RESUMEN
COVID-19 is a highly heterogeneous and complex medical disorder; indeed, severe COVID-19 is probably amongst the most complex of medical conditions known to medical science. While enormous strides have been made in understanding the molecular pathways involved in patients infected with coronaviruses an overarching and comprehensive understanding of the pathogenesis of COVID-19 is lacking. Such an understanding is essential in the formulation of effective prophylactic and treatment strategies. Based on clinical, proteomic, and genomic studies as well as autopsy data severe COVID-19 disease can be considered to be the connection of three basic pathologic processes, namely a pulmonary macrophage activation syndrome with uncontrolled inflammation, a complement-mediated endothelialitis together with a procoagulant state with a thrombotic microangiopathy. In addition, platelet activation with the release of serotonin and the activation and degranulation of mast cells contributes to the hyper-inflammatory state. Auto-antibodies have been demonstrated in a large number of hospitalized patients which adds to the end-organ damage and pro-thrombotic state. This paper provides a clinical overview of the major pathogenetic mechanism leading to severe COVID-19 disease.
Asunto(s)
COVID-19/virología , SARS-CoV-2/patogenicidad , COVID-19/sangre , COVID-19/inmunología , COVID-19/fisiopatología , Activación de Complemento , Proteínas del Sistema Complemento/metabolismo , Citocinas/sangre , Progresión de la Enfermedad , Interacciones Huésped-Patógeno , Humanos , Inflamación/sangre , Inflamación/inmunología , Inflamación/fisiopatología , Inflamación/virología , Mediadores de Inflamación/sangre , Síndrome de Activación Macrofágica/sangre , Síndrome de Activación Macrofágica/inmunología , Síndrome de Activación Macrofágica/fisiopatología , Síndrome de Activación Macrofágica/virología , Activación Plaquetaria , SARS-CoV-2/inmunología , Serotonina/sangre , Índice de Severidad de la Enfermedad , Microangiopatías Trombóticas/sangre , Microangiopatías Trombóticas/inmunología , Microangiopatías Trombóticas/fisiopatología , Microangiopatías Trombóticas/virologíaRESUMEN
BACKGROUND: Cytokine storm in COVID-19 is heterogenous. There are at least three subtypes: cytokine release syndrome (CRS), macrophage activation syndrome (MAS), and sepsis. METHODS: A retrospective study comprising 276 patients with SARS-CoV-2 pneumonia. All patients were tested for ferritin, interleukin-6, D-Dimer, fibrinogen, calcitonin, and C-reactive protein. According to the diagnostic criteria, three groups of patients with different subtypes of cytokine storm syndrome were identified: MAS, CRS or sepsis. In the MAS and CRS groups, treatment results were assessed depending on whether or not tocilizumab was used. RESULTS: MAS was diagnosed in 9.1% of the patients examined, CRS in 81.8%, and sepsis in 9.1%. Median serum ferritin in patients with MAS was significantly higher (5894 vs. 984 vs. 957 ng/mL, p < 0.001) than in those with CRS or sepsis. Hypofibrinogenemia and pancytopenia were also observed in MAS patients. In CRS patients, a higher mortality rate was observed among those who received tocilizumab, 21 vs. 10 patients (p = 0.043), RR = 2.1 (95% CI 1.0-4.3). In MAS patients, tocilizumab decreased the mortality, 13 vs. 6 patients (p = 0.013), RR = 0.50 (95% CI 0.25-0.99). CONCLUSIONS: Tocilizumab therapy in patients with COVID-19 and CRS was associated with increased mortality, while in MAS patients, it contributed to reduced mortality.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Síndrome de Liberación de Citoquinas/clasificación , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Anciano , COVID-19/clasificación , COVID-19/inmunología , COVID-19/mortalidad , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/mortalidad , Femenino , Ferritinas/sangre , Humanos , Síndrome de Activación Macrofágica/tratamiento farmacológico , Síndrome de Activación Macrofágica/mortalidad , Síndrome de Activación Macrofágica/virología , Masculino , Estudios Retrospectivos , Sepsis/tratamiento farmacológico , Sepsis/virología , Resultado del TratamientoRESUMEN
OBJECTIVES: Assess the pathologic changes in the lungs of COVID-19 decedents and correlate these changes with demographic data, clinical course, therapies, and duration of illness. METHODS: Lungs of 12 consecutive COVID-19 decedents consented for autopsy were evaluated for gross and histopathologic abnormalities. A complete Ghon "en block" dissection was performed on all cases; lung weights and gross characteristics recorded. Immunohistochemical studies were performed to characterize lymphocytic infiltrates and to assess SARS-CoV-2 capsid protein. RESULTS: Two distinct patterns of pulmonary involvement were identified. Three of 12 cases demonstrated a predominance of acute alveolar damage (DAD) while 9 of 12 cases demonstrated a marked increase in intra-alveolar macrophages in a fashion resembling desquamative interstitial pneumonia or macrophage activation syndrome (DIP/MAS). Two patterns were correlated solely with a statistically significant difference in the duration of illness. The group exhibiting DAD had duration of illness of 5.7 days while the group with DIP/MAS had duration of illness of 21.5 days (t-test p = 0.014). CONCLUSIONS: The pulmonary pathology of COVID-19 patients demonstrates a biphasic pattern, an acute phase demonstrating DAD changes while the patients with a more prolonged course exhibit a different pattern that resembles DIP/MAS-like pattern. The potential mechanisms and clinical significance are discussed.
Asunto(s)
COVID-19/patología , Inmunohistoquímica/métodos , Enfermedades Pulmonares Intersticiales/patología , Pulmón/patología , Síndrome de Activación Macrofágica/patología , Adulto , Anciano , Anciano de 80 o más Años , Autopsia , COVID-19/complicaciones , COVID-19/diagnóstico , COVID-19/virología , Proteínas de la Cápside/metabolismo , Comorbilidad , Femenino , Humanos , Pulmón/metabolismo , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/virología , Linfocitos/metabolismo , Linfocitos/patología , Síndrome de Activación Macrofágica/etiología , Síndrome de Activación Macrofágica/virología , Macrófagos/patología , Masculino , Persona de Mediana Edad , Alveolos Pulmonares/inmunología , Alveolos Pulmonares/patología , SARS-CoV-2/genética , Ausencia por EnfermedadRESUMEN
BACKGROUND: Many laboratory parameters have been associated with morbidity and mortality in SARS-CoV-2 (COVID-19), which emerged in an animal market in Wuhan, China in December 2019 and has infected over 20 million people. This study investigated the relationship between serum interleukin (IL)-18, IL-1 receptor antagonist (IL-1Ra), and alpha defensin levels and the clinical course and prognosis of COVID-19. MATERIALS AND METHODS: This study included 100 patients who were admitted to the chest diseases department and intensive care unit of our hospital and diagnosed with COVID-19 by real-time polymerase chain reaction (PCR) of nasopharyngeal swab samples between March 24 and May 31, 2020. The control group consisted of 50 nonsymptomatic health workers with negative real-time PCR results in routine COVID-19 screening in our hospital. RESULTS: Serum alpha defensin, IL-1Ra, and IL-18 levels were significantly higher in patients who developed macrophage activation syndrome (MAS) and acute respiratory distress syndrome (ARDS) compared to patients who did not (p < .001 for all). Alpha defensin, IL-1Ra, and IL-18 levels were significantly higher in COVID-19 patients with and without MAS or ARDS when compared to the control group (p < .001 for all). When the 9 patients who died were compared with the 91 surviving patients, IL-1Ra and IL-18 levels were found to be significantly higher in the nonsurvivors (p < .001). CONCLUSION: Our findings of correlations between alpha defensin and levels of IL-1Ra and IL-18, which were previously shown to be useful in COVID-19 treatment and follow-up, indicates that it may also be promising in treatment.
Asunto(s)
COVID-19/inmunología , Proteína Antagonista del Receptor de Interleucina 1/sangre , Interleucina-18/sangre , Síndrome de Activación Macrofágica/virología , Síndrome de Dificultad Respiratoria/virología , alfa-Defensinas/sangre , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , TurquíaRESUMEN
In light of the outbreak of the 2019 novel coronavirus disease (COVID-19), the international scientific community has joined forces to develop effective treatment strategies. The Angiotensin-Converting Enzyme (ACE) 2, is an essential receptor for cell fusion and engulfs the SARS coronavirus infections. ACE2 plays an important physiological role, practically in all the organs and systems. Also, ACE2 exerts protective functions in various models of pathologies with acute and chronic inflammation. While ACE2 downregulation by SARS-CoV-2 spike protein leads to an overactivation of Angiotensin (Ang) II/AT1R axis and the deleterious effects of Ang II may explain the multiorgan dysfunction seen in patients. Specifically, the role of Ang II leading to the appearance of Macrophage Activation Syndrome (MAS) and the cytokine storm in COVID-19 is discussed below. In this review, we summarized the latest research progress in the strategies of treatments that mainly focus on reducing the Ang II-induced deleterious effects rather than attenuating the virus replication.
Asunto(s)
Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus/fisiopatología , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/fisiopatología , Enzima Convertidora de Angiotensina 2 , COVID-19 , Infecciones por Coronavirus/enzimología , Infecciones por Coronavirus/virología , Citocinas/metabolismo , Regulación hacia Abajo , Humanos , Síndrome de Activación Macrofágica/virología , Insuficiencia Multiorgánica/virología , Pandemias , Peptidil-Dipeptidasa A/genética , Neumonía Viral/enzimología , Neumonía Viral/virología , SARS-CoV-2RESUMEN
We describe a case of an adult with dermatomyositis (DM) who presents with a rash, high fevers, tachycardia and hypotension, initially concerning for an infectious aetiology or a DM flare. She was found to have cytomegalovirus viraemia which improved after starting valganciclovir. After extensive workup and lack of improvement with broad-spectrum antimicrobial therapy, intravenous immunoglobulin and steroids, the patient was diagnosed with macrophage activation syndrome after bone marrow biopsy and levels of soluble CD25 (soluble interleukin (IL)-2 receptor) and IL2 were obtained. Unfortunately, despite therapy with dexamethasone, anakinra and etoposide, the patient decompensated and the patient's family opted for comfort care. The patient subsequently expired in the intensive care unit.
Asunto(s)
Infecciones por Citomegalovirus/fisiopatología , Dermatomiositis/fisiopatología , Ganciclovir/análogos & derivados , Inmunoglobulinas Intravenosas/uso terapéutico , Síndrome de Activación Macrofágica/diagnóstico , Infecciones por Citomegalovirus/sangre , Infecciones por Citomegalovirus/tratamiento farmacológico , Dermatomiositis/sangre , Dermatomiositis/tratamiento farmacológico , Dermatomiositis/virología , Resultado Fatal , Femenino , Ganciclovir/uso terapéutico , Humanos , Síndrome de Activación Macrofágica/fisiopatología , Síndrome de Activación Macrofágica/virología , Persona de Mediana Edad , Valganciclovir , ViremiaRESUMEN
This study aims to investigate the clinical significance of serum soluble CD163 (sCD163) levels as a predictor of the disease activity of systemic juvenile idiopathic arthritis (s-JIA). In this study, we examined 63 patients with s-JIA, four with Epstein-Barr virus-induced hemophagocytic lymphohistiocytosis (EBV-HLH), and seven with Kawasaki disease (KD), along with 14 healthy controls. We quantified serum cytokine levels (sCD163, neopterin, IL-18, IL-6) by enzyme-linked immunosorbent assay and compared the results with the clinical features of s-JIA. Serum sCD163 levels were significantly elevated in patients with s-JIA associated macrophage activation syndrome (MAS) and EBV-HLH compared to those in patients with acute-phase s-JIA and KD. In addition, serum sCD163 levels profoundly increased with the progress of MAS and correlated positively with the disease activity of s-JIA, even in patients receiving tocilizumab. Furthermore, serum sCD163 levels significantly decreased in the inactive phase compared to those in the active phase and normalized in remission. The correlation between macrophage activation and serum sCD163 levels might be a unique indicator of the disease activity and a potential diagnostic laboratory criterion for clinical remission in patients with s-JIA, including those receiving tocilizumab.
Asunto(s)
Antígenos CD/sangre , Antígenos de Diferenciación Mielomonocítica/sangre , Artritis Juvenil/sangre , Biomarcadores/sangre , Herpesvirus Humano 4/patogenicidad , Activación de Macrófagos/fisiología , Receptores de Superficie Celular/sangre , Anticuerpos Monoclonales Humanizados/farmacología , Artritis Juvenil/tratamiento farmacológico , Niño , Citocinas/sangre , Femenino , Humanos , Interleucina-18/sangre , Interleucina-6/sangre , Linfohistiocitosis Hemofagocítica/sangre , Linfohistiocitosis Hemofagocítica/virología , Activación de Macrófagos/efectos de los fármacos , Síndrome de Activación Macrofágica/sangre , Síndrome de Activación Macrofágica/virología , Masculino , Síndrome Mucocutáneo Linfonodular/sangre , Síndrome Mucocutáneo Linfonodular/virología , Neopterin/farmacologíaAsunto(s)
Infecciones por Virus de Epstein-Barr/diagnóstico , Fiebre/diagnóstico , Enfermedades Linfáticas/diagnóstico , Síndrome de Activación Macrofágica/diagnóstico , Sudoración , Adolescente , Antiinflamatorios/uso terapéutico , Artritis Juvenil/diagnóstico , Dexametasona/uso terapéutico , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Infecciones por Virus de Epstein-Barr/virología , Fiebre/tratamiento farmacológico , Fiebre/virología , Herpesvirus Humano 4/patogenicidad , Humanos , Enfermedades Linfáticas/tratamiento farmacológico , Enfermedades Linfáticas/virología , Síndrome de Activación Macrofágica/tratamiento farmacológico , Síndrome de Activación Macrofágica/virología , MasculinoRESUMEN
Bacterial respiratory infections have an important impact on the development and progression of pulmonary disease in cystic fibrosis (CF). Viral infections are possible triggers of acute deterioration in the clinical status of CF patients. Macrophage activation syndrome (MAS) is a life-threatening complication of rheumatic disease characterized by pancytopenia, hepatitis, hyperferritinemia, coagulopathy, and neurologic symptoms. This syndrome is thought to be caused by the activation and uncontrolled proliferation of T lymphocytes and well-differentiated macrophages, leading to widespread hemophagocytosis and cytokine overproduction. Here, we report the case of a boy affected by CF who developed MAS triggered by pandemic H1N1 influenza; good clinical response was obtained through high dose prednisone treatment.