Severe COVID-19, Another Piece in the Puzzle of the Hyperferritinemic Syndrome. An Immunomodulatory Perspective to Alleviate the Storm

Abstract

The coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has been declared as a worldwide public health emergency. Interestingly, severe COVID-19 is characterized by fever, hyperferritinemia, and a hyper-inflammatory process with a massive release of pro-inflammatory cytokines, which may be responsible for the high rate of mortality. These findings may advocate for a similarity between severe COVID-19 and some challenging rheumatic diseases, such as adult onset Still's disease, secondary hemophagocytic lymphohistiocytosis, and catastrophic anti-phospholipid syndrome, which have been included in the "hyperferritinemic syndrome" category. Furthermore, as performed in these hyper-inflammatory states, severe COVID-19 may benefit from immunomodulatory therapies.

Keywords: COVID-19; adult onset Still's disease; catastrophic anti-phospholipid syndrome; haemophagocytic lymphohistiocytosis; hyper-inflammation; hyperferritinaemic syndrome; hyperferritinemia.

Figure 1

Coronavirus RNAs may act as pathogen-associated molecular patterns, detected by the pattern recognition receptors, triggering downstream cascades molecules, and leading to the production of pro-inflammatory mediators. Interestingly, during the acute respiratory distress syndrome of coronavirus disease 2019 (COVID-19), the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) may trigger a hyper-inflammatory reaction strongly resembling what observed in the lung involvement of systemic juvenile idiopathic arthritis, in which the development of a pulmonary hyper-inflammatory process, has been reported, mediated by an increased release of interleukin (IL)-1β and IL-6, associated with a tissue hyper-expression of interferon (IFN)-related genes. The final result of all these mechanisms is the uncontrolled proliferation of activated immune cells, the massive production of pro-inflammatory mediators, and the development of cytokine storm syndrome. On these bases, it is reasonable to postulate the clinical usefulness of IL-1 β, IL-6, and IFN-y inhibition on targeting severe COVID-19, as reported in other hyper-inflammatory diseases.