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1.
Sci Rep ; 12(1): 10240, 2022 Jun 17.
Article in English | MEDLINE | ID: covidwho-1921703

ABSTRACT

This study investigated the role of Toll-like receptor 1 (TLR1), TLR2, TLR4, TLR7, and TLR9 in patients with adult-onset Still's disease (AOSD). This study included 20 patients with AOSD and 15 healthy controls (HCs). TLR expression in the peripheral blood was quantified using flow cytometry; TLR expression pattern, in the skin lesions and lymph nodes (LNs) of patients with AOSD, was evaluated immunohistochemically. Significantly higher mean intensities of cells presenting TLR2 and TLR7 from whole blood were observed in patients with AOSD than in HCs. TLR2 expression in whole cells correlated with systemic scores, levels of lactate dehydrogenase and ferritin and serum levels of interleukin-1ß (IL-1ß), IL-6, and IL-18. The percentage of TLR2-positive inflammatory cells was higher in skin biopsy samples from patients with AOSD than those in HCs. TLR9-expressing positive inflammatory cell counts were higher in skin lesions from patients with AOSD than those in the HC, eczema, and psoriasis groups. The expression levels of TLR1, TLR4, TLR7, and TLR9 were higher in LNs of patients with AOSD than in those with T cell lymphoma and reactive lymphadenopathy. Circulating TLR2- and TLR7-positive cells may contribute to the pathogenesis of AOSD. Furthermore, immunohistochemical staining for TLRs in skin lesions and LNs may aid in differentiating AOSD from similar conditions.


Subject(s)
Skin Diseases , Still's Disease, Adult-Onset , Toll-Like Receptor 2 , Adult , Biomarkers , Humans , Skin Diseases/genetics , Still's Disease, Adult-Onset/genetics , Toll-Like Receptor 2/genetics , Toll-Like Receptors
2.
Autoimmun Rev ; 21(7): 103114, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1859332

ABSTRACT

From the introduction of hyperferritinemic syndrome concept, a growing body of evidence has suggested the role of ferritin as a pathogenic mediator and a relevant clinical feature in the management of patients with inflammatory diseases. From a pathogenic point of view, ferritin may directly stimulate the aberrant immune response by triggering the production of pro-inflammatory mediators in inducing a vicious pathogenic loop and contributing to the occurrence of cytokine storm syndrome. The latter has been recently defined as a clinical picture characterised by elevated circulating cytokine levels, acute systemic inflammatory symptoms, and secondary organ dysfunction beyond that which could be attributed to a normal response to a pathogen It is noteworthy that the occurrence of hyperferritinemia may be correlated with the development of the cytokine storm syndrome in the context of an inflammatory disease. In addition to adult onset Still's disease, macrophage activation syndrome, catastrophic anti-phospholipids syndrome, and septic shock, recent evidence has suggested this association between ferritin and life-threatening evolution in patients with systemic lupus erythematosus, with anti-MDA5 antibodies in the context of poly-dermatomyositis, with severe COVID-19, and with multisystem inflammatory syndrome. The possible underlying common inflammatory mechanisms, associated with hyperferritinemia, may led to the similar clinical picture observed in these patients. Furthermore, similar therapeutic strategies could be suggested inhibiting pro-inflammatory cytokines and improving long-term outcomes in these disorders. Thus, it could be possible to expand the spectrum of the hyperferritinemic syndrome to those diseases burdened by a dreadful clinical picture correlated with hyperferritinemia and the occurrence of the cytokine storm syndrome. In addition, the assessment of ferritin may provide useful information to the physicians in clinical practice to manage these patients. Therefore, ferritin may be considered a relevant clinical feature to be used as biomarker in dissecting the unmet needs in the management of these disorders. Novel evidence may thus support an expansion of the spectrum of the hyperferritinemic syndrome to these diseases burdened by a life-threatening clinical picture correlated with hyperferritinemia and the occurrence of the cytokine storm syndrome.


Subject(s)
COVID-19 , Hyperferritinemia , Macrophage Activation Syndrome , Still's Disease, Adult-Onset , Adult , COVID-19/complications , Cytokine Release Syndrome/therapy , Cytokines , Ferritins , Humans , Hyperferritinemia/therapy , Macrophage Activation Syndrome/complications , Macrophage Activation Syndrome/diagnosis , Macrophage Activation Syndrome/therapy , Still's Disease, Adult-Onset/complications , Still's Disease, Adult-Onset/diagnosis , Still's Disease, Adult-Onset/therapy
4.
Clin Rheumatol ; 41(5): 1591-1596, 2022 May.
Article in English | MEDLINE | ID: covidwho-1729320

ABSTRACT

We report the case of an 18-year-old male with Still's disease for the last 3 years, in remission, who developed two flares of his disease after receiving two doses of the ChAdOX1 nCoV-19 vaccine. While the first flare was mild requiring steroid initiation and resolved rapidly, the second flare after the second dose was much severe, requiring pulse steroid and tocilizumab. We also review three reported cases of flares of Still's disease after COVID-19 vaccination. The temporal association of the flares with both vaccine doses strengthens the association between the vaccine administration and the flare. The proposed mechanism may be due to activation of the innate immune system by the vaccine adjuvants. This review serves to inform the medical community regarding a possible role of the vaccine in producing a systemic inflammatory response. Early detection and treatment can help reduce morbidity in these cases.


Subject(s)
Arthritis, Juvenile , COVID-19 , Still's Disease, Adult-Onset , Adolescent , Arthritis, Juvenile/drug therapy , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , ChAdOx1 nCoV-19 , Humans , Male , Still's Disease, Adult-Onset/complications
5.
Clin Rheumatol ; 41(5): 1583-1589, 2022 May.
Article in English | MEDLINE | ID: covidwho-1704897

ABSTRACT

The upheaval caused by the coronavirus disease 2019 (COVID-19) pandemic has allowed to large population to use new vaccines urgently. Although vaccine development programs and available epidemiological data reassure us, there are concerns about specific risks associated with vaccinations in patients with autoimmune-autoinflammatory diseases. These patients have the potential to decrease humoral and cellular immune responses caused by biologic agents and develop an acute flare of underlying disease following vaccination. We herein present a rare case of a 49-year-old female with a flare of adult-onset Still's disease (AOSD) after the first dose of BNT162b2 mRNA COVID-19 vaccination. She had been diagnosed with AOSD 7 years earlier and had achieved remission with tocilizumab. This patient came to the emergency room with fever and nausea that occurred 4 days after the first vaccination. Based on laboratory results and clinical manifestations, we suspected AOSD flare and was treated with steroid pulse therapy. In this report, we also discuss possible mechanisms linking vaccination with a flare of AOSD. Considering the close time relationship between COVID-19 vaccinations and a flare of AOSD, physicians should be aware of adverse events from this new vaccination and evaluate the benefits and risks of vaccination for each patient. KEY POINTS: • COVID-19 vaccination may cause an AOSD flare in patients who are in remission with tocilizumab.


Subject(s)
COVID-19 , Still's Disease, Adult-Onset , Adult , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Female , Humans , Middle Aged , RNA, Messenger , Still's Disease, Adult-Onset/complications , Still's Disease, Adult-Onset/etiology , Vaccination/adverse effects
6.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1194: 123184, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1701949

ABSTRACT

INTRODUCTION: Ferritin is the major iron-storage glycoprotein found in all tissues. Ferritin glycosylation can be assessed by the differential affinities of ferritin glycoforms for Concanavalin A (ConA), a lectin. The fraction of serum ferritin bound to ConA is called "glycosylated ferritin" (GF). Low GF reflects macrophagic activation and is an essential biomarker used in adult-onset Still's disease (AOSD), macrophage activation syndrome (MAS) and Gaucher disease diagnosis and therapeutic management. To date, no complete assay description and method validation according to the ISO 15189 standard has been published. This study aimed to describe and validate our method used for GF measurement and describe GF values observed in patients. MATERIALS AND METHODS: Ferritin glycoforms were separated based on their affinities for ConA using commercially available TRIS-barbital buffer, Sepharose and ConA/Sepharose 4B gels. Ferritin concentrations were measured on the Siemens Dimension Vista 1500®. We analysed 16,843 GF values obtained between 2000 and 2021 from our database of patients. RESULTS: Optimal separation of ferritin glycoforms was obtained by 15-min incubation of serum with ConA/Sepharose at pH 8. The optimized volume were 0.4 mL for total serum ferritin (TSF) 30-1000 µg/L and 0.5 mL for TSF 1000-2500 µg/L. Serum with higher TSF should be pre-diluted in the TRIS-barbital buffer. Reproducibility of ferritin measurement in the TRIS-barbital buffer matrix was excellent (intra-assay CV < 1%; inter-assay CV < 4%). Reproducibility of GF assay was good (intra-assay CV < 10% for low and high ferritin samples, respectively; and inter-assay CV < 10%). Inter-operator variability was 21.6% for GF < 20%. Ferritin was stable for up to 3 days in the TRIS-barbital buffer. An inter-laboratory exchange program conducted with another French hospital showed good agreement between results. In our database, <20% GF levels were scarce, compatible with the low prevalence of Still's disease, MAS, and Gaucher disease. The 95% confidence interval for GF was [26-58]%, lower than values described in the literature for healthy individuals. CONCLUSION: Thanks to good performances, this technique can become readily available for laboratories servicing patients with AOSD, MAS (including severe COVID-19 patients) and Gaucher disease patients.


Subject(s)
Chemistry Techniques, Analytical/methods , Concanavalin A/metabolism , Ferritins/blood , Macrophage Activation Syndrome/blood , Still's Disease, Adult-Onset/blood , Biomarkers/blood , Biomarkers/metabolism , Ferritins/metabolism , Gaucher Disease/blood , Gaucher Disease/metabolism , Humans , Macrophage Activation Syndrome/metabolism , Protein Binding , Still's Disease, Adult-Onset/metabolism
7.
Exp Biol Med (Maywood) ; 247(4): 338-344, 2022 02.
Article in English | MEDLINE | ID: covidwho-1649460

ABSTRACT

The current SARS-CoV-2 pandemic diffused worldwide has encouraged the rapid development of vaccines to counter the spread of the virus. At present in Italy, 75.01% of the population completed the vaccination course (AIFA.gov.it) and very few adverse events have been recorded by now. Side-effects related to a theoretical over-reaction of the immune system in response to vaccines administration have been described, and the possibility that an autoimmune or a hyperinflammatory condition may occur was recently observed. Herein, we report four cases of hyperinflammatory syndrome with features indicative of Adult-onset Still's disease (AOSD) and macrophage activation syndrome (MAS), occurred after anti-SARS-CoV-2 vaccine injection and seen at our Unit between March and May 2021. Since interleukin (IL)-1 is one of the pivotal cytokines involved in AOSD pathogenesis, the inhibition of IL-1 is crucial in ameliorating the clinical symptoms of those patients. Moreover, it has been highlighted the central role of IL-1 as a hallmark of the hyperinflammatory status elicited by SARS-CoV-2 infection. In this case series, we successfully employed the IL-1 receptor antagonist anakinra to curb the cytokine release likely unleashed by the vaccine stimulation in potentially predisposed subjects. We also made a literature search to detect other patients with hyperinflammation temporally related to vaccines injection who benefited from IL-1 inhibition, while other AOSD/MAS-like described syndromes improved with other immunomodulatory strategies.


Subject(s)
COVID-19 Vaccines/adverse effects , Inflammation/chemically induced , Inflammation/drug therapy , Interleukin 1 Receptor Antagonist Protein/therapeutic use , mRNA Vaccines/adverse effects , BNT162 Vaccine/adverse effects , ChAdOx1 nCoV-19/adverse effects , Female , Humans , Interleukin-1/immunology , Interleukin-1/metabolism , Male , Middle Aged , Still's Disease, Adult-Onset/chemically induced , Still's Disease, Adult-Onset/etiology , Vaccines, DNA/adverse effects
8.
Clin Rheumatol ; 41(5): 1569-1575, 2022 May.
Article in English | MEDLINE | ID: covidwho-1636219

ABSTRACT

We report a series of 3 Adult-onset Still's disease (AOSD)-like presentations in previously healthy females following vaccination with the ChAdOx1 nCoV-19 vaccine, and also compare them with similar cases reported in literature through a PubMed database search. Our first patient had a high spiking bi-quotidian type of fever with myalgia, sore throat, and arthritis with onset 10-day post-vaccination, with laboratory features of hyper inflammation responding to only naproxen. She was off treatment after 2 months. The second patient, with onset 3-week post-vaccination, had a more severe illness, requiring high dose immunosuppression. In our third case, the onset of illness was slightly delayed i.e., 3-month post-vaccination, but she had the most severe disease with macrophage activation syndrome at presentation requiring immunosuppression and biologicals. The underlying mechanism may be linked to the activation of Toll-like receptors (TLR)-TLR-7 and TLR-9-leading to a robust immune response. These 3 cases highlight the immunogenicity of COVID-19 vaccines, with the possibility of occurrence of new-onset systemic hyper-inflammation illness which can happen a few days following the vaccination, sometimes even delayed to months, and can range in severity from mild to even life-threatening. More cases need to be studied to understand the profile and prognosis of these syndromes in the long run.


Subject(s)
COVID-19 , Still's Disease, Adult-Onset , Adult , COVID-19 Vaccines/adverse effects , ChAdOx1 nCoV-19 , Female , Humans , Inflammation , Still's Disease, Adult-Onset/drug therapy , Vaccination/adverse effects
9.
J Korean Med Sci ; 36(50): e344, 2021 Dec 27.
Article in English | MEDLINE | ID: covidwho-1596795

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic is being overcome by widespread inoculation with various COVID-19 vaccines, but concerns about the safety of the vaccines are a major hurdle to widespread vaccination. We report the first case of adult-onset Still's disease (AOSD) developing in a 36-year-old, previously healthy woman after the first dose of BNT162b2 mRNA COVID-19 vaccine (Pfizer). She visited our hospital due to high spiking fever and sore throat that developed 10 days after vaccination. Based on thorough investigations and changes in symptoms and signs after admission, she was diagnosed with AOSD and treated with high dose steroids and tocilizumab. This report suggests the possibility that AOSD could be triggered by COVID-19 vaccines through activation of the innate immune system.


Subject(s)
/adverse effects , Still's Disease, Adult-Onset/etiology , Vaccination/adverse effects , Adult , Female , Humans , Immunity, Innate , Still's Disease, Adult-Onset/drug therapy
10.
11.
Rheumatol Int ; 42(4): 743-748, 2022 04.
Article in English | MEDLINE | ID: covidwho-1525532

ABSTRACT

Vaccination is a cornerstone for reducing the risk of COVID-19 infection during a pandemic. Although the currently used COVID-19 vaccine is considered safe, some concerns persist regarding the likelihood of flares of rheumatic diseases. Still's disease is a rare auto-inflammatory disorder of unknown etiology, and the data on the flare of Still's disease following COVID-19 vaccination are limited. Therefore, we hereby present the case of a 34-year-old female patient with Still's disease who experienced a flare after a ChAdOx1 nCoV-19 vaccination. The patient visited the emergency department complaining of fever, arthralgia, myalgia, pleuritic chest pain and macular salmon-pink rash on her back for the past 2 days. She had maintained low Still's disease activity with etanercept and low-dose glucocorticoid for 14 years. She received the ChAdOx1 nCoV-19 vaccine 7 days before the flare. Laboratory investigations revealed leucocytosis and elevated serum levels of erythrocyte sedimentation rate, C-reactive protein, and ferritin. Computed tomography showed no specific findings. She received methylprednisolone pulse therapy, etanercept, and methotrexate for treating the Still's disease flare. However, her symptoms were not fully controlled, and she developed pericarditis, pleuritis, fever and macular rashes expanding to her extremities. After excluding infectious conditions by blood culture and pleural fluid analysis, we administered tocilizumab with methotrexate and prednisolone. Her symptoms and laboratory findings improved significantly, and she was discharged without symptoms 7 days later. Although rare, this case of a patient with Still's disease undergoing a flare following vaccination suggests that close observation of disease activity is warranted following COVID-19 vaccination.


Subject(s)
COVID-19 , Still's Disease, Adult-Onset , Adult , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Female , Humans , Still's Disease, Adult-Onset/diagnosis , Still's Disease, Adult-Onset/drug therapy , Still's Disease, Adult-Onset/etiology , Vaccination
13.
Mod Rheumatol Case Rep ; 6(1): 101-105, 2022 01 07.
Article in English | MEDLINE | ID: covidwho-1443057

ABSTRACT

The coronavirus disease (COVID-19) is known to cause hyperferritinemia and haemophagocytic lymphohistiocytosis. Including this laboratory parameter, symptoms similar to COVID-19 have been observed in adult-onset Still's disease (AOSD), catastrophic antiphospholipid syndrome, macrophage activation syndrome, and septic shock, which has led to the proposal of a concept called 'hyperferritinemic syndromes'. High levels of some clinical markers in both COVID-19 and AOSD make them difficult to differentiate. While the efficacy of ciclesonide had been expected for mild pneumonia with COVID-19, the efficacy of tocilizumab (TCZ), which is a known treatment for AOSD, was not established. We report the first known occurrence of COVID-19 diagnosed in March 2020, preceded by the diagnosis of AOSD in April 2019. The patient was given prednisolone and TCZ, which led to remission. With the dyspnea and ground-glass appearance on chest computed tomography, PCR test revealed COVID-19 infection. Ciclesonide was started on Day 7 of the disease onset, which led to improved inflammatory markers. We infer that while TCZ is theoretically useful for COVID-19 due to its inhibition of interleukin 6. AOSD and COVID-19 may be differentiated by levels of ferritin, and appropriate treatment must be allocated.


Subject(s)
COVID-19 , Macrophage Activation Syndrome , Still's Disease, Adult-Onset , Adult , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/diagnosis , COVID-19/drug therapy , Ferritins , Humans , Macrophage Activation Syndrome/diagnosis , Macrophage Activation Syndrome/drug therapy , Prednisolone/therapeutic use , Still's Disease, Adult-Onset/diagnosis , Still's Disease, Adult-Onset/drug therapy
15.
Front Immunol ; 12: 719544, 2021.
Article in English | MEDLINE | ID: covidwho-1348491

ABSTRACT

Background: Hyperinflammation with dysregulated production of galectins and cytokines may develop in COVID-19 or adult-onset Still's disease (AOSD). Given the similar clinical features in both diseases, it is necessary to identify biomarkers that can differentiate COVID-19 from AOSD. However, the related data remain scarce currently. Methods: In this cross-sectional study, plasma levels of galectin-3, galectin-9, and soluble TIM-3 (sTIM-3) were determined by ELISA in 55 COVID-19 patients (31 non-severe and 24 severe), 23 active AOSD patients, and 31 healthy controls (HC). The seropositivity for SARS-CoV-2 was examined using an immunochromatographic assay, and cytokine profiles were determined with the MULTIPLEX platform. Results: Significantly higher levels of galectin-3, galectin-9, IL-1ß, IL-1Ra, IL-10, IFN-α2, IL-6, IL-18, and TNF-α were observed in severe COVID-19 and active AOSD patients compared with HC (all p<0.001). AOSD, but not COVID-19, showed significantly higher IFN-γ and IL-17A compared with HC (both p<0.01). Moreover, active AOSD patients had 68-fold higher IL-18 levels and 5-fold higher ferritin levels than severe COVID-19 patients (both p<0.001). IL-18 levels at the cut-off value 190.5pg/mL had the highest discriminative power for active AOSD and severe COVID-19, with AUC 0.948, sensitivity 91.3%, specificity 95.8%, and accuracy of 91.5% (p<0.005). Multivariate regression analysis revealed IL-18 as a significant predictor of active AOSD (p<0.05). Conclusion: Active AOSD patients share features of hyperinflammation and cytokine storm with severe COVID-19 patients but possess a distinct cytokine profile, including elevated IL-18, IL-6, IFN-γ, and IL-17A. IL-18 is a potential discriminator between AOSD and COVID-19 and may significantly predict active AOSD.


Subject(s)
COVID-19 , Interleukin-18 , SARS-CoV-2 , Still's Disease, Adult-Onset , Adult , Biomarkers/blood , COVID-19/blood , COVID-19/immunology , Cross-Sectional Studies , Female , Humans , Interleukin-18/blood , Interleukin-18/immunology , Male , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Still's Disease, Adult-Onset/blood , Still's Disease, Adult-Onset/immunology
16.
BMJ Case Rep ; 14(6)2021 Jun 22.
Article in English | MEDLINE | ID: covidwho-1280404

ABSTRACT

Adult-onset Still's disease (AOSD) is a rare inflammatory disorder affecting just over one in a million people. Due to its rarity, understanding of its pathophysiology and the spectrum of its clinical associations are limited. Improved case identification and creation of patient registries have begun to reveal sporadic reports of deep venous thromboses associated with AOSD. Herein, we report the first case of recurrent deep venous thrombosis in a patient with AOSD despite treatment with therapeutic dose anticoagulant medication. This case points for a judicious approach to the selection of an anticoagulation strategy for deep venous thromboses in the setting of active AOSD. This case is of contemporary interest in its clinical similarity with COVID-19 symptoms and pathophysiology for which a careful diagnostic approach with a broad differential should be considered given the limitations of SARS-CoV-2 testing and the risk associated with treatment in the event of misdiagnosis.


Subject(s)
COVID-19 , Still's Disease, Adult-Onset , Venous Thrombosis , Adult , COVID-19 Testing , Humans , SARS-CoV-2 , Still's Disease, Adult-Onset/complications , Still's Disease, Adult-Onset/diagnosis , Still's Disease, Adult-Onset/drug therapy , Venous Thrombosis/diagnosis , Venous Thrombosis/drug therapy , Venous Thrombosis/etiology
17.
Front Immunol ; 11: 603389, 2020.
Article in English | MEDLINE | ID: covidwho-1069720

ABSTRACT

The catastrophic outbreak of coronavirus disease 2019 (COVID-19) is currently a public emergency. Adult-onset Still's disease (AOSD) is an autoinflammatory disease characterized by life-threatening complications. Systemic hyperinflammation and cytokine storm play a critical role in the pathogenesis of both COVID-19 and AOSD. We aimed to compare the similarities and differences focusing on ferritin and cytokine levels between severe COVID-19 and active AOSD. A literature search was performed using the databases PubMed, EMBASE, and Web of Science to collect the levels of cytokine including IL-1ß, IL-6, IL-18, TNF-α, IL-10, and ferritin in severe COVID-19 patients. After extracting available data of indicators of interest, we acquired these statistics with a single-arm meta-analysis. Furthermore, a comparison was conducted between 52 patients with active AOSD in our center and severe COVID-19 patients from databases. The levels of IL-6 and IL-10 were higher in severe COVID-19 compared with those in active AOSD. There were no significant differences on the cytokine of IL-1ß and TNF-α. Fold changes of IL-18 were defined as the mean expression level ratio of severe COVID-19 to healthy controls in the COVID-19 study and active AOSD to healthy controls in our study, individually. Although the fold change of IL-18 in patients with AOSD was significantly higher than patients with severe COVID-19 (fold change: 594.00 vs 2.17), there was no statistical comparability. In addition, the level of ferritin was higher in active AOSD in comparison with severe COVID-19. Our findings suggest that severe COVID-19 and active AOSD have differences in cytokine panel and ferritin level, indicating the pathogenic role of ferritin in overwhelming inflammation. And it paves the way to make efficacy therapeutic strategy targeting the hyperinflammatory process in COVID-19 according to AOSD management, especially in severe COVID-19.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Inflammation/immunology , Still's Disease, Adult-Onset/immunology , Adult , Aged , COVID-19/epidemiology , Cytokine Release Syndrome/epidemiology , Cytokines/blood , Female , Ferritins/blood , Humans , Male , Middle Aged , Still's Disease, Adult-Onset/epidemiology
20.
RMD Open ; 6(1)2020 05.
Article in English | MEDLINE | ID: covidwho-334790

ABSTRACT

Some of the articles being published during the severe acute respiratory syndrome-coronavirus (SARS-CoV)-2 pandemic highlight a link between severe forms of coronavirus disease 2019 (COVID-19) and the so-called cytokine storm, also with increased ferritin levels. However, this scenario is more complex than initially thought due to the heterogeneity of hyperinflammation. Some patients with coronavirus 2019 disease (COVID-19) develop a fully blown secondary haemophagocytic lymphohistiocytosis (sHLH), whereas others, despite a consistent release of pro-inflammatory cytokines, do not fulfil sHLH criteria but still show some features resembling the phenotype of the hyperferritinemic syndrome. Despite the final event (the cytokine storm) is shared by various conditions leading to sHLH, the aetiology, either infectious, autoimmune or neoplastic, accounts for the differences in the various phases of this process. Moreover, the evidence of a hyperinflammatory microenvironment provided the rationale to employ immunomodulating agents for therapeutic purposes in severe COVID-19. This viewpoint aims at discussing the pitfalls and issues to be considered with regard to the use of immunomodulating agents in COVID-19, such as timing of treatment based on the viral load and the extent of cytokine/ferritin overexpression. Furthermore, it encompasses recent findings in the paediatric field about a novel multisystem inflammatory disease resembling toxic shock syndrome and atypical Kawasaki disease observed in children with proven SARS-CoV2 infection. Finally, it includes arguments in favour of adding COVID-19 to the spectrum of the recently defined 'hyperferritinemic syndrome', which already includes adult-onset Still's disease, macrophage activation syndrome, septic shock and catastrophic anti-phospholipid syndrome.


Subject(s)
Coronavirus Infections/immunology , Coronavirus/immunology , Cytokines/immunology , Macrophage Activation Syndrome/immunology , Pneumonia, Viral/immunology , Adult , Antiphospholipid Syndrome , Betacoronavirus , COVID-19 , Child , Coronavirus/pathogenicity , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Humans , Lymphohistiocytosis, Hemophagocytic , Macrophage Activation Syndrome/complications , Macrophage Activation Syndrome/pathology , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology , SARS-CoV-2 , Still's Disease, Adult-Onset , Viral Load
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