A Rare STXBP2 Mutation in Severe COVID-19 and Secondary Cytokine Storm Syndrome

Abstract

Background: Primary (familial) hemophagocytic lymphohistiocytosis (pHLH) is a potentially lethal syndrome of infancy, caused by genetic defects in natural killer (NK) cell and CD8 T cell cytotoxicity, leading to hyperinflammation, elevated cytokine levels, and a disorganized immune response resulting in multi-organ system failure and frequently death. Secondary HLH (sHLH) can be triggered in the setting of malignances, diseases of chronic immune system activation, or by infectious etiologies. While pHLH is usually a result of homozygous gene mutations, monoallelic hypomorphic and dominant-negative mutations in pHLH genes have been implicated in sHLH. Coronavirus disease 2019 (COVID-19) has been an omnipresent viral infection since its arrival, and severe cases can present with cytokine storm and have clinical features and laboratory findings consistent with sHLH. Herein, we report an adolescent with severe COVID-19, decreased NK cell function, and features of sHLH. Her genetic evaluation identified a monoallelic missense mutation in the pHLH gene STXBP2, and NK cell assays of her blood showed decreased cytolysis and degranulation ex vivo. Methods: Patient data was extracted through an electronic medical record review. Using a lentiviral approach, the patient’s STXBP2 mutation and wild-type (WT) STXBP2 were separately transduced into the NK-92 human NK cell line. The WT and mutant STXBP2 transduced NK-92 cells were stimulated with NK-sensitive K562 erythroleukemia target cells in vitro, and NK cell degranulation and cytolysis were measured via CD107a expression and Live/Dead near-IR dye, respectively. Results: Compared to WT STXBP2, the patient’s STXBP2 mutation caused significantly decreased NK cell cytolysis and associated degranulation in vitro. Conclusion: These findings add weight to the hypothesis that some severe cases of COVID-19 may be accompanied by sHLH and hyperinflammation, especially in the setting of heterozygous pHLH genetic mutations. This has implications both diagnostically and therapeutically for severe COVID-19.

Impact of SARS-CoV-2 infection and COVID-19 on patients with inborn errors of immunity

“…Over the past 2 years, outcomes of SARS-CoV-2 infection have been reported for ∼1330 individuals with IEI. These studies range from reports of single cases or small numbers of patients 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 to cohort studies from Iran, 89 , 90 , 91 Turkey, 92 , 93 , 94 Brazil, 95 , 96 Israel, 97 Italy, 98 , 99 , 100 , 101 Spain, 102 the United Kingdom, 15 , 103 , 104 Mexico, 105 Denmark, 106 , 107 Poland, 108 …”

Intravenous anakinra for the treatment of haemophagocytic lymphohistiocytosis/macrophage activation syndrome: A systematic review

“…In comparison, infection was the predominant underlying trigger for adult patients (50%, n = 26) (Figure 2C). Of these, 69.2% ( n = 19, across three articles 46,47,53,56 ) were triggered by COVID‐19. Rheumatological diagnoses were present in around a quarter of adult patients (25.9%, n = 14), oncological diagnoses in 13%, no known triggers for 5.7% and 5.6% other.…”

“…54,57 In comparison, infection was the predominant underlying trigger for adult patients (50%, n = 26) (Figure 2C). Of these, 69.2% (n = 19, across three articles 46,47,53,56 ) were triggered by COVID-19.…”

DOCK2 Mutation and Recurrent Hemophagocytic Lymphohistiocytosis

“…Thus, both DOCK2 and DOCK8 missense mutations may contribute to sHLH in susceptible hosts by diminishing NK cell lytic function. Dominant-negative patient-derived missense mutations have been studied for several pHLH genes, including PRF1 , STXBP2 , and RAB27A [ 10 , 12 , 25 , 26 , 27 , 28 , 29 ]. While some missense variants in HLH genes can act as complete dominant-negative mutations, most have partial dominant-negative effects on perforin-mediated cytolysis, as is noted for the DOCK2 mutation reported herein [ 28 ].…”

“…Statistical analyses were performed with GraphPad Prism 6 (GraphPad Software, La Jolla, CA, USA) software. Two-way ANOVA analysis was used to calculate p values (α = 0.05) for the NK-92 cell cytotoxicity assays [ 10 ].…”