival analysis. In total, 490 patients were enrolled (median age 65 ± 23 (21-100) years (years, median ± IQR, min-max); 49.18% elderly; 59.59% male). Elderly patients were admitted to the hospital significantly earlier (7 ± 5 days vs. 8 ± 4 days; p = 0.02), experienced a higher occurrence of severe COVID-19 (121/241, 50.21% vs. 98/249, 39.36%; p = 0.02), and required the use of non-invasive ventilation at baseline (167/225, 74.22% vs. 153/236, 64.83%; p = 0.03). At 1 year, all-cause mortality was significantly higher in the elderly subgroup (111/241, 46.06% vs. 29/249, 11.65%; p < 0.01). At 90 days and 1 year, rates of any severe secondary infection were also more prevalent among the elderly (56/241, 23.24% vs. 37/249 14.86%; p = 0.02 and 58/241, 24.07% vs. 39/249, 15.66%; p = 0.02). In conclusion, elderly SARS-CoV-2-infected patients experience a more severe clinical course, higher secondary infection rates, and increased risk for long-term mortality, regardless of immunomodulatory therapy.
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Azetidinas , COVID-19 , Coinfección , Purinas , Pirazoles , Sulfonamidas , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tratamiento Farmacológico de COVID-19 , Hungría , SARS-CoV-2 , Adulto Joven , AdultoRESUMEN
The COVID-19 pandemic has exacerbated mortality rates among immunocompromised patients, accentuating the need for novel, targeted therapies. Transplant recipients, with their inherent immune vulnerabilities, represent a subgroup at significantly heightened risk. Current conventional therapies often demonstrate limited effectiveness in these patients, calling for innovative treatment approaches. In immunocompromised transplant recipients, several viral infections have been successfully treated by adoptive transfer of virus-specific T-cells (VST). This paper details the successful application of SARS-CoV-2-specific memory T-cell therapy, produced by an interferon-γ cytokine capture system (CliniMACS® Prodigy device), in three stem cell transplant recipients diagnosed with COVID-19 (case 1: alpha variant, cases 2 and 3: delta variants). These patients exhibited persistent SARS-CoV-2 PCR positivity accompanied by bilateral pulmonary infiltrates and demonstrated only partial response to standard treatments. Remarkably, all three patients recovered and achieved viral clearance within 3 to 9 weeks post-VST treatment. Laboratory follow-up investigations identified an increase in SARS-CoV-2-specific T-cells in two of the cases. A robust anti-SARS-CoV-2 S (S1/S2) IgG serological response was also recorded, albeit with varying titers. The induction of memory T-cells within the CD4 + compartment was confirmed, and previously elevated interleukin-6 (IL-6) and IL-8 levels normalized post-VST therapy. The treatment was well tolerated with no observed adverse effects. While the need for specialized equipment and costs associated with VST therapy present potential challenges, the limited treatment options currently available for COVID-19 within the allogeneic stem cell transplant population, combined with the risk posed by emerging SARS-CoV-2 mutations, underscore the potential of VST therapy in future clinical practice. This therapeutic approach may be particularly beneficial for elderly patients with multiple comorbidities and weakened immune systems.
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COVID-19 , Trasplante de Células Madre Hematopoyéticas , Anciano , Humanos , SARS-CoV-2 , Pandemias , Receptores de Trasplantes , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Tratamiento Basado en Trasplante de Células y TejidosRESUMEN
Introduction: The selective Bcl-2 inhibitor venetoclax has shown promising therapeutic potential in multiple myeloma, particularly in cases associated with t(11;14) IGH::CCND1 translocation. However, the efficacy of venetoclax in myeloma patients with the t(6;14) IGH::CCND3 translocation remains less investigated. Methods: In this study, we conducted a retrospective analysis to investigate the efficacy of venetoclax-based therapy in relapsed/refractory myeloma patients with t(6;14) translocation. The treatment courses of three patients, that included previous therapies and responses to venetoclax, were assessed. Clinical data, laboratory results, and adverse events were analyzed to evaluate treatment outcomes. Results: Our findings demonstrated remarkable therapeutic responses in three consecutive patients with t(6;14) translocation-associated myeloma who received venetoclax-based therapy. Patient 1, a lenalidomide-bortezomib-daratumumab and alkylator treatment refractory patient, achieved sustained stringent complete remission (sCR) after combining carfilzomib-dexamethasone with venetoclax, which was his best response ever. Similarly, Patient 2, refractory to frontline bortezomib-thalidomide-dexamethasone therapy, attained CR following a transition to bortezomib-dexamethason-venetoclax treatment. Patient 3, who was immunomodulatory (IMID)-intolerant, showed a highly favorable response to venetoclax-dexamethasone therapy after his first relapse following autologous stem cell transplantation. No significant adverse effects were observed in any of the patients. Discussion: Our study provides compelling preliminary evidence for the efficacy of venetoclax in t(6;14) translocation-associated myeloma. The outcomes observed in our patients suggest that venetoclax-based therapy holds substantial promise as an effective treatment option for this specific genetic subgroup. Furthermore, the similarities in treatment response between t(11;14) and t(6;14) translocation subgroups highlight the importance of personalized approaches targeting specific genetic abnormalities to optimize therapeutic outcomes.
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Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Bortezomib/uso terapéutico , Estudios Retrospectivos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Trasplante Autólogo , Resultado del Tratamiento , Dexametasona/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Introduction: Acquired factor V inhibitor (AFVI) is a rare autoimmune bleeding disorder. The treatment of AFVI is challenging, and patients often require both bleeding control and inhibitor eradication. Methods: We conducted a retrospective analysis of the medical records of a 35-year-old Caucasian woman who presented with severe AFVI-induced bleeding and subsequent immunosuppressive therapy. Results: To provide haemostasis, rFVIIa was given with good efficacy. The patient was treated with various combinations of immunosuppressive regimens over the course of 2.5 years, including plasmapheresis plus immunoglobulins, dexamethasone + rituximab, cyclophosphamide + dexamethasone + rituximab + cyclosporine, cyclosporin + sirolimus + cyclophosphamide + dexamethasone, bortezomib + sirolimus + methylprednisolone, and sirolimus + mycophenolate mofetil. Although these treatment modalities resulted in intermittent partial reversals of AFVI over 2.5 years, eventually the inhibitor became therapy-resistant. However, following the discontinuation of all immunosuppressive therapy, the patient experienced a partial spontaneous remission, which was followed by a pregnancy. During the pregnancy, the FV activity increased to 54% and the coagulation parameters returned to normal levels. The patient underwent Caesarean section without any bleeding complications and delivered a healthy child. Discussion: The use of an activated bypassing agent for bleeding control is effective in patients with severe AFVI. The presented case is unique because the treatment regimens included multiple combinations of immunosuppressive agents. This demonstrates that AFVI patients may undergo spontaneous remission even after multiple courses of ineffective immunosuppressive protocols. Additionally, pregnancy-associated improvement of AFVI is an important finding that warrants further investigation.
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Cesárea , Factor V , Embarazo , Niño , Humanos , Femenino , Adulto , Rituximab , Remisión Espontánea , Estudios Retrospectivos , Inmunosupresores/uso terapéutico , Ciclofosfamida/uso terapéutico , Ciclosporina , Dexametasona , Terapia de Inmunosupresión , SirolimusRESUMEN
Multiple myeloma (MM) is an incurable plasma cell malignancy, which is predominantly a disease of older adults (the median age at diagnosis is 70 years). The slow progression from asymptomatic stages and the late-onset of MM suggest fundamental differences compared to many other hematopoietic system-related malignancies. The concept discussed in this review is that age-related changes at the level of terminally differentiated plasma cells act as the main risk factors for the development of MM. Epigenetic and genetic changes that characterize both MM development and normal aging are highlighted. The relationships between cellular aging processes, genetic mosaicism in plasma cells, and risk for MM and the stochastic processes contributing to clonal selection and expansion of mutated plasma cells are investigated. In line with the DNA damage accumulation theory of aging, in this review, the evolution of monoclonal gammopathy to symptomatic MM is considered. Therapeutic consequences of age-dependent comorbidities that lead to frailty and have fundamental influence on treatment outcome are described. The importance of considering geriatric states when planning the life-long treatment course of an elderly MM patient in order to achieve maximal therapeutic benefit is emphasized.
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Fragilidad , Gammopatía Monoclonal de Relevancia Indeterminada , Mieloma Múltiple , Humanos , Anciano , Mieloma Múltiple/terapia , Mieloma Múltiple/tratamiento farmacológico , Gerociencia , Gammopatía Monoclonal de Relevancia Indeterminada/genética , Gammopatía Monoclonal de Relevancia Indeterminada/terapia , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Factores de RiesgoRESUMEN
Acquired hemophilia A (AHA) is a rare severe autoimmune bleeding disorder with significant morbidity and mortality. Although critical for disease control, there is no consensus for the best immunosuppressive regimen. Most authors use steroids first line, followed by other agents for steroid failures. Upfront combined regimens offer the advantage of reduced steroid exposure and toxicity as well as increased efficacy. We retrospectively analyzed data from 32 patients with AHA treated on an identical such institutional protocol: cyclophosphamide 1000 mg on days 1 and 22, dexamethasone 40 mg on days 1, 8, 15, and 22, and rituximab 100 mg on days 1, 8, 15, and 22 (the regimen was termed CyDRi). All patients received at least 1 cycle of CyDRi. If necessary, CyDRi was repeated until remission, no sooner than day 43 of the previous cycle. Bleeding control was rapidly achieved. The median time for bleeding control was 15.5 days (range, 0-429 days; interquartile range, 2.5-29.5 days). Thirty-one (96.8%) of 32 patients achieved durable complete remission (CR); 29 (90.6%) of 32 patients were alive at last follow-up, all of them in CR. The median time to reach first CR was 77 days (range, 19-939 days; interquartile range, 31-115 days). Toxicity and side effects were acceptable and milder than those of commonly used, prolonged steroid therapies. In conclusion, the CyDRi regimen produced markedly higher CR rates and overall survival than currently used sequential regimens. Taken together, CyDRi proved to be an attractive option for the immunosuppression of elderly patients with AHA.
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Hemofilia A , Humanos , Anciano , Estudios Retrospectivos , Ciclofosfamida/efectos adversos , Hemorragia/tratamiento farmacológico , Hemorragia/etiología , Terapia de Inmunosupresión , Esteroides/uso terapéuticoRESUMEN
One characteristic type of the common somatic mutations causing myeloproliferative neoplasias is the frameshift mutation of the calreticulin gene that leads to proteins of abnormal structure. The pathologic protein induces novel cell biological processes that are fundamental to the onset and maintenance of myeloproliferative diseases. In this review, an insight is provided into these processes, aiding better understanding of the underlining pathobiological processes and eventually to more effective therapy in the future.
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Calreticulina , Trastornos Mieloproliferativos , Calreticulina/genética , Calreticulina/metabolismo , Mutación con Ganancia de Función , Humanos , Mutación , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/patologíaRESUMEN
Plerixafor can rescue the outcome of failing chemotherapy-based stem cell mobilization. However, the optimal time for plerixafor injection in this setting has not been determined. This was investigated by retrospective analysis of data from 48 mobilizations with plerixafor, chemotherapy, and granulocyte-colony stimulating factor (G-CSF). The required yield of 2.0 × 10(6) CD34+ cells/kg was collected from 71% of patients; the median total yield was 4.1 × 10(6) CD34+ cells/kg. Patients to whom plerixafor was administered late (≥ 15 days) after chemotherapy, after a long duration (≥ 13 days) of treatment with G-CSF, or when the white blood cell count was high (≥ 20 × 10(9)/L) were mobilized as efficiently as other patients. Plerixafor was shown to rescue mobilizations at a comparable rate in patients with critically low levels of peripheral blood CD34+ cells (<3/µL) and those with higher concentrations. These data suggest that late administration of plerixafor in the course of chemotherapy-based mobilization does not contribute to the failure of this strategy.