COVID-19, haemophagocytic lymphohistiocytosis, and infection-induced cytokine storm syndromes.

We welcome the Grand Round by Danielle Steed and colleagues describing bartonella-associated haemophagocytic lymphohistiocytosis in an immunosuppressed patient. This paper highlights the broader topic of infection-induced cytokine storm syndromes. Recent research in COVID-19 cytokine storm syndrome and Castleman disease has expanded the concept of pathological immune activation and established important principles applicable to other infection-induced cytokine storms.

First, key cytokines and chemokines driving the pathological process can be identified, and inhibiting these cytokines can improve outcomes (table ). For example, interleukin (IL)-6 drives much of the pathophysiology of COVID-19 cytokine storm syndrome and Castleman disease, and inhibition of IL-6 is effective in both diseases. Second, immunomodulation in cytokine storms can be beneficial even in the absence of effective antimicrobial therapies. In the case presented by Steed and colleagues, there were effective treatments for both microbes involved; antiretroviral therapy for HIV and doxycycline for bartonella. By contrast, immunomodulatory therapies, such as IL-6 inhibition and Janus kinase (JAK) inhibition, decrease mortality in patients with severe COVID-19 even without antiviral therapies. Third, although Steed and colleagues are correct in highlighting etoposide and dexamethasone-based therapies as the cornerstone of haemophagocytic lymphohistiocytosis treatment, recent advances in treatment for this disease that parallel treatment of COVID-19 cytokine storm syndrome are worth noting. Emapalumab, an inhibitor of interferon γ (IFNγ), is highly active and has minimal toxicity in paediatric patients with primary haemophagocytic lymphohistiocytosis. Additionally, JAK inhibitors, such as ruxolitinib, can salvage patients with haemophagocytic lymphohistiocytosis associated with infection and malignancy who would otherwise be difficult to treat with chemotherapy.

Table

Infection-induced cytokine storm syndromes

	Microbe	Key cytokines or chemokines	Targeted therapies
COVID-19 cytokine storm	SARS-CoV-2	IL-6	IL-6 inhibitors (tocilizumab) and JAK inhibition (baricitinib)
Human herpes virus-8-positive Castleman disease	HIV and human herpes virus-8	IL-6 and CXCL-13	IL-6 inhibitors (siltuximab) and B-cell depletion (rituximab)
Primary haemophagocytic lymphohistiocytosis	Various (eg, Epstein-Barr virus and cytomegalovirus)	IFNγ and CXCL-9	IFNγ inhibition (emapalumab) and JAK inhibition (ruxolitinib)
Secondary haemophagocytic lymphohistiocytosis or macrophage activation syndrome	Various (eg, Mycobacterium tuberculosis, Leishmania parasites, and Bartonella spp)	IL-1, IL-6, IL-18, and IFNγ	IL-1 inhibition (anakinra), IL-6 inhibition (tocilizumab), and JAK inhibition (ruxolitinib)

CXCL=CXC motif chemokine. IFN=interferon. IL-interleukin. JAK=Janus kinase.

Finally, the statement that “Bone marrow aspiration has been shown to be the most likely test to lead to recognition of haemophagocytic lymphohistiocytosis” requires a caveat. Although bone marrow aspiration is indeed a very important test in patients suspected of having haemophagocytic lymphohistiocytosis, haemophagocytosis does not always signify the pathological immune activation that defines a cytokine storm. Reactive haemophagocytosis can be seen in a wide variety of conditions, including haemolysis, autoimmune disease, sepsis, and after blood transfusions. Additionally, the presence of haemophagocytosis in the bone marrow is not required for diagnosis of haemophagocytic lymphohistiocytosis if other criteria are met. Specialised tests to help distinguish haemophagocytic lymphohistiocytosis from other conditions, such as flow cytometry for perforin, natural killer-cell cytotoxicity, and T-cell activation profiles, and measurement of serum soluble IL-2 receptor, CXCL-9, and IL-18, are not widely available. Haemophagocytic lymphohistiocytosis is a clinicopathological diagnosis that requires a clinician to combine the available clinical and laboratory evidence to determine that a patient has a pathological immune activation.

LYCC received advisory board fees from EUSA-Pharma, and speakers fees from GlaxoSmithKline, outside of the submitted work. LYCC's research is supported by the Hsu & Taylor Family, a philanthropic fund at the VGH & UBC Hospital Foundation. All other authors declare no competing interests.