Interferon Gamma, a Link between Hemophagocytic Lymphohistiocytosis and Dengue Fever Virus: A Literature Review of a Shared Inflammatory Pathway Resulting in Cytopenias and Potential Future Treatment Directions
Authors: Liles Darla K , Brody Heather , Alvarez Posada Juan , Hebishi Karim , Thiele John 
Published: November 2019

Our patient was an elderly female, previously healthy, who presented with fever, anemia, thrombocytopenia, and enlarged spleen. Her complaints were progressive over the course of two months. She was treated with antibiotics with no improvement. Underlying lymphoproliferative disorder was suspected, and a bone marrow biopsy and aspiration was completed. While there was no evidence for lymphoproliferative disorder, there was hemophagocytosis. Further evaluation revealed ferritin 1,151 ng/mL, soluble IL2 receptor 32,186 u/mL, and natural killer activity was low. She was diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH). During her evaluation, her condition acutely worsened; she became encephalopathic with hypotension requiring vasopressor support and respiratory failure. The patient was given etoposide with rapid improvement in overall clinical status though further cytopenias secondary to etoposide prevented further treatment.
She was ultimately diagnosed with Dengue Fever Virus by IgM Antibody, 4.54, with positive result >/= 2.84. A positive result is highly suggestive of acute disease, though cross reactivity is possible with other flavi viruses. The result was confirmed. The patient lived in a rural community in Eastern NC and had no travel history; the diagnosis was reported to the North Carolina public health department and the Center for Disease Control. Despite recognition and treatment of the HLH and Dengue fever, the patient died of complications.
Both Dengue Fever and HLH cause significant morbidity and mortality. Their disease courses, while unique, do have some interesting parallels. They both can be associated with significant suppression of bone marrow function, frequently being associated with cytopenias. This is a major source of morbidity in both disease states.
While Dengue Fever is a known, though rare, cause of HLH, it has not previously been reported in the continental United States.
In this case report, we examine the known cytokine pathway activations in each disease state and their commonalities, focusing on bone marrow suppressive cytokines and subsequently suggesting mechanisms for targeted treatment of HLH.
Even with our best treatments, in HLH, the associated mortality among all causes is around 42%. The mortality for untreated severe dengue is as high as 20% though with appropriate care, that is much improved at 1-2%.
In HLH and Dengue, IL-1B, IFN-Ƴ, IL6, and TNF-α are increased. A common cytokine, IFN-Ƴ, directly affects bone marrow activity and can alter hematopoiesis. IFN-Ƴ is directly implicated in several bone marrow failure syndromes making it an attractive target to modulate. Based on results of an in vitro study of CD34+ hematopoietic stem cells (HSC) in the presence and absence of IFN-Ƴ in differing concentrations, IFN-Ƴ inhibited the ability of HSC to repopulate themselves though it did not affect their ability to differentiate. This was also shown in vivo in a mouse HSC transplant model with mirroring results. In our patient, it follows logical and chronological progression that her cytopenias worsened over time as her pool of CD34+ HSC was depleted. Additional studies of IFN-Ƴ and hematopoiesis suggest that IFN-Ƴ directly negatively affects the supportive bone marrow mesenchymal stoma cells which provide the cytokine environment that supports HSC repopulation.
IFN-Ƴ is produced from the innate immune system via dendritic cells, natural killer (NK), and natural killer T (NKT) cell and in the adaptive immune system via Th1 T lymphocytes. IFN-Ƴ is a major activator of macrophages which in turn are responsible for secreting multiple other pro-inflammatory cytokines as previously mentioned. In Dengue, the innate immune system is activated via macrophage and dendritic cells. In HLH, IFN-Ƴ is primarily produced by T-cells. IFN-Ƴ is known to stimulate the janus kinase-STAT (JAK-STAT) signaling pathway in macrophages to increase inflammation. We suggest that modulation of the cytokines directly involved in the inflammatory syndrome might be considered.
In summary, we report a case of Dengue fever with associated secondary HLH. This is the first report of Dengue fever in the continental United States in a person without travel history. In addition, this case report highlights the commonalities of the immune activation seen in both Dengue fever as well as secondary HLH and may indicate the potential for more targeted immunomodulation.

Disclosures
Liles: Imara: Other: PI on Clinical trial- Sickle cell ; Novartis: Other: PI on clinical trial Sickle cell ; Shire: Other: PI on clinical trial Sickle cell .