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Review

Macrophage Activation Syndrome in Viral Sepsis

by
Despoina Papageorgiou
1,*,
Charalambos Gogos
1,2 and
Karolina Akinosoglou
1,3
1
Department of Medicine, University of Patras, Rio, 26504 Patras, Greece
2
Metropolitan General Hospital, 15562 Athens, Greece
3
Department of Internal Medicine and Infectious Diseases, University of Patras, Rio, 26504 Patras, Greece
*
Author to whom correspondence should be addressed.
Viruses 2024, 16(7), 1004; https://doi.org/10.3390/v16071004
Submission received: 25 May 2024 / Revised: 19 June 2024 / Accepted: 20 June 2024 / Published: 22 June 2024
(This article belongs to the Special Issue Viral Sepsis: Pathogenesis, Diagnostics and Therapeutics)
Browse Figure
Review Reports Versions Notes

Abstract

:
Macrophage activation syndrome (MAS) is a life-threatening systemic hyperinflammatory syndrome triggered by various infections, particularly viral infections, autoimmune disorders, and malignancy. The condition is characterized by an increased production of proinflammatory cytokines resulting in a cytokine storm and has been associated with poor clinical outcomes. During the COVID-19 pandemic, patients with severe manifestations developed features similar to those of MAS, although these characteristics remained well defined within the lung. Additionally, other viral infections including EBV, the herpes family of viruses, hepatitis viruses, influenza, HIV, and hemorrhagic fevers can be complicated by MAS. The diagnosis and management of the condition remain challenging due to the lack of consensus on specific guidelines, especially among the adult population. Currently, therapeutic options primarily rely on medications that are typically used to treat primary hemophagocytic lymphohistiocytosis, such as corticosteroids and etoposide. In addition, cytokine-targeted therapies present promising treatment options. The objective of this review is to discuss the emergence of MAS in the context of viral infections including, but not limited to, its occurrence in COVID-19.

1. Introduction

Macrophage activation syndrome (MAS) is a life-threatening systemic hyperinflammatory syndrome typically associated with autoimmune/autoinflammatory diseases. It is considered to be a form of secondary hemophagocytic lymphohistiocytosis (sHLH), which is triggered by various infections, autoimmune diseases and malignancy. In contrast, primary HLH (pHLH) occurs due to genetic disorders [1]. However, distinguishing between secondary HLH and primary HLH in clinical settings is challenging. MAS and HLH are sometimes used interchangeably or misused in studies, while distinguishing between triggers is also difficult.
The main pathophysiologic feature of MAS is excessive activation and expansion of T cells, particularly cytotoxic CD8+ T cells, and macrophages. This prolonged immune activation results in the increased production of proinflammatory cytokines, leading to a cytokine storm [2]. These cytokines include IFNγ, TNFα, IL-2, IL-1, IL-6, IL-18, as well as macrophage colony-stimulating factor (M-CSF) [3]. Although, the exact mechanism remains unknown, MAS shares many etiologic similarities with pHLH, which is a result of homozygous or compound heterozygous mutations in genes involved in the perforin-mediated pathway of cytolysis shared by NK cells and cytotoxic CD8 T cells. Interestingly, heterozygous mutations in known pHLH genes are increasingly recognized in MAS patients [4]. Clinical characteristics of MAS include non-remitting high fever, hepatomegaly/splenomegaly, lymphadenopathy, hemorrhagic manifestations, and multiorgan dysfunction, while laboratory findings typically involve cytopenias, hyperferritinemia, coagulopathy, abnormal liver function tests, hypertriglyceridemia, hypofibrinogenemia, and markers of immune activation. Hemophagocytosis is also commonly observed [5].
The diagnosis and management of MAS/sHLH pose significant challenges to clinicians due to the heterogenous nature of triggering factors and underlying conditions, the rarity of the condition, and the lack of consensus regarding broad classification [1]. The diagnosis primarily relies on the fulfillment of at least five out of eight clinical and laboratory criteria outlined in the HLH-2004 protocol [1]. However, these guidelines mostly apply to the diagnosis and treatment of pHLH in the pediatric population [6]. Alternatively, another effective diagnostic tool, the HScore, has been developed and is widely used to assess an individual’s risk for both pHLH and sHLH [7]. Of note, specific diagnostic guidelines for MAS in the setting of autoimmune diseases have been developed [8,9].
During the COVID-19 pandemic, a significant number of patients developed severe complications such as the virus-induced cytokine storm and MAS/HLH, which are associated with poor clinical outcomes, highlighting the substantial role of infectious triggers, particularly viral infections, in the pathogenesis of HLH [10]. The objective of this review is to investigate the occurrence of MAS/HLH within the framework of viral infections, including—but not limited to—its emergence in patients with COVID-19.

2. Materials and Methods

We performed a literature review, searching the Pubmed database from September 2003 until May 2024 for viral infections associated with MAS. We used the terms “Macrophage activation syndrome” OR “secondary hemophagocytic lymphohistiocytosis” AND the viral infection of interest, including “COVID-19”, “EBV”, “CMV”, “HSV-1”, “HSV-2”, “VZV”, “Influenza”, “H1N1” “Adenovirus”, “Parvovirus B19”, “HAV”, “HBV”, “HCV”, “HIV”, “Ebola virus”, and “dengue fever”. Relative publications were identified by their abstracts and title by two independent reviewers. Respective articles were also hand-searched for relative references. Only English articles were studied. Duplicates and non-human articles were excluded, as well as articles irrelevant to virus-associated MAS, such as papers inconclusive about MAS triggers or sHLH associated with etiology other than infection. Case reports were excluded. In the absence of relevant findings, and following extensive discussion, the authors decided that, for the sake of information completeness, case reports would be recorded in a table for parvovirus-B19 only. The results were discussed and disagreements resolved. A study flowchart is shown in Figure 1.

3. Discussion

3.1. MAS and COVID-19

Patients with SARS-CoV-2 infection may experience a range of clinical manifestations, from asymptomatic to severe disease and critical illness. Severe cases are characterized by a pronounced immune dysregulation with lymphopenia and increased expression of inflammatory mediators resulting in a cytokine storm. Early studies suggested that COVID-19 cytokine storms share significant similarities with MAS [11]. Specifically, interleukin-1β (IL-1β), IL-2, IL-6, IL-7, IL-17, tumor necrosis factor-α (TNF-α), granulocyte colony-stimulating factor (G-CSF), C-X-C motif chemokine ligand 10 (CXCL10), and C-C motif chemokine ligand 3 (CCL3) were reported to be upregulated in patients with severe COVID-19, especially among patients treated in intensive care units (ICUs) [12,13]. COVID-19 induces alternations in cytokine profiles that exhibit similarities to those seen in MAS. Cytokines such as IP10, IL-18, and macrophage colony-stimulating factor (M-CSF), which are key molecules in MAS, were identified as the most predictive of severe disease [14,15,16,17]. In addition, laboratory parameters of severely ill COVID-19 patients, such as cytopenia, hyperferritinemia, hyperfibrinogenemia, and hypoalbuminemia, resembled those of MAS, although they did not exhibit the typical features of the condition [18,19,20]. Of note, particularly among pediatric population with COVID-19, there is a subset of patients that may develop multisystem inflammatory syndrome (MIS-C), a rare post-infectious hyperinflammatory disorder [21]. The clinical and immunological features of MIS-C resemble those of MAS, complicating the distinction between these two conditions [22,23,24]. Additionally, patients diagnosed with MIS-C were found to carry heterozygous mutations in pHLH or HLH-associated genes [25]. Interestingly, several authors observed that patients with MIS-C may also meet the diagnostic criteria for MAS [26,27].
The overlapping profiles between severe COVID-19 and MAS have led to the hypothesis that the latter may be involved in COVID-19 pathogenesis and may drive some of its serious complications including ARDS [28]. Due to a temporary virus-induced immunodeficiency state which is associated with lymphopenia and NK cell abnormalities, the underlying mechanism of MAS in COVID-19 may resemble a pHLH-like phenotype. In contrast, a more typical MAS/sHLH presentation could be the result of an exaggerated immune response that clears the virus but induces pulmonary tissue damage and ARDS [28]. Of importance, the role of macrophages in severe COVID-19 cases is pivotal as the development of ARDS largely depends on a dysregulated macrophage activation pattern and the accumulation of activated macrophages in the lung [29,30]. Moreover, a post-mortem study identified diffuse interstitial pneumonia-like/MAS-like changes in patients with COVID-19 suggesting that these histopathological findings could represent a variant of MAS. Of interest, as these changes appear to be a late development of the disease, direct viral infection is unlikely to induce the macrophage dysregulation [31].
The immunological and pathological manifestations of MAS in COVID-19 patients are mainly observed to be lung-centric rather than systematic. Also, there are differences including the absence of organomegaly and the concentration of serum ferritin which is increased but lower than that in typical MAS [32,33]. In addition, the coagulation profile of COVID-19 patients differs from those with typical MAS, as indicated by the normal circulatory fibrinogen with elevated d-Dimers. Hence, these parameters may point towards pulmonary intravascular coagulopathy rather than diffuse intravascular coagulation (DIC) which is a feature of typical MAS [28,34].
The unique presentation of MAS in COVID-19 patients poses a great diagnostic challenge. Many studies have reported that a considerable number of patients do not meet the diagnostic criteria of HLH or the HScore [35,36,37]. In order to address this matter, studies focused on developing criteria which will provide a better characterization of COVID-19 cytokine storm in the context of the usage of immunomodulatory therapies [38,39]. Also, some studies have analyzed serum biomarker profiles to identify target molecules that could guide effective treatment, while others have aimed to predict COVID-19 progression towards MAS [40,41,42,43,44,45].

3.2. MAS and Other Viral Infections

3.2.1. Epstein–Barr Virus

Epstein–Barr virus (EBV) is a well-recognized trigger of HLH. HLH can emerge as a result of EBV infection in various clinical contexts, including pHLH in genetically predisposed individuals, sHLH in those without a known genetic predisposition, and HLH associated with EBV-positive neoplasms [46]. Although, EBV-associated HLH is prevalent in East Asia, it has been reported among non-Asian populations, especially in those who are Hispanic [47]. The proposed mechanism by which EBV induces HLH involves the proliferation of cytotoxic T cells and activation of macrophages by EBV-infected B cells, resulting in uncontrolled immune activation and hypercytokinemia. Additionally, EBV targets CD8+ T or NK cells via CD21, leading to uncontrolled cytokine production [48]. A recent study evaluated NK cell cytotoxicity in patients with sHLH and found decreased cytotoxicity among HLH patients. However, no significant difference was observed between patients with EBV-HLH and non-EBV HLH [49]. The diagnosis of HLH in patients with EBV infection can be challenging, as these patients may develop some of the hallmarks of HLH as part of natural infection [50]. The clinical and laboratory characteristics of patients with EBV-HLH, as well as those associated with other viral infections, are presented in Table 1. One study compared the laboratory parameters of patients with EBV and non-EBV sHLH and found that ferritin, LDH, and liver function tests were significantly higher in EBV-associated HLH patients. Also, they reported that EBV DNA load influences disease development in sHLH [51]. Among the diverse etiologies of HLH, EBV-associated HLH has the highest mortality [52]. Thus, it has been suggested that an improved HLH index (IH index), which combines parameters such as sCD25, procalcitonin, and eGFR, can be used to identify adult patients with EBV-HLH who have a poor prognosis. However, further validation will be needed [53]. Importantly, central nervous system (CNS) involvement in EBV-HLH has been associated with poor clinical outcomes [54].

3.2.2. Cytomegalovirus

Other members of the herpes virus family have been associated with HLH. Although CMV-HLH remains poorly characterized, HLH can emerge as a result of primary CMV infection or CMV reactivation [67]. HLH occurs more frequently among immunodeficient individuals; however, it has been reported in several immunocompetent cases [68]. Of note, in immunocompetent patients HLH seems to follow a severe disease course, such as CMV pneumonia [69,70,71]. Regarding immunodeficient cases, an association between CMV-HLH, inflammatory bowel disease (IBD), and immunomodulatory treatment with thiopurines has been described since IBD has been observed as the main comorbidity in this patient population [56,67,72].

3.2.3. Herpes Simplex Virus and Varicella Zoster Virus

Herpes simplex virus (HSV) infection has been rarely associated with HLH. The literature on HSV-HLH is scarce, with only a few case reports available. Most documented cases involve infants with disseminated HSV infection, whereas comparatively fewer cases pertain to adults [73]. Interestingly, even though disseminated HSV infection usually occurs in immunocompromised patients the majority of HSV-HLH, adult patients were immunocompetent [73]. Several authors have noted significantly elevated ferritin levels in patients with HSV-HLH, posing a diagnostic challenge as cytopenia and hyperferritinemia, which characterize HLH, can result solely from disseminated HSV infection [74,75,76,77]. Also, a study conducted in neonates revealed that high ferritin levels, along with other factors, may indicate a more severe form of the disease and are correlated with poor outcomes [78]. Lastly, there are few reported cases of varicella-zoster virus (VZV) infection as a trigger of HLH, primarily in the pediatric population. However, some cases have been associated with underlying immune system disorders, such as adenosine deaminase 2 (ADA2) deficiency or Griscelli syndrome [79,80,81,82].

3.2.4. Influenza Virus

Additionally, MAS is known to complicate influenza virus infection. Severe influenza A (pandemic strain H1N1) infection may develop many similarities with HLH. First, there are plenty of overlapping features in the cytokine storms induced by H1N1 and MAS [13]. Moreover, a study conducted in critically ill patients with H1N1 infection reported similarities in clinical and laboratory parameters among patients who developed HLH secondary to the infection and those who did not. However, HLH patients showed more extensive signs of inflammation, had higher ferritin concentration, and had lower albumin and organomegaly [57]. The same study found an inverse correlation between serum ferritin concentration and NK and cytotoxic T cell percentages which may indicate a potential role for reduced NK cell numbers in the pathogenesis of sHLH [57]. These findings are in line with previous reports indicating the presence of heterozygous mutations in established pHLH genes, which were shown to decrease NK cell cytolytic function among fatal cases of H1N1 infection [83]. Also, HLH is associated with avian influenza (H5N1) infection [84]. In H5N1 infection, excessive IL-18 production and a subsequent cytokine storm result from a prolonged NLRP3 (expressed in macrophages) activation by the PB1F2 viral protein. Thus, IL-18 could potentially contribute to the development of MAS [85].

3.2.5. Human Adenovirus and Parvovirus B19

Human adenovirus infection is seldom associated with HLH. The majority of reported cases pertain to children, while only a few cases have involved adults [58,86,87,88]. A recent study investigated the risk factors associated with HLH development in children with severe adenovirus pneumonia and found that patients with longer duration of fever (over 12.5 days) and elevated triglyceride levels (over 3.02 mmol/L) were at higher risk of developing HLH [89]. Also, parvovirus B19 is another rare HLH trigger, and associated cases seem to follow a relatively benign course compared with other HLH etiologies [90]. Pediatric patients, immunocompromised individuals, and those with hematologic pathology are the populations most commonly affected [60,61,62,91].

3.2.6. Hepatitis Viruses

Moreover, HLH can result from infection with hepatitis viruses, with the majority of cases involving HAV and, less commonly, HBV or HCV infection [92,93,94]. Two systematic reviews of HAV-associated HLH cases have identified hepatomegaly and splenomegaly as distinguishing features of HAV-HLH, as these signs are rarely observed in patients with HAV infection who do not develop HLH [63,95]. Also, they noted that thrombocytopenia could be an early sign of HAV-HLH [63,95]. However, while hyperferritinemia can occur solely due to HAV infection, higher levels may indicate the presence of HLH [63].

3.2.7. Human Immunodeficiency Virus

In HIV-positive patients, HLH can manifest as a complication in various disease-related clinical scenarios. Firstly, HLH may develop during acute HIV infection [64,96,97]. Secondly, it can be triggered by opportunistic infections to which HIV-positive patients are predisposed [98,99,100]. Also, it may arise due to immune reconstitution inflammatory syndrome (IRIS), which is an exaggerated inflammatory immune response following the initiation of highly active antiretroviral treatment (HAART) [101,102]. Lastly, HLH can emerge as a result of virus-associated malignancies [103,104]. The diagnosis of HLH in HIV-positive individuals can be challenging because the clinical and laboratory abnormalities that define HLH may also occur in advanced HIV/AIDS [65]. Maintaining a high degree of clinical suspicion is crucial for diagnosing HLH in HIV-positive patients, particularly those who are non-compliant to ART (uncontrolled HIV), with opportunistic infections. On the other hand, HLH may also occur in patients with low viral loads and CD4+ T cell counts, driven by the HIV-induced immune dysregulation [65].

3.2.8. Hemorrhagic Fevers

Viral hemorrhagic fevers, such as Ebola virus disease and dengue fever, have been associated with HLH. Ebola virus disease, especially severe forms, share significant similarities with HLH. Symptoms such as fever, cytopenia, hyperferritinemia, hypofibrinogenemia, and low NK cell counts that characterize HLH are commonly found in Ebola virus disease. Thus, there has been the hypothesis that infection with Ebola virus is associated with overwhelming macrophage activation [105]. In a recent study, macrophage activation maker soluble CD163 has been found upregulated in severe Ebola virus disease. This finding provides additional support for the hypothesis [106]. Similarly, a hyperinflammatory/MAS phenotype occurs in dengue and is associated with disease severity [107,108,109]. A recent systematic review and meta-analysis noted that dengue-associated HLH has a lower fatality rate compared to other infection-associated HLHs; however, the presence of HLH increases the mortality of dengue patients [66]. Therefore, since the diagnosis of dengue-related HLH could be challenging, clinicians should consider diagnostic indicators such as elevated LDH, ferritin, prolonged fever duration, persistent thrombocytopenia, anemia, and hepatomegaly as potential signs of disease progression towards HLH [66,110].

3.3. Therapeutic Options

Concerning the treatment of sHLH/MAS, definitive guidelines have not yet been established. This is partly attributable to the heterogeneity of triggering agents [1]. Management of the condition primarily relies on guidelines and protocols derived from other disease contexts, such as the HLH-2004 protocol. Early recognition and combination chemo-immunotherapy, including corticosteroids, etoposide, and cyclosporine A, constitute the cornerstone of therapeutic options [6]. Additionally, cytokine-targeted therapies which have been previously used to treat autoimmunity-associated MAS are expanding the armamentarium for therapeutic intervention [9]. However, when it comes to infectious HLH, achieving a balance between the immunosuppressive treatment, which is necessary for managing the cytokine storm, and infection control is crucial [56]. Table 2 summarizes the therapeutic regimens that have been used for various viral infections triggering MAS. Although the majority of cases are treated using the standard HLH medications, there is a significant lack of literature regarding studies focusing on the treatment of sHLH, particularly among adult populations.
In a recent study, 93 patients with EBV-associated HLH were divided into two groups according to whether the initial treatment contained etoposide or not. The etoposide group had a better survival rate compared to those who did not receive the drug with significantly higher survival rates among the adult population [135]. Also, two studies evaluated the efficacy of liposomal doxorubicin, etoposide, and methylprednisolone (L-DEP) as an initial therapy for adults with EBV-HLH and as salvage therapy for pediatric patients [136,137]. Additionally, due to EBV’s tropism for B lymphocytes, the anti-CD20 antibody rituximab can be used in combination with other HLH-directed medications for effective infection control. As demonstrated in one study, when combined with conventional HLH therapy, rituximab improves symptoms, reduces viral load, and diminishes inflammation [138]. Recently, a trial investigated the role of ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor in the treatment of EBV-associated HLH. In this study, ruxolitinib demonstrated a notably high favorable overall response. Of importance, all the responding patients achieved their first response within 3 days, indicating that ruxolitinib has a rapid onset of action in controlling HLH manifestations [139].
Moreover, the COVID-19 pandemic created an opportunity to conduct larger studies on drugs for the treatment of MAS, particularly focusing on cytokine-targeted therapies. Studies on COVID-19-associated MAS patients showed that early use of IL-1 blocker anakinra reduces the need for intensive care and contributes to the improvement in laboratory and radiological findings [140,141,142]. Another study supported that the addition of anakinra to steroid treatment results in a significant decrease in biochemical parameters. However, no significant difference was observed concerning oxygen requirements or mortality rates between patients treated solely with steroids versus those who received anakinra as well [143]. Regarding IL-6 blockade with tocilizumab in COVID-19-associated MAS, the results are controversial. Some studies have reported that treatment with tocilizumab contributes to reduced mortality and favorable outcomes [144,145]. Conversely, another study noted that tocilizumab demonstrated limited efficacy for COVID-19-related MAS [146]. In another recent trial, tocilizumab led to an increased incidence of secondary infections among critically ill patients with COVID-19-associated MAS, while treatment with anakinra resulted in favorable responses [147]. Lastly, alternative treatment options targeting IL-18, IFN-γ, and the JAK pathway have been under discussion [148].

3.4. Conclusions

Although MAS is a rare complication of viral infections, the condition is characterized by poor clinical outcomes. Diagnosing MAS, particularly in adult patients, remains a formidable challenge due to the absence of universally accepted classification and diagnostic criteria. The management of the condition relies on established protocols for pHLH. However, recent advances in cytokine-targeted therapies have demonstrated promising potential, offering hope for improved treatment outcomes.

Author Contributions

K.A. and C.G. conceived the idea; D.P. and K.A. performed the literature search; D.P. wrote the manuscript and drew the figures and tables; K.A. and C.G. critically corrected the manuscript; K.A. oversaw the study. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Carter, S.J.; Tattersall, R.S.; Ramanan, A.V. Macrophage activation syndrome in adults: Recent advances in pathophysiology, diagnosis and treatment. Rheumatology 2019, 58, 5–17. [Google Scholar] [CrossRef]
  2. Schulert, G.S.; Grom, A.A. Pathogenesis of macrophage activation syndrome and potential for cytokine-directed therapies. Annu. Rev. Med. 2015, 66, 145–159. [Google Scholar] [CrossRef]
  3. Lerkvaleekul, B.; Vilaiyuk, S. Macrophage activation syndrome: Early diagnosis is key. Open Access Rheumatol. 2018, 10, 117–128. [Google Scholar] [CrossRef] [PubMed]
  4. Crayne, C.B.; Albeituni, S.; Nichols, K.E.; Cron, R.Q. The immunology of macrophage activation syndrome. Front. Immunol. 2019, 10, 433348. [Google Scholar] [CrossRef]
  5. Cron, R.Q.; Davi, S.; Minoia, F.; Ravelli, A. Clinical features and correct diagnosis of macrophage activation syndrome. Expert. Rev. Clin. Immunol. 2015, 11, 1043–1053. [Google Scholar] [CrossRef]
  6. Henter, J.I.; Horne, A.C.; Aricó, M.; Egeler, R.M.; Filipovich, A.H.; Imashuku, S.; Ladisch, S.; McClain, K.; Webb, D.; Winiarski, J.; et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr. Blood Cancer 2007, 48, 124–131. [Google Scholar] [CrossRef]
  7. Fardet, L.; Galicier, L.; Lambotte, O.; Marzac, C.; Aumont, C.; Chahwan, D.; Coppo, P.; Hejblum, G. Development and validation of the hscore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014, 66, 2613–2620. [Google Scholar] [CrossRef] [PubMed]
  8. Parodi, A.; Davì, S.; Pringe, A.B.; Pistorio, A.; Ruperto, N.; Magni-Manzoni, S.; Miettunen, P.; Bader-Meunier, B.; Espada, G.; Sterba, G.; et al. Macrophage activation syndrome in juvenile systemic lupus erythematosus: A multinational multicenter study of thirty-eight patients. Arthritis Rheum. 2009, 60, 3388–3399. [Google Scholar] [CrossRef] [PubMed]
  9. Ravelli, A.; Minoia, F.; Davì, S.; Horne, A.; Bovis, F.; Pistorio, A.; Aricò, M.; Avcin, T.; Behrens, E.M.; De Benedetti, F.; et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Arthritis Rheumatol. 2016, 68, 566–576. [Google Scholar]
  10. Soy, M.; Atagündüz, P.; Atagündüz, I.; Sucak, G.T. Hemophagocytic lymphohistiocytosis: A review inspired by the COVID-19 pandemic. Rheumatol. Int. 2021, 41, 7–18. [Google Scholar] [CrossRef]
  11. Mehta, P.; McAuley, D.F.; Brown, M.; Sanchez, E.; Tattersall, R.S.; Manson, J.J. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020, 395, 1033–1034. [Google Scholar] [CrossRef] [PubMed]
  12. Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395, 497–506. [Google Scholar] [CrossRef]
  13. Morris, G.; Bortolasci, C.C.; Puri, B.K.; Marx, W.; O’Neil, A.; Athan, E.; Walder, K.; Berk, M.; Olive, L.; Carvalho, A.F.; et al. The cytokine storms of COVID-19, H1N1 influenza, CRS and MAS compared. Can one sized treatment fit all? Cytokine 2021, 144, 155593. [Google Scholar] [CrossRef]
  14. Huntington, K.E.; Louie, A.D.; Lee, C.G.; Elias, J.A.; Ross, E.A.; El-Deiry, W.S. Cytokine ranking via mutual information algorithm correlates cytokine profiles with presenting disease severity in patients infected with SARS-CoV-2. eLife 2021, 10, e64958. [Google Scholar] [CrossRef] [PubMed]
  15. Satış, H.; Özger, H.S.; Aysert Yıldız, P.; Hızel, K.; Gulbahar, Ö.; Erbaş, G.; Aygencel, G.; Guzel Tunccan, O.; Öztürk, M.A.; Dizbay, M.; et al. Prognostic value of interleukin-18 and its association with other inflammatory markers and disease severity in COVID-19. Cytokine 2021, 137, 155302. [Google Scholar] [CrossRef]
  16. Kerget, B.; Kerget, F.; Aksakal, A.; Aşkın, S.; Sağlam, L.; Akgün, M. Evaluation of alpha defensin, IL-1 receptor antagonist, and IL-18 levels in COVID-19 patients with macrophage activation syndrome and acute respiratory distress syndrome. J. Med. Virol. 2021, 93, 2090–2098. [Google Scholar] [CrossRef] [PubMed]
  17. Nasser, S.M.T.; Rana, A.A.; Doffinger, R.; Kafizas, A.; Khan, T.A.; Nasser, S. Elevated free interleukin-18 associated with severity and mortality in prospective cohort study of 206 hospitalised COVID-19 patients. Intensive Care Med. Exp. 2023, 11, 9. [Google Scholar] [CrossRef] [PubMed]
  18. Gürsoy, B.; Sürmeli, C.D.; Alkan, M.; Satıcı, C.; Altunok, E.S.; Kamat, S.; Demirok, B.; Demirkol, M.A.; Börü, A. Cytokine storm in severe COVID-19 pneumonia. J. Med. Virol. 2021, 93, 5474–5480. [Google Scholar] [CrossRef]
  19. Viana-Llamas, M.C.; Arroyo-Espliguero, R.; Silva-Obregón, J.A.; Uribe-Heredia, G.; Núñez-Gil, I.; García-Magallón, B.; Torán-Martínez, C.G.; Castillo-Sandoval, A.; Díaz-Caraballo, E.; Rodríguez-Guinea, I.; et al. Hypoalbuminemia on admission in COVID-19 infection: An early predictor of mortality and adverse events. A retrospective observational study. Med. Clin. 2021, 156, 428–436. [Google Scholar] [CrossRef]
  20. Volfovitch, Y.; Tsur, A.M.; Gurevitch, M.; Novick, D.; Rabinowitz, R.; Mandel, M.; Achiron, A.; Rubinstein, M.; Shoenfeld, Y.; Amital, H. The intercorrelations between blood levels of ferritin, sCD163, and IL-18 in COVID-19 patients and their association to prognosis. Immunol. Res. 2022, 70, 817–828. [Google Scholar] [CrossRef]
  21. Patel, J.M. Multisystem Inflammatory Syndrome in Children (MIS-C). Curr. Allergy Asthma Rep. 2022, 22, 53–60. [Google Scholar] [CrossRef] [PubMed]
  22. Panaro, S.; Cattalini, M. The Spectrum of Manifestations of Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV2) Infection in Children: What We Can Learn from Multisystem Inflammatory Syndrome in Children (MIS-C). Front. Med. 2021, 8, 747190. [Google Scholar] [CrossRef]
  23. Boyarchuk, O.; Volokha, A. Editorial: Macrophage activation syndrome in children in the era of COVID-19. Front. Pediatr. 2023, 11, 1222522. [Google Scholar] [CrossRef] [PubMed]
  24. Rodriguez-Smith, J.J.; Verweyen, E.L.; Clay, G.M.; Esteban, Y.M.; de Loizaga, S.R.; Baker, E.J.; Do, T.; Dhakal, S.; Lang, S.M.; Grom, A.A.; et al. Inflammatory biomarkers in COVID-19-associated multisystem inflammatory syndrome in children, Kawasaki disease, and macrophage activation syndrome: A cohort study. Lancet Rheumatol. 2021, 3, e574–e584. [Google Scholar] [CrossRef]
  25. Vagrecha, A.; Zhang, M.; Acharya, S.; Lozinsky, S.; Singer, A.; Levine, C.; Al-ghafry, M.; Levy, C.F.; Cron, R.Q. Hemophagocytic Lymphohistiocytosis Gene Variants in Multisystem Inflammatory Syndrome in Children. Biology 2022, 11, 417. [Google Scholar] [CrossRef] [PubMed]
  26. Buda, P.; Strauss, E.; Januszkiewicz-Lewandowska, D.; Czerwinska, E.; Ludwikowska, K.; Szenborn, L.; Gowin, E.; Okarska-Napierała, M.; Kuchar, E.; Ksiązyk, J. Clinical characteristics of children with MIS-C fulfilling classification criteria for macrophage activation syndrome. Front. Pediatr. 2022, 10, 981711. [Google Scholar] [CrossRef] [PubMed]
  27. Avrusin, I.S.; Abramova, N.N.; Belozerov, K.E.; Bregel, L.V.; Efremova, O.S.; Vilnits, A.A.; Konstantinova, J.E.; Isupova, E.A.; Kornishina, T.L.; Masalova, V.V.; et al. Using HScore for Evaluation of Hemophagocytosis in Multisystem Inflammatory Syndrome Associated with COVID-19 in Children. Biomedicines 2024, 12, 294. [Google Scholar] [CrossRef] [PubMed]
  28. McGonagle, D.; Sharif, K.; O’Regan, A.; Bridgewood, C. The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease. Autoimmun. Rev. 2020, 19, 102537. [Google Scholar] [CrossRef] [PubMed]
  29. Kosyreva, A.; Dzhalilova, D.; Lokhonina, A.; Vishnyakova, P.; Fatkhudinov, T. The Role of Macrophages in the Pathogenesis of SARS-CoV-2-Associated Acute Respiratory Distress Syndrome. Front. Immunol. 2021, 12, 682871. [Google Scholar] [CrossRef]
  30. Marik, P.E.; Iglesias, J.; Varon, J.; Kory, P. A scoping review of the pathophysiology of COVID-19. Int. J. Immunopathol. Pharmacol. 2021, 35, 20587384211048026. [Google Scholar] [CrossRef]
  31. Felix, J.C.; Sheinin, Y.M.; Suster, D.; Ronen, N.; Ratiani, M.; Vanden Heuvel, T.; Winge, E.; Patton, M.D.; Rau, M.J.; Ge, L.; et al. Diffuse interstitial pneumonia-like/macrophage activation syndrome-like changes in patients with COVID-19 correlate with length of illness. Ann. Diagn. Pathol. 2021, 53, 151744. [Google Scholar] [CrossRef] [PubMed]
  32. Otsuka, R.; Seino, K.I. Macrophage activation syndrome and COVID-19. Inflamm. Regen. 2020, 40, 19. [Google Scholar] [CrossRef] [PubMed]
  33. Retamozo, S.; Brito-Zerón, P.; Sisó-Almirall, A.; Flores-Chávez, A.; Soto-Cárdenas, M.J.; Ramos-Casals, M. Haemophagocytic syndrome and COVID-19. Clin. Rheumatol. 2021, 40, 1233–1244. [Google Scholar] [CrossRef] [PubMed]
  34. Hanff, T.C.; Mohareb, A.M.; Giri, J.; Cohen, J.B.; Chirinos, J.A. Thrombosis in COVID-19. Am. J. Hematol. 2020, 95, 1578–1589. [Google Scholar] [CrossRef] [PubMed]
  35. Wood, H.; Jones, J.R.; Hui, K.; Mare, T.; Pirani, T.; Galloway, J.; Metaxa, V.; Benjamin, R.; Rutherford, A.; Cain, S.; et al. Secondary HLH is uncommon in severe COVID-19. Br. J. Haematol. 2020, 190, e283–e285. [Google Scholar] [CrossRef]
  36. Yongzhi, X. COVID-19-associated cytokine storm syndrome and diagnostic principles: An old and new Issue. Emerg. Microbes Infect. 2021, 10, 266–276. [Google Scholar] [CrossRef]
  37. Hakim, N.N.; Chi, J.; Olazagasti, C.; Liu, J.M. Secondary hemophagocytic lymphohistiocytosis versus cytokine release syndrome in severe COVID-19 patients. Exp. Biol. Med. 2020, 246, 5–9. [Google Scholar] [CrossRef]
  38. Webb, B.J.; Peltan, I.D.; Jensen, P.; Hoda, D.; Hunter, B.; Silver, A.; Starr, N.; Buckel, W.; Grisel, N.; Hummel, E.; et al. Clinical criteria for COVID-19-associated hyperinflammatory syndrome: A cohort study. Lancet Rheumatol. 2020, 2, e754–e763. [Google Scholar] [CrossRef]
  39. Caricchio, R.; Gallucci, M.; Dass, C.; Zhang, X.; Gallucci, S.; Fleece, D.; Bromberg, M.; Criner, G.J. Preliminary predictive criteria for COVID-19 cytokine storm. Ann. Rheum. Dis. 2021, 80, 88–95. [Google Scholar] [CrossRef]
  40. Kessel, C.; Vollenberg, R.; Masjosthusmann, K.; Hinze, C.; Wittkowski, H.; Debaugnies, F.; Nagant, C.; Corazza, F.; Vély, F.; Kaplanski, G.; et al. Discrimination of COVID-19 From Inflammation-Induced Cytokine Storm Syndromes Using Disease-Related Blood Biomarkers. Arthritis Rheumatol. 2021, 73, 1791–1799. [Google Scholar] [CrossRef]
  41. Kerget, B.; Araz, Ö.; Akgün, M. The role of exhaled nitric oxide (FeNO) in the evaluation of lung parenchymal involvement in COVID-19 patients. Intern. Emerg. Med. 2022, 17, 1951–1958. [Google Scholar] [CrossRef] [PubMed]
  42. Kerget, F.; Kerget, B. Frequency of Interleukin-6 rs1800795 (-174G/C) and rs1800797 (−597G/A) Polymorphisms in COVID-19 Patients in Turkey Who Develop Macrophage Activation Syndrome. Jpn. J. Infect. Dis. 2021, 74, 543–548. [Google Scholar] [CrossRef]
  43. Hailemichael, W.; Kiros, M.; Akelew, Y.; Getu, S.; Andualem, H. Neopterin: A Promising Candidate Biomarker for Severe COVID-19. J. Inflamm. Res. 2021, 14, 245–251. [Google Scholar] [CrossRef] [PubMed]
  44. Franco-Martínez, L.; Cerón, J.J.; Vicente-Romero, M.R.; Bernal, E.; Cantero, A.T.; Tecles, F.; Resalt, C.S.; Martínez, M.; Tvarijonaviciute, A.; Martínez-Subiela, S. Salivary Ferritin Changes in Patients with COVID-19. Int. J. Environ. Res. Public Health 2021, 19, 41. [Google Scholar] [CrossRef] [PubMed]
  45. Zanchettin, A.C.; Barbosa, L.V.; Dutra, A.A.; Prá, D.M.M.; Pereira, M.R.C.; Stocco, R.B.; Martins, A.P.C.; Vaz de Paula, C.B.; Nagashima, S.; de Noronha, L.; et al. Role of Genetic Polymorphism Present in Macrophage Activation Syndrome Pathway in Post Mortem Biopsies of Patients with COVID-19. Viruses 2022, 14, 1699. [Google Scholar] [CrossRef]
  46. El-Mallawany, N.K.; Curry, C.V.; Allen, C.E. Haemophagocytic lymphohistiocytosis and Epstein–Barr virus: A complex relationship with diverse origins, expression and outcomes. Br. J. Haematol. 2022, 196, 31–44. [Google Scholar] [CrossRef]
  47. Shamriz, O.; Kumar, D.; Shim, J.; Briones, M.; Quarmyne, M.O.; Chonat, S.; Lucas, L.; Edington, H.; White, M.H.; Mahajan, A.; et al. T Cell-Epstein-Barr Virus–Associated Hemophagocytic Lymphohistiocytosis (HLH) Occurs in Non-Asians and Is Associated with a T Cell Activation State that Is Comparable to Primary HLH. J. Clin. Immunol. 2021, 41, 1582–1596. [Google Scholar] [CrossRef]
  48. Ishii, E. Hemophagocytic lymphohistiocytosis in children: Pathogenesis and treatment. Front. Pediatr. 2016, 4, 202648. [Google Scholar] [CrossRef]
  49. Oh, E.J.; Yoon, J.H.; Park, K.H.; Bae, H.J.; Yun, S.J.; Min, G.J.; Park, S.S.; Park, S.; Lee, S.E.; Cho, B.S.; et al. Natural-killer cell cytotoxicity as a diagnostic and prognostic marker for adult patients with secondary hemophagocytic lymphohistiocytosis: A prospective phase II observational study. Ther. Adv. Hematol. 2021, 12, 20406207211020544. [Google Scholar] [CrossRef]
  50. Marsh, R.A. Epstein-Barr virus and hemophagocytic lymphohistiocytosis. Front. Immunol. 2018, 8, 317920. [Google Scholar] [CrossRef]
  51. Chen, J.; Wang, X.; He, P.; Li, Y.; Si, M.; Fan, Z.; Chang, X.; Xie, Q.; Jiao, X. Viral etiology, clinical and laboratory features of adult hemophagocytic lymphohistiocytosis. J. Med. Virol. 2016, 88, 541–549. [Google Scholar] [CrossRef]
  52. Pei, Y.; Zhu, J.; Yao, R.; Cao, L.; Wang, Z.; Liang, R.; Jia, Y.; Su, Y. Prognostic factors in patients with secondary hemophagocytic lymphohistioc ytosis in a Chinese cohort. Ann. Hematol. 2024, 103, 695–703. [Google Scholar] [CrossRef] [PubMed]
  53. Yao, S.; He, L.; Zhang, R.; Liu, M.; Hua, Z.; Zou, H.; Wang, Z.; Wang, Y. Improved hemophagocytic lymphohistiocytosis index predicts prognosis of adult Epstein-Barr virus-associated HLH patients. Ann. Med. 2023, 55, 89–100. [Google Scholar] [CrossRef] [PubMed]
  54. Yin, Q.; Wang, J.; Wang, Z. Epstein-Barr virus central nervous system involvement in Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Ann. Hematol. 2022, 101, 2471–2476. [Google Scholar] [CrossRef] [PubMed]
  55. Lai, W.; Wang, Y.; Wang, J.; Wu, L.; Jin, Z.; Wang, Z. Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults and adolescents—A life-threatening disease: Analysis of 133 cases from a single center. Hematology 2018, 23, 810–816. [Google Scholar] [CrossRef] [PubMed]
  56. Rolsdorph, L.A.; Mosevoll, K.A.; Helgeland, L.; Reikvam, H. Concomitant Hemophagocytic Lymphohistiocytosis and Cytomegalovirus Disease: A Case Based Systemic Review. Front. Med. 2022, 9, 819465. [Google Scholar] [CrossRef]
  57. von Bahr Greenwood, T.; Holzgraefe, B.; Chiang, S.C.C.; Wang, Y.; Tesi, B.; Bryceson, Y.T.; Henter, J.I. Clinical and laboratory signs of haemophagocytic lymphohistiocytosis associated with pandemic influenza A (H1N1) infection in patients needing extracorporeal membrane oxygenation A retrospective observational study. Eur. J. Anaesthesiol. 2021, 38, 692–701. [Google Scholar] [CrossRef] [PubMed]
  58. Mellon, G.; Henry, B.; Aoun, O.; Boutolleau, D.; Laparra, A.; Mayaux, J.; Sanson, M.; Caumes, E. Adenovirus related lymphohistiocytic hemophagocytosis: Case report and literature review. J. Clin. Virol. 2016, 78, 53–56. [Google Scholar] [CrossRef]
  59. Leelaviwat, N.; Armin, S.; Mekraksakit, P.; Nugent, K.; Leelaviwat, N.; Armin, S.; Mekraksakit, P.; Nugent, K. Reactivation of Parvovirus B19 Infection: An Uncommon Trigger of Macrophage Activation Syndrome in Adult-Onset Still’s Disease. Cureus 2023, 15, e37231. [Google Scholar] [CrossRef]
  60. Soldo-Juresa, D.; Radman, M.; Pejsa, V.; Bozikov, V. Reactive macrophage activation syndrome in a patient with parvovirus B19 infection, lymphocytic lichenoid vasculitis, urticaria and angioedema. Ann. Saudi Med. 2010, 30, 88. [Google Scholar] [CrossRef]
  61. Orth, H.M.; Fuchs, A.; Lübke, N.; Jensen, B.E.O.; Luedde, T. Recurrent parvovirus B19 viremia resulting in two episodes of hemophagocytic lymphohistiocytosis. Virol. J. 2022, 19, 107. [Google Scholar] [CrossRef] [PubMed]
  62. Macauley, P.; Abu-Hishmeh, M.; Dumancas, C.; Alexander-Rajan, V.; Piedra-Chavez, F.; Nada, K.; Habtes, I.; Popescu, A.; Mamorska-Dyga, A. Hemophagocytic Lymphohistiocytosis Associated with Parvovirus B19 in a Patient with Acquired Immunodeficiency Syndrome. J. Investig. Med. High. Impact Case Rep. 2019, 7, 2324709619883698. [Google Scholar] [CrossRef] [PubMed]
  63. Mallick, B.; Daniel, P.; Dutta, U. Hepatitis A infection related haemophagocytic syndrome: A case report and systematic review. Trop. Dr. 2019, 49, 234–238. [Google Scholar] [CrossRef] [PubMed]
  64. Fazal, F.; Gupta, N.; Mittal, A.; Ray, A. Haemophagocytic lymphohistiocytosis in human immunodeficiency virus: A systematic review of literature. Drug Discov. Ther. 2020, 14, 226–231. [Google Scholar] [CrossRef] [PubMed]
  65. Tabaja, H.; Kanj, A.; El Zein, S.; Comba, I.Y.; Chehab, O.; Mahmood, M. A Review of Hemophagocytic Lymphohistiocytosis in Patients With HIV. Open Forum Infect. Dis. 2022, 9, ofac071. [Google Scholar] [CrossRef] [PubMed]
  66. Giang, H.T.N.; Banno, K.; Minh, L.H.N.; Trinh, L.T.; Loc, L.T.; Eltobgy, A.; Tai, L.L.T.; Khan, A.; Tuan, N.H.; Reda, Y.; et al. Dengue hemophagocytic syndrome: A systematic review and meta-analysis on epidemiology, clinical signs, outcomes, and risk factors. Rev. Med. Virol. 2018, 28, e2005. [Google Scholar] [CrossRef] [PubMed]
  67. Chevalier, K.; Schmidt, J.; Coppo, P.; Galicier, L.; Noël, N.; Lambotte, O. Hemophagocytic Lymphohistiocytosis Associated with Cytomegalovirus Infection: 5 Cases and a Systematic Review of the Literature. Clin. Infect. Dis. 2023, 76, 351–358. [Google Scholar] [CrossRef]
  68. Geng, F.; Yang, M.; Zhang, X.; Zhao, H.; Zhou, D.; Hu, J. Typical hemophagocytic syndrome associated with cytomegalovirus infection in an immunocompetent patient: A case report and literature review. J. Zhejiang Univ. Sci. B 2023, 24, 1159–1164. [Google Scholar] [CrossRef]
  69. Patil, S.M.; Beck, P.P.; Patel, T.P.; Hunter, M.P.; Johnson, J.; Acevedo, B.A.; Roland, W. Cytomegalovirus pneumonitis-induced secondary hemophagocytic lymphohistiocytosis and SIADH in an immunocompetent elderly male literature review. IDCases 2020, 22, e00972. [Google Scholar] [CrossRef]
  70. Bonnecaze, A.K.; Willeford, W.G.; Lichstein, P.; Ohar, J.; Bonnecaze, A.K.; Willeford, W.G.; Lichstein, P.; Ohar, J. Acute Cytomegalovirus (CMV) Infection Associated with Hemophagocytic Lymphohistiocytosis (HLH) in an Immunocompetent Host Meeting All Eight HLH 2004 Diagnostic Criteria. Cureus 2017, 9, e1070. [Google Scholar] [CrossRef]
  71. Singh, A.; Chauhan, A.; Padole, V.; Chhabra, D.; Upneja, R. The great masquerader: Hemophagocytic lymphohistiocytosis secondary to cytomegalovirus infection in an immunocompetent young man. J. Fam. Med. Prim. Care 2020, 9, 3762. [Google Scholar]
  72. Brambilla, B.; Barbosa, A.M.; Scholze, C.D.S.; Riva, F.; Freitas, L.; Balbinot, R.A.; Balbinot, S.; Soldera, J. Hemophagocytic Lymphohistiocytosis and Inflammatory Bowel Disease: Case Report and Systematic Review. Inflamm. Intest. Dis. 2020, 5, 49–58. [Google Scholar] [CrossRef]
  73. Yabushita, T.; Yoshioka, S.; Koba, Y.; Ono, Y.; Hiramoto, N.; Tabata, S.; Itou, M.; Shimizu, N.; Tomii, K.; Ishikawa, T. Successful Treatment of Herpes Simplex Virus (HSV)-1-associated Hemophagocytic Lymphohistiocytosis (HLH) with Acyclovir: A Case Report and Literature Review. Intern. Med. 2017, 56, 2919–2923. [Google Scholar] [CrossRef] [PubMed]
  74. Halstead, E.S.; Rajasekaran, S.; Fitzgerald, J.C.; Weiss, S.L. Hyperferritinemic sepsis: An opportunity for earlier diagnosis and intervention? Front. Pediatr. 2016, 4, 206380. [Google Scholar] [CrossRef] [PubMed]
  75. Nishitani, M.; Alali, M.; Hageman, J.R.; Nubani, R.; Chong, G.; Tran, L.; Husain, A.N.; Rosebush, J. Hyperferritinemia: A Diagnostic Marker for Disseminated Neonatal Herpes Simplex Virus Infection? Pediatr. Ann. 2021, 50, e264–e267. [Google Scholar] [CrossRef]
  76. Liew, J.W.; Jones, B.L.; Hunter, A.J. Disseminated Herpes Simplex Masquerading as Hemophagocytic Lymphohistiocytosis: A Case Report. Perm. J. 2019, 23, 18–202. [Google Scholar] [CrossRef] [PubMed]
  77. Jongbloed, E.M.; Hermans, M.A.W.; Wabbijn, M.; Van Kampen, J.J.A.; Van Laar, J.A.M. HLH caused by an HSV-2 infection: A case report and review of the literature. Neth J. Med. 2020, 78, 282–285. [Google Scholar] [PubMed]
  78. Sonoda, M.; Ishimura, M.; Eguchi, K.; Shiraishi, A.; Kanno, S.; Kaku, N.; Inoue, H.; Motomura, Y.; Ochiai, M.; Sakai, Y.; et al. Prognostic factors for survival of herpes simplex virus-associated hemophagocytic lymphohistiocytosis. Int. J. Hematol. 2020, 111, 131–136. [Google Scholar] [CrossRef]
  79. Nozawa, T.; Nishimura, K.; Ohara, A.; Hara, R.; Ito, S. Primary varicella infection in children with systemic juvenile idiopathic arthritis under tocilizumab therapy. Mod. Rheumatol. 2019, 29, 558–562. [Google Scholar] [CrossRef]
  80. Gur, G.; Cakar, N.; Uncu, N.; Ayar, G.; Basaran, O.; Taktak, A.; Koksoy, A.Y.; Acar, B.; Cayci, F.S. Hemophagocytic lymphohistiocytosis secondary to Varicella zoster infection in a child with Henoch–Schönlein purpura. Pediatr. Int. 2015, 57, e37–e38. [Google Scholar] [CrossRef]
  81. Nodehi, H.; Faranoush, M.; Arshi, S.; Nabavi, M.; Bemanian, M.H.; Shokri, S.; Saghafi, M.R.; Fallah, M.S.; Fallahpour, M. Neonatal Onset of Hemophagocytic Lymphohistiocytosis Due to Prenatal Varicella-Zoster Infection in a Neonate with Griscelli Syndrome Type 2. Iran. J. Allergy Asthma Immunol. 2022, 21, 488–493. [Google Scholar] [CrossRef]
  82. Drago, E.; Garbarino, F.; Signa, S.; Grossi, A.; Schena, F.; Penco, F.; Santori, E.; Candotti, F.; Boztug, K.; Volpi, S.; et al. Case Report: Susceptibility to viral infections and secondary hemophagocytic lymphohistiocytosis responsive to intravenous immunoglobulin as primary manifestations of adenosine deaminase 2 deficiency. Front. Immunol. 2022, 13, 937108. [Google Scholar] [CrossRef] [PubMed]
  83. Schulert, G.S.; Zhang, M.; Fall, N.; Husami, A.; Kissell, D.; Hanosh, A.; Zhang, K.; Davis, K.; Jentzen, J.M.; Napolitano, L.; et al. Whole-Exome Sequencing Reveals Mutations in Genes Linked to Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome in Fatal Cases of H1N1 Influenza. J. Infect. Dis. 2016, 213, 1180–1188. [Google Scholar] [CrossRef] [PubMed]
  84. Henter, J.I.; Chow, C.B.; Leung, C.W.; Lau, Y.L. Cytotoxic therapy for severe avian influenza A (H5N1) infection. Lancet 2006, 367, 870–873. [Google Scholar] [CrossRef] [PubMed]
  85. Kaplanski, G. Interleukin-18: Biological properties and role in disease pathogenesis. Immunol. Rev. 2018, 281, 138–153. [Google Scholar] [CrossRef]
  86. Otto, W.R.; Behrens, E.M.; Teachey, D.T.; Lamson, D.M.; Barrett, D.M.; Bassiri, H.; Lambert, M.P.; Mount, S.; Petrosa, W.L.; Romberg, N.; et al. Human Adenovirus 7-Associated Hemophagocytic Lymphohistiocytosis-like Illness: Clinical and Virological Characteristics in a Cluster of Five Pediatric Cases. Clin. Infect. Dis. 2021, 73, e1532–e1538. [Google Scholar] [CrossRef]
  87. Pal, P.; Bose, N.; Poddar, A.; Chowdhury, K.; Saha, A. Experience with Cidofovir as an adjunctive therapy in a patient of adenovirus-induced macrophage activation syndrome in systemic arthritis. Clin. Rheumatol. 2020, 39, 2449–2452. [Google Scholar] [CrossRef] [PubMed]
  88. Seidel, M.G.; Kastner, U.; Minkov, M.; Gadner, H. IVIG Treatment of Adenovirus Infection-Associated Macrophage Activation Syndrome in a Two-Year-Old Boy: Case Report and Review of the Literature. Pediatr. Hematol. Oncol. 2003, 20, 445–451. [Google Scholar] [CrossRef]
  89. Zhang, H.Y.; Xiao, M.; Yan, F.; Zhang, M.R.; Zhang, Y. Risk Factors for the Development of Hemophagocytic Lymphohistiocytosis in Children with Severe Adenovirus Pneumonia: A Single-Center Retrospective Study. Front. Pediatr. 2021, 9, 654002. [Google Scholar] [CrossRef]
  90. Kalmuk, J.; Matar, S.; Feng, G.; Kilb, E.; Lim, M.Y. Parvovirus B19-induced hemophagocytic lymphohistiocytosis: Case report and review of the literature. Clin. Case Rep. 2019, 7, 2076–2081. [Google Scholar] [CrossRef]
  91. Butin, M.; Mekki, Y.; Phan, A.; Billaud, G.; Di Filippo, S.; Javouhey, E.; Cochat, P.; Belot, A. Successful immunotherapy in life-threatening parvovirus B19 infection in a child. Pediatr. Infect. Dis. J. 2013, 32, 789–792. [Google Scholar] [CrossRef] [PubMed]
  92. Aamri, H.; Elqadiry, R.; Nassih, H.; Bourrahouat, A.; Ait Sab, I. HAV Infection Associated with Hemophagocytic Syndrome. Case Rep. Infect. Dis. 2023, 2023, 7799252. [Google Scholar] [CrossRef] [PubMed]
  93. Canoz, P.Y.; Afat, E.; Temiz, F.; Azizoglu, N.O.; Citilcioglu, H.B.; Tumgor, G.; Leblebisatan, G.; Turgut, M. Reactive Hemophagocytic Lymphohistiocytosis After Hepatitis A Infection. Indian. J. Hematol. Blood Transfus. 2014, 30, 46–48. [Google Scholar] [CrossRef] [PubMed]
  94. Bendari, M.; Delsa, H.; Bouanani, N.; Jabouri, R.; Darouich, S.; Nejjari, S.; Guessous, F.; Doghmi, K. Hemophagocytic lymphohistiocytosis associated with HBV-HCV coinfection in adult: Case report. Clin. Case Rep. 2021, 9, e04328. [Google Scholar] [CrossRef] [PubMed]
  95. Termsinsuk, P.; Sirisanthiti, P. Acute hepatitis A infection-associated hemophagocytic lymphohistiocytosis in adult presenting as impending acute liver failure: A case report and literature review. Clin. Case Rep. 2022, 10, e05334. [Google Scholar] [CrossRef] [PubMed]
  96. Kim, B.; Choi, Y.W.; Pai, H.; Kim, J. A Case of Human Immunodeficiency Virus-triggered Hemophagocytic Lymphohistocytosis Presenting with Severe Bleeding Tendency. Infect. Chemother. 2021, 53, 802–807. [Google Scholar] [CrossRef] [PubMed]
  97. Jariwal, R.; Jaber, F.S.; Ipalawatte, H.; Petersen, G. An Unusual Case of Hemophagocytic Lymphohistiocytosis Presentation in Acute Human Immunodeficiency Virus. J. Investig. Med. High Impact Case Rep. 2021, 9, 23247096211021696. [Google Scholar] [CrossRef] [PubMed]
  98. Divyashree, K.; Singh, H.; Parkhi, M.; Karmakar, I.; Sachdeva, M.; Suri, V.; Bhalla, A. Hemophagocytic lymphohistiocytosis due to disseminated histoplasmosis in a patient with HIV infection. J. Glob. Infect. Dis. 2023, 15, 124–126. [Google Scholar] [CrossRef] [PubMed]
  99. Pipitò, L.; Medaglia, A.A.; Trizzino, M.; Mancuso, A.; Catania, B.; Mancuso, S.; Calà, C.; Florena, A.M.; Cascio, A. Hemophagocytic lymphohistiocytosis secondary to histoplasmosis: A case report in a patient with AIDS and recent SARS-CoV-2 infection and minireview. Heliyon 2023, 9, e18537. [Google Scholar] [CrossRef]
  100. Warren, B.C.; Yadav, H.; Graham, M.; Tudor, M.; Warren, B.C.; Yadav, H.; Graham, R.M.; Tudor, M. Hemophagocytic Lymphohistiocytosis in the Setting of Disseminated Histoplasmosis and Uncontrolled HIV. Cureus 2022, 14, 124–126. [Google Scholar] [CrossRef]
  101. Liu, X.; Zhu, X.; Zhou, X.; Xie, Y.; Xiang, D.; Wan, Z.; Huang, Y.; Zhu, B. Case report: Ruxolitinib as first-line therapy for secondary hemophagocytic lymphohistiocytosis in patients with AIDS. Front. Immunol. 2022, 13, 1012643. [Google Scholar] [CrossRef] [PubMed]
  102. Rocco, J.M.; Laidlaw, E.; Galindo, F.; Anderson, M.; Rupert, A.; Higgins, J.; Sortino, O.; Ortega-Villa, A.M.; Sheikh, V.; Roby, G.; et al. Severe Mycobacterial Immune Reconstitution Inflammatory Syndrome (IRIS) in Advanced Human Immunodeficiency Virus (HIV) Has Features of Hemophagocytic Lymphohistiocytosis and Requires Prolonged Immune Suppression. Clin. Infect. Dis. 2023, 76, e561–e570. [Google Scholar] [CrossRef] [PubMed]
  103. Mo, P.; Deng, L.; Chen, X.; Xiong, Y.; Zhang, Y. Rapid Progression of Kaposi’s sarcoma complicated with hemophagocytic syndrome in a severely immunosuppressed patient with HIV-infection: A case report. AIDS Res. Ther. 2020, 17, 58. [Google Scholar] [CrossRef] [PubMed]
  104. Kanitthamniyom, C.; Osorio, A.; Saowapa, S.; Siladech, P.; Kanitthamniyom, C.; Osorio, A.; Saowapa, S.; Siladech, P. A Case of Subcutaneous Panniculitis-Like T-cell Lymphoma with Hemophagocytic Lymphohistiocytosis in an HIV Patient. Cureus 2023, 15, e49564. [Google Scholar] [CrossRef] [PubMed]
  105. van der Ven, A.J.A.M.; Netea, M.G.; van der Meer, J.W.M.; de Mast, Q. Ebola virus disease has features of hemophagocytic lymphohistiocytosis syndrome. Front. Med. 2015, 2, 132071. [Google Scholar] [CrossRef] [PubMed]
  106. McElroy, A.K.; Shrivastava-Ranjan, P.; Harmon, J.R.; Martines, R.B.; Silva-Flannery, L.; Flietstra, T.D.; Kraft, C.S.; Mehta, A.K.; Lyon, G.M.; Varkey, J.B.; et al. Macrophage Activation Marker Soluble CD163 Associated with Fatal and Severe Ebola Virus Disease in Humans1. Emerg. Infect. Dis. 2019, 25, 290–298. [Google Scholar] [CrossRef]
  107. Ab-Rahman, H.A.; Rahim, H.; Abubakar, S.; Wong, P.F. Macrophage Activation Syndrome-Associated Markers in Severe Dengue. Int. J. Med. Sci. 2016, 13, 179–186. [Google Scholar] [CrossRef]
  108. Vuong, N.L.; Cheung, K.W.; Periaswamy, B.; Vi, T.T.; Duyen, H.T.L.; Leong, Y.S.; Binte Hamis, Z.N.; Gregorova, M.; Ooi, E.E.; Sessions, O.; et al. Hyperinflammatory Syndrome, Natural Killer Cell Function, and Genetic Polymorphisms in the Pathogenesis of Severe Dengue. J. Infect. Dis. 2022, 226, 1338–1347. [Google Scholar] [CrossRef] [PubMed]
  109. Singh, D.; Raghunathan, V.; Dhaliwal, M.; Rastogi, N.; Chadha, R.; Yadav, S.P. Soluble Interleukin-2 Receptor Level as a Marker of Hemophagocytic Lymphohistiocytosis in Children with Severe Dengue. Front. Pediatr. 2021, 9, 721857. [Google Scholar] [CrossRef]
  110. Ellis, E.M.; Sharp, T.M.; Pérez-Padilla, J.; González, L.; Poole-Smith, B.K.; Lebo, E.; Baker, C.; Delorey, M.J.; Torres-Velasquez, B.; Ochoa, E.; et al. Incidence and Risk Factors for Developing Dengue-Associated Hemophagocytic Lymphohistiocytosis in Puerto Rico, 2008–2013. PLoS Negl. Trop. Dis. 2016, 10, e0004939. [Google Scholar] [CrossRef]
  111. Abdelgabar, A.; Abdelgabar, A.; Elsayed, M. A Case of Delayed COVID-19-Related Macrophage Activation Syndrome. J. Med. Cases 2022, 13, 207–211. [Google Scholar] [CrossRef] [PubMed]
  112. da Cruz, F.J.F.; de Figueiredo, E.A.P.; Batista, F.P.; Gallindo, M.A.C.; Fernandes, A.C. da S. Coronavirus Disease 2019 Infection and Early Diagnosis of Macrophage Activation Syndrome: A Case Report of a 62-year-old man. Rev. Soc. Bras. Med. Trop. 2022, 55, e0377–e2021. [Google Scholar]
  113. Hieber, M.L.; Sprute, R.; Eichenauer, D.A.; Hallek, M.; Jachimowicz, R.D. Hemophagocytic lymphohistiocytosis after SARS-CoV-2 vaccination. Infection 2022, 50, 1399–1404. [Google Scholar] [CrossRef] [PubMed]
  114. Reiff, D.D.; Zhang, M.; Smitherman, E.A.; Mannion, M.L.; Stoll, M.L.; Weiser, P.; Cron, R.Q. A Rare STXBP2 Mutation in Severe COVID-19 and Secondary Cytokine Storm Syndrome. Life 2022, 12, 149. [Google Scholar] [CrossRef] [PubMed]
  115. Macaraeg, M.; Schulert, G.S. Complications of complications: Diagnosis and treatment of recurrent macrophage activation syndrome in a patient with well-controlled systemic juvenile idiopathic arthritis. RMD Open 2023, 9, e002611. [Google Scholar] [CrossRef] [PubMed]
  116. Shaw, T.Y.; Schivo, M. Weathering a cytokine storm: A case of EBV-induced hemophagocytic lymphohistiocytosis. J. Investig. Med. High. Impact Case Rep. 2016, 4, 2324709616647409. [Google Scholar] [CrossRef]
  117. Zhu, M.; Zhang, J.; Shi, Q.; Sun, X.; Wang, H.; Sun, M.; Liu, Y. Rescue of HLH with T and B Lymphocyte Involvement Due to Epstein-Barr Virus by PD-1 Inhibitor/Ruxolitinib and Rituximab Combination Regimens: A Case Report. Iran. J. Immunol. 2023, 20, 466–472. [Google Scholar]
  118. Contreras-Chavez, P.; Anampa-Guzmán, A.; Gaznabi, S.; Lansigan, F.; Contreras-Chavez, P.; Anampa-Guzmán, A.; Gaznabi, S.; Lansigan, F. Epstein-Barr Virus Infection-associated Hemophagocytic Lymphohistiocytosis. Cureus 2020, 12, e7563. [Google Scholar] [CrossRef] [PubMed]
  119. Sakaguchi, M.; Nagata, Y.; Terasaki, Y.; Takeyoshi, A.; Yasuda, S.; Honma, S.; Kinoshita, R.; Marumo, A.; Asayama, T.; Yui, S.; et al. Epstein-Barr Virus-Related Hemophagocytic Lymphohistiocytosis with Central Nervous System Symptoms. J. Nippon. Med. Sch. 2023, 90, 126–135. [Google Scholar] [CrossRef]
  120. Quadri, S.P.; Jain, N.K.; Brandon, B.L.; Modi, H.; Bawaadam, H.; Quadri, S.P.; Jain, N.K.; Brandon, B.L.; Modi, H.; Bawaadam, H. An Intriguing Presentation of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis. Cureus 2020, 12, e9561. [Google Scholar] [CrossRef]
  121. Ioannou, P.; Akoumianaki, E.; Alexakis, K.; Proklou, A.; Psyllaki, M.; Stamatopoulos, E.; Koulentaki, M.; Kondili, E.; Kofteridis, D.P. Hemophagocytic lymphohistiocytosis syndrome associated with Epstein-Barr infection in an immunocompetent patient. A case study. Germs 2020, 10, 266–271. [Google Scholar] [CrossRef] [PubMed]
  122. Awasthi, S.; Upreti, S. Macrophage activation syndrome in a patient with systemic lupus erythematosus (SLE) and dual viremia. J. Community Hosp. Intern. Med. Perspect. 2020, 10, 470–474. [Google Scholar] [CrossRef] [PubMed]
  123. Silwedel, C.; Frieauff, E.; Thomas, W.; Liese, J.G.; Speer, C.P. Secondary haemophagocytic lymphohistiocytosis triggered by postnatally acquired cytomegalovirus infection in a late preterm infant. Infection 2017, 45, 355–359. [Google Scholar] [CrossRef] [PubMed]
  124. Lau, A.; Youn, H.; Caricchio, R.; Brent, L.; Lau, A.; Youn, H.; Caricchio, R.; Brent, L. A Case of Cytomegalovirus-Induced Hemophagocytic Lymphohistiocytosis in a Patient with an Underlying Rheumatic Disease. Cureus 2020, 12, e8130. [Google Scholar] [CrossRef] [PubMed]
  125. Gullickson, M.; Nichols, L.; Scheibe, M.; Gullickson, M.; Nichols, L.; Scheibe, M. A Novel Therapy for a Rare Condition: Continuous Anakinra Infusion for a Patient with Macrophage Activation Syndrome. Cureus 2023, 15, e42968. [Google Scholar] [CrossRef] [PubMed]
  126. McKeone, D.J.; DeMartini, T.K.M.; Kavanagh, R.P.; Halstead, E.S. Case Report: Rapid Recognition and Immune Modulation of Secondary HLH Due to Disseminated HSV Infection. Front. Pediatr. 2021, 9, 681055. [Google Scholar] [CrossRef] [PubMed]
  127. Mazzotta, E.; Fiorda Diaz, J.; Echeverria-Villalobos, M.; Eisinger, G.; Sprauer, S.; Singha, A.; Lyaker, M.R. Case report: Disseminated herpes simplex virus 1 infection and hemophagocytic lymphohistiocytosis after immunomodulatory therapy in a patient with coronavirus disease 2019. Front. Med. 2022, 9, 1053012. [Google Scholar] [CrossRef] [PubMed]
  128. Jayashree, K.; Rao, S.; Kamath, N. Influenza B Virus Triggering Macrophage Activation Syndrome in an Infant. Indian. J. Crit. Care Med. 2017, 21, 802–803. [Google Scholar] [CrossRef] [PubMed]
  129. Casciaro, R.; Cresta, F.; Favilli, F.; Naselli, A.; De Alessandri, A.; Minicucci, L. Macrophage activation syndrome induced by A/H1N1 influenza in cystic fibrosis. Pediatr. Pulmonol. 2014, 49, E10–E12. [Google Scholar] [CrossRef]
  130. Dogan, A.; Demircioglu, S.; Ekinci, O. Acute hepatitis-a virus infection as a rare cause of hemophagocytic lymphohistiocytosis. J. Coll. Physicians Surg. Pak. 2021, 31, 232–234. [Google Scholar]
  131. Tong, Q.J.; Godbole, M.M.; Biniwale, N.; Jamshed, S.; Tong, Q.J.; Godbole, M.M.; Biniwale, N.; Jamshed, S. An Elusive Diagnosis: Case Reports of Secondary Hemophagocytic Lymphohistiocytosis and Review of Current Literature. Cureus 2019, 11, e4548. [Google Scholar] [CrossRef] [PubMed]
  132. Ray, U.; Dutta, S.; Mondal, S.; Bandyopadhyay, S. Severe dengue due to secondary hemophagocytic lymphohistiocytosis: A case study. IDCases 2017, 8, 50–53. [Google Scholar] [CrossRef]
  133. Acharya, S.; Shukla, S.; Sontakke, T.; VS, I.; Bagga, C.; Dronamraju, S.; Giri, A.; Acharya, S.; Shukla, S.; Sontakke, T.; et al. A Case Report of Hemophagocytic Lymphohistiocytosis (HLH)—An Unusual Complication of Dengue Infection. Cureus 2022, 14, e26504. [Google Scholar] [CrossRef] [PubMed]
  134. Pradeep, C.; Karunathilake, P.; Abeyagunawardena, S.; Ralapanawa, U.; Jayalath, T. Hemophagocytic lymphohistiocytosis as a rare complication of dengue haemorrhagic fever: A case report. J. Med. Case Rep. 2023, 17, 224. [Google Scholar] [CrossRef]
  135. Song, Y.; Wang, Y.; Wang, Z. Requirement for etoposide in the initial treatment of Epstein-Barr virus–associated haemophagocytic lymphohistiocytosis. Br. J. Haematol. 2019, 186, 717–723. [Google Scholar] [CrossRef] [PubMed]
  136. Chen, L.; Wang, J.; Wang, Z. L-DEP regimen is effective as an initial therapy for adult EBV-HLH. Ann. Hematol. 2022, 101, 2461–2470. [Google Scholar] [CrossRef]
  137. Zhao, Y.; Li, Z.; Zhang, L.; Lian, H.; Ma, H.; Wang, D.; Zhao, X.; Zhang, Q.; Wang, T.; Zhang, R. L-DEP regimen salvage therapy for paediatric patients with refractory Epstein-Barr virus-associated haemophagocytic lymphohistiocytosis. Br. J. Haematol. 2020, 191, 453–459. [Google Scholar] [CrossRef]
  138. Chellapandian, D.; Das, R.; Zelley, K.; Wiener, S.J.; Zhao, H.; Teachey, D.T.; Nichols, K.E. Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br. J. Haematol. 2013, 162, 376–382. [Google Scholar] [CrossRef]
  139. Zhang, Q.; Zhao, Y.Z.; Ma, H.H.; Wang, D.; Cui, L.; Li, W.J.; Wei, A.; Wang, C.J.; Wang, T.Y.; Li, Z.G.; et al. A study of ruxolitinib response–based stratified treatment for pediatric hemophagocytic lymphohistiocytosis. Blood 2022, 139, 3493–3504. [Google Scholar] [CrossRef]
  140. Siyer, O.; Aksakal, B.; Basat, S. Evaluation of the effects of anakinra treatment on clinic and laboratory results in patients with COVID-19. N. Clin. Istanb. 2023, 10, 189–196. [Google Scholar] [CrossRef]
  141. Amikishiyev, S.; Deniz, R.; Gunver, M.G.; Aghamuradov, S.; Koca, N.; Ince, B.; Bektas, M.; Yilmaz, A.; Canturk, Y.; Durak, G.; et al. Pos1216 Potential Predictors of Outcome for Anakinra Treatment in COVID-19 Patients with Macrophage Activation Syndrome. Ann. Rheum. Dis. 2022, 81, 937–938. [Google Scholar] [CrossRef]
  142. Huet, T.; Beaussier, H.; Voisin, O.; Jouveshomme, S.; Dauriat, G.; Lazareth, I.; Sacco, E.; Naccache, J.M.; Bézie, Y.; Laplanche, S.; et al. Anakinra for severe forms of COVID-19: A cohort study. Lancet Rheumatol. 2020, 2, e393–e400. [Google Scholar] [CrossRef] [PubMed]
  143. Guclu, K.G.; Geyiktepe-Guclu, C.; Bayramlar, O.F.; Tuncer, G.; Aydin, M. Use of high-dose steroid therapy: Addition of anakinra in the treatment of severe COVID-19. Rev. Assoc. Med. Bras. 2024, 70, e20230671. [Google Scholar] [CrossRef] [PubMed]
  144. Oliynyk, O.; Barg, W.; Slifirczyk, A.; Oliynyk, Y.; Gurianov, V.; Rorat, M. Efficacy of Tocilizumab Therapy in Different Subtypes of COVID-19 Cytokine Storm Syndrome. Viruses 2021, 13, 1067. [Google Scholar] [CrossRef] [PubMed]
  145. Mert, A.; Vahaboğlu, H.; Arslan, F.; Batirel, A.; Saraçoğlu, K.T.; Bastug, A.; Çağatay, A.; Irmak, İ.; Dizman, G.T.; Ertenli, İ.; et al. Tocilizumab treatment in severe COVID-19: A multicenter retrospective study with matched controls. Rheumatol. Int. 2022, 42, 457–467. [Google Scholar] [CrossRef] [PubMed]
  146. Akleylek, C.; Gür, S.G.; Sever, İ.H.; Koçulu Demir, S.; Çevik, E.; Eken, E.; Gökkaya, Z.; Çağatay, Y.; Yılmaz, N. What are the main factors affecting the outcome of tocilizumab therapy in COVID-19-induced cytokine release syndrome? Diagn. Interv. Radiol. 2022, 9, 126–131. [Google Scholar] [CrossRef] [PubMed]
  147. Karakike, E.; Dalekos, G.N.; Koutsodimitropoulos, I.; Saridaki, M.; Pourzitaki, C.; Papathanakos, G.; Kotsaki, A.; Chalvatzis, S.; Dimakopoulou, V.; Vechlidis, N.; et al. ESCAPE: An Open-Label Trial of Personalized Immunotherapy in Critically lll COVID-19 Patients. J. Innate Immun. 2022, 14, 218–228. [Google Scholar] [CrossRef]
  148. Chen, S.; Zhang, C.; Chen, D.; Dong, L.; Chang, T.; Tang, Z.H. Advances in attractive therapeutic approach for macrophage activation syndrome in COVID-19. Front. Immunol. 2023, 14, 1200289. [Google Scholar] [CrossRef]
Viruses 16 01004 g001
Figure 1. Study flowchart.
Figure 1. Study flowchart.
Viruses 16 01004 g001
Table 1. Clinical and laboratory findings of MAS in different viral infections.
Table 1. Clinical and laboratory findings of MAS in different viral infections.
Viral InfectionAuthorYearPatient PopulationClinical and Laboratory Findings
EBV-HLHLai et al.
[55]		2018133 adult patients
91 males
42 females		Fever 91.2%
Splenomegaly 89.5%
Hyperferritinemia 92%
Cytopenia (reduction of 2 or 3 lines) 93.2%
Hypertriglyceridemia 34.7%
Hypofibrinogenemia 59%
Elevated liver enzymes 80%
Hemophagocytosis 86.2%
sIL-2R 87.7%
NK cell activity 44.5%
CMV-HLHRolsdolph et al.
[56]		202271 adult patients
29 males
42 females		Fever 71/71 (100%)
Hepatomegaly 3/71
Splenomegaly 18/71
Hepatomegaly and splenomegaly 18/71
Hyperferritinemia 61/71 (86.9%)
Cytopenia (reduction of at least 2 lines) 57/71 (80.2%)
Hypertriglyceridemia 21/71
Hypofibrinogenemia 5/71
Hemophagocytosis 62/71 (87.3%)
sIL-2R (results available for 18 patients) 13/18
NK cell activity 6/71
H1N1-HLHBahr Greenwood et al.
[57]		20214 adult patients
4 males		Hepatomegaly 4/4
Splenomegaly 3/4
Hyperferritinemia 4/4
Cytopenia (reduction of 2 lines) ¾
Hypertriglyceridemia 4/4
Elevated liver enzymes 4/4
Hemophagocytosis 4/4
sIL-2R (results available for 3 patients) 3/3
NK cell activity 2/4
Adenovirus-HLHMellon et al.
[58]		20166 patients
1 adult
5 pediatric
4 males
3 females		Fever 6/6
Hepatomegaly 4/6
Splenomegaly 3/6
Anemia 5/6
Leukopenia 4/6
Thrombocytopenia 5/6
Hypofibrinogenemia 2/6
Elevated liver enzymes 6/6
Parvovirus B19-HLHLeelaviwat et al. [59]
Soldo-Juresa et al. [60]
Orth et al. [61]
Macauley et al. [62]		2023
2010
2022
2019		4 patients
4 females		Fever 4/4
Splenomegaly 2/4
Hyperferritinemia 4/4
Anemia 3/4
Leukopenia 2/4
Thrombopenia 3/4
Hypertriglyceridemia 2/4
Hypofibrinogenemia 2/4
Elevated liver enzymes 3/4
Hemophagocytosis 3/4
sIL-2R 3/4
HAV-HLHMallick et al. [63]201927 patients
17 adults
10 pediatric
14 males
13 females		Fever 26/27 (96.2%)
Hepatomegaly 17/27 (62.9%)
Splenomegaly 22/27 (81.4%)
Hyperferritinemia (results available for 21 patients) 21/21 (100%)
Pancytopenia 15/23 (65.2%)
Hypertriglyceridemia (results available for 19 patients) mean value 394.9 (range 74–690)
Hypofibrinogenemia (results available for 14 patients) mean value 7.34 (range 0.3–76)
Hemophagocytosis 26/27 (96.2%)
sIL-2R (results available for 4 patients) 4/4
HIV-HLHFazal et al.
[64]		202052 patients
42 males
10 females		Fever 52/52 (100%)
Splenomegaly 42/46 (91.3%)
Hyperferritinemia 42/43 (97.6%)
Anemia 40/52 (76.9%)
Leukopenia 22/30 (73.3%)
Thrombopenia 47/51 (92.1%)
Hypertriglyceridemia 24/33 (72.7%)
Hypofibrinogenemia 6/15 (40%)
Hemophagocytosis 39/45 (86.6%)
sIL-2R 10/11 (90.9%)
NK cell activity 2/5 (40%)
Tabaja et al.
[65]		202281 patients
63 males
18 females		Fever 80/81 (98.7%)
Splenomegaly 52/71 (73.2%)
Hyperferritinema 64/64 (100%)
Cytopenia 53/70 (75.7%)
Hypertriglyceridemia 34/47 (72.3%)
Hypofibrinogenemia 10/25 (40%)
Hemophagocytosis 70/80 (87.5%)
sIL-2R 21/23 (91.3%)
NK cell activity 10/10 (100%)
Dengue-HLHGiang et al.
[66]		2018122 patients
62 males
60 females		Fever 97.2%
Splenomegaly 78.4%
Hepatomegaly 70.2%
Hyperferritinemia 97.1%
Anemia 76%
Thrombopenia 90.1%
This table summarizes the clinical characteristics and laboratory findings of patients that developed MAS in the context of different viral infections. Abbreviations: EBV: Epstein–Barr virus; CMV: cytomegalovirus; HAV: hepatitis A virus; HIV: human immunodeficiency virus; HLH: hemophagocytic lymphohistiocytosis.
Table 2. Therapeutic regimens for viral infection associated MAS.
Table 2. Therapeutic regimens for viral infection associated MAS.
Viral InfectionReferenceTreatmentOutcomeAdditional Information
COVID-19Abdelgabar et al., 2022
[111]		antibiotics
remdesivir
dexamethasone
tocilizumab		Died
Cruz et al., 2022
[112]		pentaglobin
pulse therapy with dexamethasone		SurvivedOther regimes did not improve clinical condition
Hieber et al., 2022
[113]		IVIG
dexamethasone
anakinra		SurvivedMAS due to vaccination
anakinra led to improvement
Reiff et al., 2022
[114]		antibiotics
remdesivir
dexamethasone
IVIG
anakinra		Survived Heterozygous pHLH gene mutation
EBVMacaraeg et al., 2023
[115]		emapalumab
acyclovir
TMP/SMX		Survived
Shaw et al., 2016
[116]		dexamethasone
etoposide
anti-topoisomerase II agent
rituximab		DiedEtoposide discontinued due to worsening liver failure
Zhu et al., 2023
[117]		PD-1 inhibitor
rituximab		Survived
Contreras-Chavez et al., 2020
[118]		etoposide
dexamethasone
rituximab		Died
Shakaguchi et al., 2023
[119]		corticosteroids
etoposide
cyclosporine
rituximab		DiedReduced dose of etoposide due to hepatic dysfunction
Quadri et al., 2020
[120]		high dose dexamethasoneDied
Ioannou et al., 2020
[121]		acyclovir
multiple antibiotic courses
IVIG
prednisolone		Survived
CMVAwasthi et al., 2020
[122]		ganciclovir
high dose steroids
IVIG
Silwedel et al., 2017
[123]		ganciclovirSurvivedPediatric case
Lau et al., 2020
[124]		ganciclovir
anakinra
dexamethazone
etoposide		SurvivedPatient did not respond to anakinra and switched to etoposide
Gullickson et al., 2023
[125]		high dose steroids
ganciclovir
continuous anakinra infusion 		Survived
HSVMcKeone et al., 2021
[126]		dexamethasone
etoposide
emapalumab
anakinra
IVIG		DiedPediatric case
Mazzotta et al., 2022
[127]		antibiotics
acyclovir
dexamethasone		Died
InfluenzaJayashree et al., 2017
[128]		methylprednisolone
antibiotics
IVIG		SurvivedPediatric case
MAS due to influenza B virus
Casciaro et al., 2014
[129]		prednisolone
antibiotics
oseltamivir		SurvivedPediatric case
Parvovirus B19Leelaviwat et al., 2023
[59]		high-dose methylprednisolone
etoposide
Died
Macauley et al., 2019
[62]		etoposide
high-dose dexamethasone
IVIG		Survived
HAVDogan et al., 2021
[130]		IVIG
dexamethasone		Survived
HIVTong et al., 2019
[131]		etoposide
dexamethazone		Died
Kim et al., 2021
[96]		high-dose dexamethasone
elvitegravir/cobicistat/emtricitabine/tenofovir		Survived
DengueRay et al., 2017
[132]		IVIGSurvived
Acharya et al., 2022
[133]		antibiotics
dexamethasone
etoposide		Survived
Pradeep et al., 2023
[134]		dexamethasoneSurvived
This table summarizes the therapeutic regimens that have been used in reported cases of MAS triggered by viral infections. Abbreviations: MAS: macrophage activation syndrome; COVID-19: corona virus disease 2019; EBV: Epstein–Barr virus; CMV: cytomegalovirus; HSV: herpes simplex virus; HAV: hepatitis A virus; HIV: human immunodeficiency virus; PD-1: programmed cell death protein 1; IVIG: intravenous immune globulin.
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Papageorgiou, D.; Gogos, C.; Akinosoglou, K. Macrophage Activation Syndrome in Viral Sepsis. Viruses 2024, 16, 1004. https://doi.org/10.3390/v16071004

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Papageorgiou D, Gogos C, Akinosoglou K. Macrophage Activation Syndrome in Viral Sepsis. Viruses. 2024; 16(7):1004. https://doi.org/10.3390/v16071004

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Papageorgiou, Despoina, Charalambos Gogos, and Karolina Akinosoglou. 2024. "Macrophage Activation Syndrome in Viral Sepsis" Viruses 16, no. 7: 1004. https://doi.org/10.3390/v16071004

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Papageorgiou, D., Gogos, C., & Akinosoglou, K. (2024). Macrophage Activation Syndrome in Viral Sepsis. Viruses, 16(7), 1004. https://doi.org/10.3390/v16071004

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