Discussion

HLH is a life-threatening disease characterized by excessive activation of macrophages, the inability of NK cells and T-cells CD8+ to eliminate these macrophages, and cytokine storm; this condition leads to cytopenias, especially thrombocytopenia and anemia [7]. HLH can occur in two conditions: a primary form, also called Familiar HLH (fHLH), and a secondary form (sHLH) triggered by an underlying disorder. The primary form of HLH is due to genetic mutations, and the more implicated genes are involved in the perforin-mediated cytotoxicity [8]. This fact could seem contradictory, but it is not: the inability to remove the pathological antigen promotes further inflammation to reinforce the immune system in vain. On the other hand, secondary forms can be triggered by infections, typically viral ones [2], malignancies, and rheumatological diseases; in this specific case, secondary HLH is called “macrophage activation syndrome” (MAS).

The main element of both forms of HLH is the “cytokine storm” responsible for an uncontrolled and exaggerated immune response, potentially leading to organ dysfunction and death. Various cytotypes of innate and adaptive immune systems are involved in the cytokine storm. Macrophages release excessive cytokines with proinflammatory functions, such as interleukin (IL) -1, IL-6, IL18, IL-33, and tumor necrosis factor (TNF), which cause serious tissue injury with potential organ dysfunction.

Activated macrophages are also responsible for excessive haemophagocytosis in bone marrow, leading to cytopenias common in patients affected by HLH [1]. NK cells in normal conditions can harm pathological cells mainly with a granzyme and perforin-mediated process; during cytokine storm, the large amount of IL-6 seems to inhibit this process, encouraging the pathogens’ persistence and the development of further phlogosis.

Neutrophils injure tissues and amplify inflammation; furthermore, they release extracellular traps capable of promoting the creation of thrombi. T helper-1 (Th1) cells are the most involved during cytokine storm and release a large number of proinflammatory cytokines, such as interferon-γ, IL-6, and TNF; on the other hand, Th17 cells promote the recruitment of neutrophils, Th2 cells encourage the activation of eosinophils and basophils, Th9 cells activate mast cells. Like NK cells, the cytotoxic action of T cells CD8+ against pathogens is weakened, leading to inflammation maintenance. B cells seem not to be involved in the process of the cytokine storm. The diagnosis of HLH is based on the presence of five of the following eight HLH-2004 criteria: Fever (T >38,5 C°), splenomegaly, bicytopenia, hypertriglyceridemia and hypofibrinogenemia, hyperferritinemia, the sign of hemophagocytosis in bone marrow aspiration or biopsy, low or absent NK cell activity, increased levels of soluble CD25 [9].

In this last period, the novel Coronavirus infection, COVID-19, has established itself as another cause of Hemophagocytic lymphohistiocytosis. There are two different hypotheses of the pathogenesis of COVID-19-related cytokine storm: the first one identifies the viral infection as the trigger for the storm’s development. This model is common to the other viruses mentioned above, such as EBV; on the other hand, the second one suggests that the immunodeficiency induced by SARS-CoV-2, characterized by lymphopenia, and the consequent inability to remove the virus could lead to the development of a “second wave inflammation”, similarly to primary HLH: in this scenario, IL-6 seems to play a critical role in the development of HLH, justifying the rationale of the therapeutic use of Tocilizumab, a monoclonal antibody against the IL-6 receptor [4].

The clinical case we have described is characterized by the onset of a hemophagocytic lymphohistiocytosis in a patient with a recent SARS-CoV-2 infection. During hospitalization, we observed spontaneous clinical and laboratory improvement in the absence of therapeutic measures of any kind, confirming the resolution of the picture through a six-month follow-up by hematochemical tests (Table 1). The fact that symptomatology started once the patient stopped the COVID-19 therapy with steroids suggests a possible correlation between HLH and the previous viral infection of the novel coronavirus. Furthermore, the persistence of the cytokine storm even after the recovery from COVID-19 could mean that HLH was not the result of the immunodeficiency and the consequent “second wave inflammation” provoked by SARSCoV-2 infection.

Consequently, it seems to be reasonable to hypothesize that SARS-CoV-2 triggered the development of HLH similarly to other viral infections, such as EBV; nevertheless, it is not possible to exclude that HLH started during COVID-19 caused by the immunodeficiency related to the disease and continued even after the infective trigger disappeared. Steroids could have concealed the subacute progress of HLH, which was exacerbated after the interruption of the immunosuppressive therapy. The literature currently reports a few documented cases of COVID-19 patients and HLH with signs of hemophagocytosis in bone marrow aspiration or biopsy [3].

Conclusions

Our case report suggests some possible essential and novel issues concerning the correlation between infection of Covid 19 and the insurgence of HLH with a documented sign of hemophagocytosis in bone marrow aspiration. Moreover, we hypothesized that SARSCoV-2 triggered the development of HLH similarly to other viral infections. Furthermore, our report proposes a viral etiology of sHLH even if it is impossible to exclude that HLH could have been caused by the immunodeficiency and the consequent cytokine storm and “second wave inflammation” induced by COVID-19. Sure of the fact that we have no firm evidence to determine what the exact pathogenesis of sHLH may have been in this case, we hope to have sparked a debate about the possible pathogenetic role that SARSCoV-2 virus plays in hemophagocytic syndrome, but also about whether the onset of sHLH depends on the immunocompromising and subsequent cytokine storm that the viral infection induces, two sides of a coin that we cannot yet fully visualize.

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