Interestingly, TNF concentrations in plasma were not significantly elevated in the early stages of disease in critically ill patients compared to patients admitted to the ward: median 24.0 pg/ml and 21.5 pg/ml, respectively. We and others have identified an IL-1/IL-6-driven innate immune response. Many other patients show signs of a cytokine storm syndrome, but do not fulfill the criteria of MAS/HLH. However, currently, it becomes clear that only a minority of patients with COVID-19 develop MAS/HLH. In other studies with SARS-CoV-2 pneumonia, patients that needed ICU admission more often had leukocytosis, higher neutrophil counts, lower lymphocyte counts, elevated D-dimer, and highly elevated LDH, and the main reason patients were admitted to the ICU was ARDS. In SARS-CoV-2 infection, elevated IL6 and ferritin concentrations have also been described. Another study revealed high IL-18-circulating concentrations, a cytokine that is associated with MAS, and MAS has also been reported in SARS. Lung histology in COVID-19 shares similarities to SARS, MERS, and influenza. Similar pulmonary hyperinflammation was seen on the histology in MERS patients. ARDS was thought to be due to an exacerbated innate host response to SARS-CoV.
#COVID ILLINOIS 1B SERIES#
In the case series of critically ill patients with SARS from Toronto and Singapore, ARDS and multiple organ failure were frequently observed. Underscoring the importance of the inflammasome/IL-1 pathway in MAS is the observation that a monogenetic mutation in the inflammasome underlies primary MAS.
A whole-exome study performed in fatal cases of H1N1 with signs of MAS found a high percentage of mutations in genes that are linked to genetic causes of diseases similar to MAS/HLH, suggesting that the genetic background of the patient predisposes to developing MAS in influenza. Inflammasomes are protein complexes that activate caspase-1 protease that in turn processes proinflammatory cytokines from the IL-1 family (e.g., IL-1β, IL-18) into active cytokines. Lethal complications of influenza are consistent with inflammasome-mediated disease with signs of MAS.
This phenomenon is a hallmark of macrophage activation syndrome (MAS), or named secondary HLH (sHLH). Autopsy in young, previously healthy, patients that died during the H1N1 influenza 2009 pandemic revealed evidence of “cytophagocytosis” in the lung. The most severely ill patients infected with SARS-CoV or influenza seem to develop an immune phenotype that can be described as an inflammasome-mediated hyperinflammatory status, causing respiratory failure and secondary infections. The novel coronavirus SARS-CoV-2 is highly likely to have similarities to other coronaviruses such as SARS-CoV, with which it has the strongest sequencing similarities, and other severe respiratory virus infections such as influenza. This is essential in the pathway towards developing new, or repurposing existing, therapies that can be used in the treatment of patients with SARS-CoV-2.
In addition to the lack of available treatments known to be effective, insight into the pathophysiology of this coronavirus needs to be urgently addressed. There are currently only small observational trials that contribute to the evidence for the benefit or harm of these interventions in COVID-19. Other immune modulatory treatments of interest include blocking the IL-1 or IL-6 pathway, the use of interferon-β, and many others. However, a more recent study showed that early short-course corticosteroids during admission were associated with fewer ICU admissions, and a yet to be published study on dexamethasone argues that it can save lives especially in mechanically ventilated patients. Although ICU patients have been treated with glucocorticoids, some experts have even argued, based on studies in Middle-Eastern respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome (SARS), influenza, and respiratory syncytial virus (RSV), that they are likely to do more harm than good. An important aspect of severe COVID-19 is a hyperinflammatory status, and immunomodulatory therapy might therefore be an important aspect in the treatment of COVID-19. Understanding this outbreak, including the effectiveness of supportive, immune-modulatory, and antiviral treatments, is essential. Although the majority of patients with COVID-19 are asymptomatic or have mild SARS-CoV-2 infections, many patients have been hospitalized and admitted to intensive cares (ICUs) and mortality is significant.
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