Dear Editor, we read with interest the article by McGonagle et al., which has been recently published on this Journal [1]. This article highlights the role of pro-inflammatory cytokines in inducing pneumonia and cytokine storm syndrome in patients with severe coronavirus disease 2019 (COVID-19)[1]. We agree with the Authors with the relevance of development of cytokine storm syndrome in these patients, since it is associated with a high mortality rate [2]. The term cytokine storm syndrome accommodates the observation that multiple inflammatory causes may result in a clinical picture resembling sepsis [2], clinically characterised by continuous fever, multiorgan failure, hyperferritinemia, and, potentially, death [2, 3]. Different aetiologies are consequently recognised, either iatrogenic, inflammatory, or infectious, in inducing this syndrome, which may be considered the common end point of the overwhelming massive systemic inflammation [3]. Considering iatrogenic trigger, a cytokine storm syndrome may be induced by cancer immunotherapy [4]. This is one of the most important adverse event of these therapies, as shown by T cell-engaging therapies and CD19-targeted CAR T cells [4]. As far as the inflammation is concerned, the haemophagocytic lymphohistiocytosis (HLH) represents a prototype of cytokine storm syndrome, characterised by hyperinflammatory response leading to organs damage [5]. HLH has traditionally been classified into primary and secondary forms [6]. The primary forms of HLH are those related to genetic abnormalities leading to deficiency in cytotoxic cell function, concerning perforin or molecules associated with perforin vesicular transport and release [7]. The secondary forms of HLH may be triggered by infections, cancer, or inflammatory diseases. Secondary form of HLH, which occurs in the context of rheumatic diseases is generally termed macrophage activation syndrome (MAS) or rheuma HLH [7]. The typical hallmark of all these forms of HLH is the presence of hemophagocytes, activated macrophages which are engulfed by hematopoietic cells [5]. Although this histological feature could be elusive, the peripheral blood bi-or pan-cytopenia, depending from haemophagocytosis and severe cytokine-mediated inflammation, are key laboratory markers inducing the suspicion of HLH [5–7].

During COVID-19, a virally induced cytokine storm syndrome occurs in more aggressive patients, who are characterised by severe lung involvement, probably associated with a specific genetic susceptibility [8–10]. In the article by Mc Gonagle et al.[1], following as already proposed in sepsis [11], the Authors define this clinical phenotype as MAS-like syndrome, but two of the main features of primary or secondary HLH, the hemophagocytosis and the peripheral blood bi-or pancytopenia have been not clearly demonstrated in COVID-19 [5–7, 12]. The reports from Wuhan suggested that patients developing severe COVID-19 showed an isolated lymphopenia [13, 14], and personal observations from patients enrolled in our study, including SARS-CoV2 infected patients developing severe lung involvement, confirm this