https://orcid.org/0000-0002-6490-731X
ABSTRACT
Although COVID-19 vaccines are an effective public health tool to combat the global pandemic, serious adverse events, such as hemophagocytic lymphohistiocytosis (HLH), caused by them are a concern. In this systematic review, cases of HLH reported after COVID-19 vaccination have been examined to understand the relationship between the two and propose effective therapeutic strategies. Furthermore, ruxolitinib’s potential as a cytokine inhibitor and its affinity for CD25 were initially assessed through molecular docking, aiming to aid targeted HLH therapy. PubMed and Web of Science databases were searched for published individual case reports on the occurrence of HLH after the administration of any COVID-19 vaccine. A total of 17 articles (25 patients) were included in this qualitative analysis. Furthermore, molecular docking was employed to investigate the therapeutic potential of ruxolitinib for HLH after COVID-19 vaccination. The mean age of patients who developed HLH after COVID-19 vaccination was 48.1 years. Most HLH episodes occurred after the BNT162b2 mRNA COVID-19 vaccination (14/25 cases) and to an extent after the ChAdOx1 nCov‐19 vaccination (5/25 cases). Almost all affected patients received steroid and antibiotic therapy. Three patients died despite treatment because of esophagus rupture, neutropenic fever, bacteroides bacteremia, refractory shock, and encephalopathy and shock. Visual docking results of IL-2 Rα and ruxolitinib using the Discovery Studio 2019 Client software yielded a model score of 119.879. The findings highlight the importance of considering and identifying the adverse effects of vaccination and the possibility of using ruxolitinib for treating HLH after COVID-19 vaccination.
GRAPHICAL ABSTRACT
Introduction
As of February 13, 2023, approximately 13.2 billion vaccine doses have been administered worldwide as a defense against the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (https://covid19.who.int/?gclid=CjwKCAjwrcH3BRApEiwAxjdPTcruNm9OZHGuwIcAzLl6ZMuoBXCXswyh8SI2_DCQiVaAZliNViNrGhoCBKsQAvD_BwE). Over 165 vaccines against SARS-CoV-2 have so far been developed by various companies and institutions worldwide, 28 of which have been approved for use, including virus vaccines, viral vector vaccines, and nucleic acid vaccines.Citation1,Citation2 With the increase in the use of these vaccines, rare and severe hematologic side effects, such as hemophagocytic lymphohistiocytosis (HLH) and thrombotic thrombocytopenic purpura (TTP), have occurred.
HLH, also called hemophagocytic syndrome (HPS), is an acute and severe hyperinflammatory disease characterized by cytokine increase, progressive cytopenia, and hyperferritinemia.Citation3 The pathophysiological mechanisms of HLH tend to vary and are not entirely definite, but one common pathogenesis is cytokine storm, which exhibits significant similarities with cytokine storms caused by COVID-19.Citation4 Some studies have indicated a close relationship between severe COVID-19 and HLH.Citation5–7 In this study, 25 case reports of HLH/HPS after the administration of COVID-19 vaccination were collected to analyze whether the vaccination is potentially associated with HLH. Timely diagnosis is of immense significance for COVID-19 vaccine recipients experiencing HLH as it can aid in reducing mortality rates.
Elevated levels of CD25, a diagnostic criterion for HLH, are a major indicator of its presence. CD25 represents the α chain of interleukin (IL)-2 R, which emphasizes its relevance. Consequently, targeted reduction of the CD25 level could potentially exert inhibitory effects on the occurrence of HLH. As the mechanism of action of ruxolitinib involves the suppression of proinflammatory cytokines, such as IL-2 R, IL‐6, IL‐10, and interferon (IFN)‐γ, and the drug possesses the distinctive feature of rapid and reversible modulation, it is a compelling therapeutic avenue for addressing the complexities of HLH.
The research on cytokine storm performed in this systematic review provides a possibility for improving the prognosis of patients with COVID-19 using the cytokine-targeting drug ruxolitinib.
Search strategies
The included case reports in terms of HPS/HLH after receiving the COVID-19 vaccine were obtained from PubMed and the Web of Science without any restrictions on the publishing year, country of origin, or language. We performed the first search on December 30, 2022, followed by a second research on February 5, 2023. Furthermore, all references in the included case reports were studied to avoid any omissions. The search themes used in the Web of Science were presented as follows: TS = (“Covid-19 vaccine” OR “Coronavirus vaccine” OR “Covid-19 vaccination” OR “Coronavirus vaccination” OR “Covid-19 vaccinate” OR “Coronavirus vaccinate” OR “Covid-19 injection” OR “Coronavirus injection”) AND (“hemophagocytic syndrome” OR “hemophagocytic lymphohistiocytosis” OR “hemophagocytic reticulosis”), meanwhile the type of articles was restricted to “case report.” We searched for keywords in PubMed the same as those listed above, with the search conducted in all fields, after which the articles were selected.
Study selection
A total of 41 articles in PubMed and 17 articles in the Web of Science were retrieved from the database with the selected keywords. Next, 13 duplications were removed before the screening. In the screening section, 20 records were excluded and 25 reports were assessed for eligibility. Finally, we concluded 25 case reports for our study ().
Figure 1. PRISMA flow diagram for study selection.
The following data in the table was retrieved in each valid report: 1. Name of the first author and published year; 2. Age, gender, and region of the patient; 3. Vaccine type and the number of doses; 4. The onset of symptoms after vaccination; 5. Specific clinical test data including coagulation, hematology, hepatic and renal functions; 6. Past medical history of the patient; 7. Clinical presentation; 8. Treatment received; 9. Outcomes of patients ().
Table 1. Patients from respective case reports included in the analysis.
Results
Case review
A total of 25 patients were included in the analysis of case reports on HPS/HLH after the administration of the COVID-19 vaccine (). Both sexes were almost equally represented (12 women; 13 men). The mean age of patients who developed HPS/HLH after COVID-19 vaccination (n = 25, with n denoting the number of patients) was 48.1 years. Maximum cases were reported in the United States (n = 9), followed by the United Kingdom (n = 4) and China (n = 3). Of the patients included, four had a past medical history of hypertension,Citation8–11 two had type 2 diabetes,Citation10,Citation12 and one had familial HLH type 3.Citation13 The possibility of HLH due to previous medical history could not be ruled out. HPS/HLH episodes occurred mainly after the BNT162b2 mRNA COVID-19 vaccination (after the first dose, n = 8;Citation14 after the second dose, n = 4;Citation14 not mentioned, n = 2) and to an extent after the ChAdOx1 nCov-19 vaccination (after the first dose, n = 5) and mRNA-1273 vaccination (two doses, n = 1; not mentioned, n = 2).Citation15–17 The most typical clinical presentation was high fever, myalgia, and fatigue. Some patients presented hypotension (n = 4) and loss of weight and appetite. In addition, HBS/HLH after the COVID-19 vaccination affected the face (e.g., facial edema), sleep (e.g., lethargy and disturbed sleep), nervous system (e.g., slurred speech), skin (e.g., skin rash and erythema), and breathing (e.g., tachypnea and breathlessness). The mean duration between the vaccination and the onset of symptoms was 16.5 days (n = 23), excluding two cases (not mentioned, n = 1; shortly after vaccination, n = 1.Citation18 Almost all patients received steroid and antibiotic therapy, of which 11 received dexamethasone, 10 received methylprednisolone, 10 received prednisolone, and 6 received immunoglobulin. Three patients died because of esophagus rupture (n = 1),Citation12 neutropenic fever, bacteroides bacteremia, refractory shock (n = 1), and encephalopathy and shock (n = 1).Citation19
Molecular docking
Molecular docking was performed to explore the therapeutic potential of ruxolitinib for HLH after COVID-19 vaccination. IL-2 Rα (PDB database code: 1Z92) and ruxolitinib (PubChem database CID: 25126798) were docked using the Dock Ligands (LibDock) module in the Discovery Studio 2019 Client software.Citation20 The LibDock protocol is an interface of the LibDock program developed by Diller and Merz, which is a high-throughput algorithm for docking selected ligands to active receptor sites.Citation21 Structure files of IL-2 Rα and ruxolitinib were downloaded from the above databases and introduced into the Discovery Studio 2019 Client software. It was used for data preprocessing and molecular docking, and the results were visualized and assessed according to the LibDock score and binding energy. A higher LibDock score and lower binding energy predict better binding potential between the small-molecule drug and protein. The LibDock score and binding energy of the optimal model were 119.879 and − 131.782 (kcal/mol), which indicates that ruxolitinib binds relatively tightly to IL-2 Rα. Hence, the targeted therapy of ruxolitinib against IL-2 R is of interest in HLH following COVID-19 vaccination (, Table S1). However, it should be noted that molecular docking merely provides information on the potential for intermolecular binding, which means that the predictions do not necessarily match the facts. Nevertheless, compared with the considerable time and cost required for large-scale screening, molecular docking can aid researchers in comprehending the interaction between molecules and contribute to research progress.
Figure 2. Ruxolitinib was bound to IL-2 Rα by molecular docking. (a) mode of binding of ruxolitinib to IL-2 Rα. (b) two-dimensional interaction between ruxolitinib and IL-2 Rα, circles represent amino acid residues, numbers inside are amino acid abbreviations and numbers, lines represent interactions, colors represent interaction types, and numbers on lines represent distances. (c) 3D structure of ruxolitinib binding to IL-2 Rα.
Discussion
In the ongoing global epidemic of COVID-19, vaccination is one of the most effective defense measures. COVID-19 vaccines confer effective resistance against the disease by activating T-cell and B-cell responses and eliciting adaptive immunity in the recipient. The vaccinated individual thus receives a single, relatively mild form of COVID-19. As there are few cases of HLH after COVID-19 vaccination, examining the HLH caused by COVID-19 has a certain reference value for this study.
In past studies, considerable elevation in cytokines has been observed in several patients with COVID-19, which increases the likelihood of cytokine storms. It can lead to acute respiratory distress syndrome and multiple organ failure and is associated with poor outcomes. Of the proinflammatory cytokines, IL-1β, IL-2 R, IL-6, IL-7, IL-10, TNF-α, inducible protein-10, and monocyte chemotactic protein-3 are associated with COVID-19 progression.Citation22–24 In addition, RNA transcriptome sequencing has proved the relationship between cytokines and the severity of COVID-19.Citation25 Some cytokines are significantly upregulated in patients with severe disease, and these include IL-2, IL-2 R, IL-4, IL-6, IL-8, IL-10, and TNF-α.Citation26 IL-1β and IL-6 can aid in recruiting neutrophils and T cells, which causes acute lung injury.Citation15 IL-6 is closely associated with mortality, and IL-6 R antagonists could play a key role in decreasing mortality.Citation16
The occurrence of HLH is highly related to the excessive and disordered immune response after COVID-19 vaccination.Citation5 In the pathogenesis of HLH, the cytokine storm plays a key role in the entire process, especially IL-1β and IL-2 R. Anakinra, an IL-1 receptor antagonist, has been used in treating COVID-19 vaccine-induced HLH and has been shown to have some efficacy, thereby improving the prognosis in this patient group.Citation12,Citation27 HLH is a rare immune disease; hence, the probability of an outbreak of symptoms after COVID-19 vaccination in patients who already have HLH is very low. During the COVID-19 pandemic, it was observed that the number of COVID-19 patients meeting the HLH criteria was nearly 10 times higher than the combined count of HLH patients associated with all respiratory viruses prior to the emergence of the COVID-19 outbreak. This research is focused on patients who develop HLH after the administration of the COVID-19 vaccine and aims to explore the correlation between the two phenomena. This study not only has instructive implications for the subset of patients who experience HLH following COVID-19 vaccination but also holds potential reference value for the broader population of patients with COVID-19 although HLH occurrence may not be directly applicable.
In this systematic review, HLH was found to mainly occur after BNT162b2 mRNA, ChAdOx1 nCov‐19, and mRNA-1273 vaccinations, and almost all patients were treated with steroids and antibiotics. The review revealed that 5/25 patients were treated with etoposide, whereas anakinra was used in 5/25 patients. Only two patients did not receive combination therapy, and in just one patient, treatment was not reported.
According to HLH-2004 diagnostic criteria, elevated IL-2 R/CD25s levels are a highly specific immunological diagnostic criterion. In patients with COVID-19, studies have observed an elevation of IL-2 R/CD25s in those with severe disease, which provides new ideas for treating HLH following COVID-19 vaccination.Citation28 Ruxolitinib, a selective inhibitor of Janus-related kinases (JAKs), can block the JAK signal and transcription activator (signal transducer and activator of transcription, STAT) pathway to effectively inhibit the occurrence of cytokine storm after COVID-19. In the realm of pharmacotherapy, molecular docking serves as a pivotal tool for identifying prospective drug entities that can intricately engage with the target biomolecule under investigation. In this study, molecular docking was employed to prove the capacity of ruxolitinib in attenuating IL2R, thereby positing it as a prospective therapeutic agent for HLH following COVID-19 vaccination. However, the therapeutic efficacy of this intervention needs to be validated via clinical trials. Based on the findings and the potential impacts of the proinflammatory cytokine IL-2, this study proposes the exploration of ruxolitinib as a potential therapeutic agent via preclinical and clinical trials. The drug holds promise as a viable treatment for patients diagnosed with HLH following COVID-19 vaccination. In addition, healthcare workers should remember the possibility of HLH after COVID-19 vaccination during routine clinical treatment to rapidly identify this serious disease and initiate early and targeted therapy to reduce patient mortality and improve prognosis. In the future, serious adverse reactions after vaccination in response to the current COVID-19 pandemic should be investigated further.
Limitations
There are some limitations in this study. First, it is imperative to acknowledge that the review was not exhaustive. The cases under consideration were derived only from case reports available until February 5, 2023. The dynamic nature of medical reporting has resulted in the emergence of several new cases after this date, which highlights that this study does not encompass the entire spectrum of recent developments. Second, while acknowledging the significance of considering the vaccination background of the broader population, this aspect could not be comprehensively addressed within the scope of this systemic review. Moreover, the included case reports lacked complete data pertaining to the vaccination history, thereby precluding an in-depth analysis. And the presence of HLH in these patients cannot always be directly attributed to the vaccine, as it may be influenced by underlying medical conditions. Third, molecular docking provides an assessment of potential intermolecular binding, and hence, there exists a possibility of false positives. The definitive therapeutic efficacy of the identified compounds therefore requires validation via preclinical and clinical investigations.
Conclusion
This systematic review underscores the importance of considering the adverse effects after vaccination and provides an overview of the HLH reported after COVID-19 vaccination. The therapeutic potential of ruxolitinib in HLH developing after COVID-19 vaccination was identified via molecular docking, which has enriched the treatment options. Despite the possibility of HLH following COVID-19 vaccination, we remain convinced that immunization is an important public health tool. Close surveillance, however, is vital for the early detection of serious adverse events.
Contributions
Conceptualization, M-Y. Z and H-Q. Z; Investigation, M-Y. Z, H-Q. Z and B-Z. C; Writing – Review & Editing, M-Y. Z, H-Q. Z, B-Z. C, Q-T. C and C. L. Drawing, B-Z. C, Q-T. C, H. M and H-Q. Z. All authors read and approved the final manuscript.
Supplemental Material
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Supplementary data
Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2023.2263229.
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