The purinergic receptor P2X7 and the NLRP3 inflammasome are druggable host factors required for SARS-CoV-2 infection (preprint)

Purinergic receptors and NOD-like receptor protein 3 (NLRP3) inflammasome regulate inflammation and viral infection, but their effects on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain poorly understood. Here, we report that the purinergic receptor P2X7 and NLRP3 inflammasome are cellular host factors required for SARS-CoV-2 infection. Lung autopsies from patients with severe coronavirus disease 2019 (COVID-19) reveal that NLRP3 expression is increased in host cellular targets of SARS-CoV-2 including alveolar macrophages, type II pneumocytes and syncytia arising from the fusion of infected macrophages, thus suggesting a potential role of NLRP3 and associated signaling pathways to both inflammation and viral replication. In vitro studies demonstrate that NLRP3-dependent inflammasome activation is detected upon macrophage abortive infection. More importantly, a weak activation of NLRP3 inflammasome is also detected during the early steps of SARS-CoV-2 infection of epithelial cells and promotes the viral replication in these cells. Interestingly, the purinergic receptor P2X7, which is known to control NLRP3 inflammasome activation, also favors the replication of D614G and alpha SARS-CoV-2 variants. Altogether, our results reveal an unexpected relationship between the purinergic receptor P2X7, the NLRP3 inflammasome and the permissiveness to SARS-CoV-2 infection that offers novel opportunities for COVID-19 treatment.

Spatiotemporal analysis of SARS-CoV-2 infection reveals an expansive wave of monocyte-derived macrophages associated with vascular damage and virus clearance in hamster lungs (preprint)

Factors of the innate immune response to SARS-CoV-2 in the lungs are pivotal for the ability of the host to deal with the infection. In humans, excessive macrophage infiltration is associated with disease severity. Using 3D spatiotemporal analysis of optically cleared hamster lung slices in combination with virological, immunohistochemical and RNA sequence analyses, we visualized the spread of SARS-CoV-2 through the lungs and the rapid anti-viral response in infected lung epithelial cells, followed by a wave of monocyte-derived macrophage (MDM) infiltration and virus elimination from the tissue. These SARS-CoV-2 induced innate immune processes are closely related to the onset of necrotizing inflammatory and consecutive remodelling responses in the lungs, which manifests as extensive cell death, vascular damage, thrombosis, and cell proliferation. Here we show that MDM are directly linked to virus clearance, and appear in connection with tissue injury and blood vessel damage. Rapid initiation of prothrombotic factor upregulation, tissue repair and alveolar cell proliferation results in tissue remodelling, which is followed by fibrosis development despite a decrease in inflammatory and anti-viral activities. Thus, although the hamsters are able to resolve the infection following the MDM influx and repair lung tissue integrity, longer-term alterations of the lung tissues arise as a result of concurrent tissue damage and regeneration processes.

Single-cell transcriptomics identifies different immune signatures between macrophage activation-like syndrome and immune paralysis in sepsis (preprint)

Different immune phenotypes characterize sepsis patients, including hyperinflammation and/or immunosuppression, but the biological mechanisms driving this heterogeneity remain largely unknown. We used single-cell RNA sequencing to profile circulating leukocytes of healthy controls and sepsis patients classified as either hyperinflammatory (macrophage activation-like syndrome [MALS]), immune paralysis, or unclassified (when criteria for neither of these two immune subgroups were applicable). Pronounced differences were detected in the transcriptional signature of monocytes from sepsis patients, with clear distinction between MALS and immune paralysis patients. Unsupervised clustering analysis revealed the existence of MALS-specific monocyte clusters, as well as one sepsis-specific monocyte cluster that was linked to disease severity. In separate cohorts, urosepsis was characterized by heterogeneous MALS and immunosuppression monocyte signatures, while MALS-specific monocyte clusters showed overlapping transcriptional signatures with severe COVID-19. In conclusion, our findings shed light on the heterogeneous immune landscape underlying sepsis, and provide opportunities for patient stratification for future therapeutic development.

Intravenous anakinra to curb cytokine storm in adult-onset Still's disease and in macrophage activation syndrome: A case series.

OBJECTIVE: Adult-onset Still's disease (AOSD) is an auto-inflammatory polygenic disorder, for which the diagnosis is essentially clinical. The exclusion of mimickers [such as common bacterial and viral infections, hematologic malignancies, and, more recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] is necessary to confirm the diagnosis. Anti-interleukin (IL)-1 therapy is considered a treatment milestone for AOSD. Herein, we present a short series of newly-diagnosed AOSD or upcoming macrophage activation syndrome (MAS) cases who received intravenous (IV) anakinra, an IL-1 receptor blocker. METHODS: Four patients with newly-diagnosed AOSD or upcoming MAS were treated with IV anakinra at the Rheumatology Unit of Padova University Hospital, Italy. We obtained informed consent from the patients for use of their cases and medical images for publication purposes. RESULTS: All patients presented with AOSD or MAS during the COVID-19 pandemic, making diagnosis challenging due to similar immunological and clinical characteristics across both pathologies. All patients presented with hyperpyrexia and elevated inflammatory markers; two patients had a skin rash typically seen in AOSD. IV anakinra slowed down AOSD progression in all patients, prevented severe outcomes and mitigated the risk of multiorgan failure. All cases improved within 24hours of anakinra administration. CONCLUSION: We found that administration of anakinra in patients with newly-diagnosed AOSD and/or upcoming MAS reduced hyperinflammation and prevented life-threatening complications. The IV route appears to be preferable in the hospital setting, where comorbidities such as coagulopathies and thrombocytopenia can complicate the use of other routes of administration.

Biomarkers in Systemic Juvenile Idiopathic Arthritis, Macrophage Activation Syndrome and Their Importance in COVID Era.

Systemic juvenile idiopathic arthritis (sJIA) and its complication, macrophage activation syndrome (sJIA-MAS), are rare but sometimes very serious or even critical diseases of childhood that can occasionally be characterized by nonspecific clinical signs and symptoms at onset-such as non-remitting high fever, headache, rash, or arthralgia-and are biologically accompanied by an increase in acute-phase reactants. For a correct positive diagnosis, it is necessary to rule out bacterial or viral infections, neoplasia, and other immune-mediated inflammatory diseases. Delays in diagnosis will result in late initiation of targeted therapy. A set of biomarkers is useful to distinguish sJIA or sJIA-MAS from similar clinical entities, especially when arthritis is absent. Biomarkers should be accessible to many patients, with convenient production and acquisition prices for pediatric medical laboratories, as well as being easy to determine, having high sensitivity and specificity, and correlating with pathophysiological disease pathways. The aim of this review was to identify the newest and most powerful biomarkers and their synergistic interaction for easy and accurate recognition of sJIA and sJIA-MAS, so as to immediately guide clinicians in correct diagnosis and in predicting disease outcomes, the response to treatment, and the risk of relapses. Biomarkers constitute an exciting field of research, especially due to the heterogeneous nature of cytokine storm syndromes (CSSs) in the COVID era. They must be selected with utmost care-a fact supported by the increasingly improved genetic and pathophysiological comprehension of sJIA, but also of CSS-so that new classification systems may soon be developed to define homogeneous groups of patients, although each with a distinct disease.

Activation mechanisms of monocytes/macrophages in adult-onset Still disease.

Adult onset Still disease (AOSD) is a systemic inflammatory disorder characterized by skin rash, spiking fever, arthritis, sore throat, lymphadenopathy, and hepatosplenomegaly. Although the etiology of this disease has not been fully clarified, both innate and acquired immune responses could contribute to its pathogenesis. Hyperactivation of macrophages and neutrophils along with low activation of natural killer (NK) cells in innate immunity, as well as hyperactivation of Th1 and Th17 cells, whereas low activation of regulatory T cells (Tregs) in acquired immunity are involved in the pathogenic process of AOSD. In innate immunity, activation of monocytes/macrophages might play central roles in the development of AOSD and macrophage activation syndrome (MAS), a severe life-threating complication of AOSD. Regarding the activation mechanisms of monocytes/macrophages in AOSD, in addition to type II interferon (IFN) stimulation, several pathways have recently been identified, such as the pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs)-pattern recognition receptors (PRRs) axis, and neutrophil extracellular traps (NETs)-DNA. These stimulations on monocytes/macrophages cause activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain (NLRP) 3 inflammasomes, which trigger capase-1 activation, resulting in conversion of pro-IL-1ß and pro-IL-18 into mature forms. Thereafter, IL-1ß and IL-18 produced by activated monocytes/macrophages contribute to various clinical features in AOSD. We identified placenta-specific 8 (PLAC8) as a specifically increased molecule in monocytes of active AOSD, which correlated with serum levels of CRP, ferritin, IL-1ß, and IL-18. Interestingly, PLAC8 could suppress the synthesis of pro-IL-1ß and pro-IL-18 via enhanced autophagy; thus, PLAC8 seems to be a regulatory molecule in AOSD. These findings for the activation mechanisms of monocytes/macrophages could shed light on the pathogenesis and development of a novel therapeutic strategy for AOSD.

Haemophagocytic lymphocytic histiocytosis/macrophage activation syndrome with acute inflammatory gastroenteritis.

Haemophagocytic lymphocytic histiocytosis (HLH) is a rare, life-threatening condition caused by abnormal activation of cytotoxic T lymphocytes, natural killer cells and macrophages resulting in hypercytokinaemia and immune-mediated injury of multiple organ systems. Secondary HLH occurs in the setting of a malignant, infectious or autoimmune stimulus. Macrophage activation syndrome (MAS) is the term used to describe HLH that develops secondary to rheumatological diseases such as lupus and juvenile idiopathic arthritis, among others. Commonly observed and documented symptoms include fever, organomegaly and lymphadenopathy. Given the potential for multiorgan failure in HLH/MAS, early identification, diagnosis and initiation of treatment is essential. We present a case of secondary HLH/MAS with acute inflammatory gastroenteritis in a middle-aged woman with a history of systemic lupus erythematosus.

Liquid biomarkers of macrophage dysregulation and circulating spike protein illustrate the biological heterogeneity in patients with post-acute sequelae of COVID-19 (preprint)

Post-acute sequelae of COVID-19 (PASC) are long-term consequences of SARS-CoV-2 infection that can substantially impair quality of life. Underlying mechanisms ranging from persistent virus to innate and adaptive immune dysregulation have been discussed. Here, we profiled plasma of 181 individuals from the cohort study for digital health research in Germany (DigiHero) including individuals after mild to moderate COVID-19 with or without PASC and uninfected controls. We focused on soluble factors related to monocyte/macrophage biology and on circulating SARS-CoV-2 spike (S1) protein as potential biomarker for persistent viral reservoirs. At a median time of eight months after infection, we found pronounced dysregulation in almost all tested soluble factors including both pro-inflammatory and pro-fibrotic cytokines. These perturbations were remarkably independent of ongoing symptoms, but further correlation and regression analyses suggested PASC specific patterns involving CCL2/MCP-1 and IL-8 as well as long-term persistence of high IL-5 and IL-17F levels. None of the analyzed factors correlated with the detectability or levels of circulating S1 indicating that this represents an independent subset of patients with PASC. This data confirms prior evidence of immune dysregulation and persistence of viral protein in PASC and illustrates its biological heterogeneity that still awaits correlation with clinically defined PASC subtypes.

Role of Genetic Polymorphism Present in Macrophage Activation Syndrome Pathway in Post Mortem Biopsies of Patients with COVID-19.

COVID-19 is a viral disease associated with an intense inflammatory response. Macrophage Activation Syndrome (MAS), the complication present in secondary hemophagocytic lymphohistiocytosis (sHLH), shares many clinical aspects observed in COVID-19 patients, and investigating the cytolytic function of the responsible cells for the first line of the immune response is important. Formalin-fixed paraffin-embedded lung tissue samples obtained by post mortem necropsy were accessed for three groups (COVID-19, H1N1, and CONTROL). Polymorphisms in MAS cytolytic pathway (PRF1; STX11; STXBP2; UNC13D and GZMB) were selected and genotyping by TaqMan® assays (Thermo Fisher Scientific, MA, USA) using Real-Time PCR (Applied Biosystems, MA USA). Moreover, immunohistochemistry staining was performed with a monoclonal antibody against perforin, CD8+ and CD57+ proteins. Histopathological analysis showed high perforin tissue expression in the COVID-19 group; CD8+ was high in the H1N1 group and CD57+ in the CONTROL group. An association could be observed in two genes related to the cytolytic pathway (PRF1 rs885822 G/A and STXBP2 rs2303115 G/A). Furthermore, PRF1 rs350947132 was associated with increased immune tissue expression for perforin in the COVID-19 group. The genotype approach could help identify patients that are more susceptible, and for this reason, our results showed that perforin and SNPs in the PRF1 gene can be involved in this critical pathway in the context of COVID-19.

Expanding the spectrum of the hyperferritinemic syndrome, from pathogenic mechanisms to clinical observations, and therapeutic implications.

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.

Implications of SARS-CoV-2 Infection in Systemic Juvenile Idiopathic Arthritis.

Systemic juvenile idiopathic arthritis (sJIA) is a serious multifactorial autoinflammatory disease with a significant mortality rate due to macrophage activation syndrome (MAS). Recent research has deepened the knowledge about the pathophysiological mechanisms of sJIA-MAS, facilitating new targeted treatments, and biological disease-modifying antirheumatic drugs (bDMARDs), which significantly changed the course of the disease and prognosis. This review highlights that children are less likely to suffer severe COVID-19 infection, but at approximately 2-4 weeks, some cases of multisystem inflammatory syndrome in children (MIS-C) have been reported, with a fulminant course. Previous established treatments for cytokine storm syndrome (CSS) have guided COVID-19 therapeutics. sJIA-MAS is different from severe cases of COVID-19, a unique immune process in which a huge release of cytokines will especially flood the lungs. In this context, MIS-C should be reinterpreted as a special MAS, and long-term protection against SARS-CoV-2 infection can only be provided by the vaccine, but we do not yet have sufficient data. COVID-19 does not appear to have a substantial impact on rheumatic and musculoskeletal diseases (RMDs) activity in children treated with bDMARDs, but the clinical features, severity and outcome in these patients under various drugs are not yet easy to predict. Multicenter randomized controlled trials are still needed to determine when and by what means immunoregulatory products should be administered to patients with sJIA-MAS with a negative corticosteroid response or contraindications, to optimize their health and safety in the COVID era.

Coronavirus Disease 2019 Infection and Early Diagnosis of Macrophage Activation Syndrome: A Case Report of a 62 year old man.

A 62-year-old man presented with a history of fever, headache, anosmia, ageusia, and diarrhea for 9 days. A clinical and epidemiological diagnosis of infection with the novel coronavirus was made. After symptom refractoriness, the second step involves using human intravenous immunoglobulin. Early diagnosis of macrophage activation syndrome (MAS) involves observation of the refractory nature of clinical support treatment associated with biochemical changes to the patient's baseline characteristics, suggesting the relevance of a favorable clinical outcome of weaning from artificial life support when there is an early suspicion of a diagnosis of MAS secondary to coronavirus disease 2019 infection.

Measurement of glycosylated ferritin with Concanavalin A: Assay design, optimization and validation.

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.

N-acylethanolamine acid amide hydrolase is a novel target for drugs against SARS-CoV-2 and Zika virus (preprint)

Several compounds have been tested against SARS-CoV-2; at present, COVID-19 treatments decrease the deleterious inflammatory response and acute lung injury. However, the best therapeutic response would be expected by combining anti-inflammatory properties, while concomitantly blocking viral replication. These combined effects should drastically reduce both infection rate and severe complications induced by novel SARS-CoV-2 variants. Therefore, we explored the antiviral potency of a class of anti-inflammatory compounds that inhibit the N-Acylethanolamine acid amidase (NAAA). This enzyme catalyzes the hydrolysis of palmitoylethanolamide (PEA), a bioactive lipid that mediates anti-inflammatory and analgesic activity through the activation of peroxisome proliferator receptor- (PPAR-). Similarly, this pathway is likely to be a significant target to impede viral replication since PPAR- activation leads to dismantling of lipid droplets, where viral replication of Flaviviruses and Coronaviruses occurs. Here, we show that either genetic or pharmacological inhibition of the NAAA enzyme leads to five-fold reduction in the replication of both SARS-CoV-2 and ZIKV in various cell lines. Once NAAA enzyme is blocked, both ZIKV and SARS CoV-2 replication decrease, which parallels a sudden five-fold decrease in virion release. These effects induced by NAAA inhibition occurs concomitantly with stimulation of autophagy during infection. Remarkably, parallel antiviral and anti-inflammatory effects of NAAA antagonism were confirmed in ex-vivo experiments, within SARS-CoV-2 infected human PBMC cells, in which both viral genomes and TNF- production drop by ~60%. It is known that macrophages contribute to viral spread, excessive inflammation and macrophage activation syndrome that NAAA inhibitors might prevent, reducing the macrophage-induced acute respiratory distress syndrome and subsequent death of COVID-19 patients.

Primary human macrophages exhibit a modest inflammatory response early in SARS-CoV-2 infection (preprint)

Involvement of macrophages in the SARS-CoV-2-associated cytokine storm, the excessive secretion of inflammatory/anti-viral factors leading to the acute respiratory distress syndrome (ARDS) in COVID-19 patients, is unclear. In this study, we sought to characterize the interplay between the virus and primary human monocyte-derived macrophages (MDM). MDM were stimulated with recombinant IFN- and/or infected with either live or UV-inactivated SARS-CoV-2 or with two reassortant influenza viruses containing external genes from the H1N1 PR8 strain and heterologous internal genes from a highly pathogenic avian H5N1 or a low pathogenic human seasonal H1N1 strain. Virus replication was monitored by qRT-PCR for the E viral gene for SARS-CoV-2 or M gene for influenza and TCID50 or plaque assay, and cytokine levels were assessed semiquantitatively with qRT-PCR and a proteome cytokine array. We report that MDM are not susceptible to SARS-CoV-2 whereas both influenza viruses replicated in MDM, albeit abortively. We observed a modest cytokine response in SARS-CoV-2 infected MDM with notable absence of IFN-{beta} induction, which was instead strongly induced by the influenza viruses. Pre-treatment of MDM with IFN- enhanced proinflammatory cytokine expression upon infection. Together, the findings concur that the hyperinflammation observed in SARS-CoV-2 infection is not driven by macrophages.

ScRNA-seq Expression of IFI27 and APOC2 Identifies Four Alveolar Macrophage Superclusters in Healthy BALF (preprint)

Alveolar macrophages (AMs) reside on the luminal surface of the airways and alveoli, ensuring proper gas exchange by ingesting cellular debris and pathogens, and regulating inflammatory responses. Therefore, understanding the heterogeneity and diverse roles played by AMs, interstitial macrophages (IMs), and recruited monocytes is critical for treating airway diseases. We performed single-cell RNA sequencing on 113,213 bronchoalveolar lavage cells from four healthy and three uninflamed cystic fibrosis subjects and identified FOLR2 + SELENOP + and SPP1 + PLA2G7 + IMs, monocyte subtypes, and dendritic cell 1 (DC1), DC2, migDCs, plasmacytoid DCs, lymphocytes, epithelial cells, and four AM superclusters (families) based on the expression of IFI27 and APOC2 genes. These 4 AM families have at least eight distinct functional members (subclusters) named after their differentially expressed gene(s): IGF1, CCL18, CXCL5, Cholesterol, Chemokine, Metallothionein, Interferon and small-cluster AMs. Interestingly, the Chemokine cluster further divides with each subcluster selectively expressing a unique combination of chemokines. One of the most striking observations, besides the heterogeneity, is the conservation of AM family members in relatively equal ratio across all AM superclusters and individuals. Transcriptional data and TotalSeq technology were used to investigate cell surface markers that distinguish resident AMs from recruited monocytes. Lastly, other AM datasets were projected onto our dataset. Similar AM superclusters and functional subclusters were observed, along with changes in AM subclusters in individuals infected with COVID-19. Overall, functional specializations of the AM subclusters suggest that there are highly regulated AM niches with defined programming states, highlighting a clear division of labor. Summary Blurb There are at least 14 AM subtypes; their frequency, along with other immune cells, are highly conserved across individuals suggesting a specific niche exists for each leukocyte population. Graphical Abstract

Systemic lupus erythematosus complicated with macrophage activation syndrome mimicking COVID-19 multisystemic inflammatory syndrome in children.

BACKGROUND: Macrophage activation syndrome (MAS) is characterized by excessive activation of macrophages and lymphocytes, leading to multiorgan dysfunction. As the initial manifestation of systemic lupus erythematosus (SLE), MAS is rare in children. Due to the COVID-19 pandemic, it is vital to identify the MAS as it shares similar characteristics with the multisystem inflammatory syndrome in children (MIS-C). CASE REPORT: We report the case of an 11-year-old male adolescent with symptoms of MIS-C. Although with negative results of RT-PCR (reverse transcription-polymerase chain reaction) and serology for SARS-CoV-2, contact with a positive COVID-19 relative was reported. When admitted to a referral hospital center, the patient received standard treatment for MIS-C. Although the same scheme was given on three occasions, the patient showed no response to initial therapy. Thus, the patient was classified as a refractory case. When the study was extended to other differential diagnoses, we found MAS associated with SLE. Therefore, the patient was treated with etoposide, cyclosporine, dexamethasone, and methotrexate and showed a good clinical response. CONCLUSIONS: MAS associated with SLE is rare in the pediatric population. MAS shares inflammatory markers with the MIS-C and is often confused with rheumatologic, infectious, and neoplastic entities. Reporting this case is important to identify differential diagnoses in patients presenting as MIS-C and decide on timely treatment, as it could be harmful or even fatal if a definitive diagnosis is not obtained on time.

INTRODUCCIÓN: El síndrome de activación de macrófagos (SAM) se caracteriza por una activación excesiva de los macrófagos y de los linfocitos que conduce a una disfunción multiorgánica. Como manifestación inicial del lupus eritematoso sistémico (LES), el SAM es poco común en la infancia. Debido a la pandemia de COVID-19, es importante identificar el SAM, ya que comparte características similares con el síndrome inflamatorio multisistémico en niños (MIS-C, por sus siglas en inglés). CASO CLÍNICO: Presentamos el caso de un varón de 11 años con síntomas de MIS-C. Resultó negativo en la prueba de reacción en cadena de la polimerasa con retrotranscriptasa y en la serología para SARS-CoV-2, aunque reportó contacto con un familiar positivo para COVID-19. Ingresó en un centro hospitalario de referencia y recibió tratamiento estandarizado para MIS-C. A pesar de recibir el mismo esquema en tres ocasiones, no mostró respuesta a la terapia inicial, por lo que fue clasificado como caso refractario. Al ampliar el estudio para otros diferenciales, se encontró SAM asociado con LES, por lo que el paciente recibió tratamiento con etopósido, ciclosporina, dexametasona y metotrexato, y mostró buena respuesta clínica. CONCLUSIONES: La asociación entre el SAM y el LES es rara en la población pediátrica. El SAM comparte marcadores inflamatorios con el MIS-C y suele confundirse con enfermedades reumatológicas, infecciosas y neoplásicas. La importancia de reportar este caso es identificar los diagnósticos diferenciales en los pacientes que se presentan como MIS-C, y decidir el tratamiento con prontitud, pues podría ser dañino o incluso fatal si no se obtiene un diagnóstico definitivo a tiempo.