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.

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.

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.

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.

COVID-19 and adult-onset Still's disease as part of hyperferritinemic syndromes.

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.

Differences and similarities of multisystem inflammatory syndrome in children, Kawasaki disease and macrophage activating syndrome due to systemic juvenile idiopathic arthritis: a comparative study.

To compare the clinical and laboratory findings of multisystem inflammatory syndrome in children (MIS-C), patients with Kawasaki disease (KD) and with macrophage activating syndrome due to systemic juvenile idiopathic arthritis (sJIA-MAS) on real-life data. Patients diagnosed with MIS-C, KD, and sJIA-MAS from 12 different centers in Turkey who were followed for at least 6 months were included in the study. Demographic, clinical, and laboratory findings of all patients were analyzed. A total of 154 MIS-C, 59 KD, and 31 sJIA-MAS patients were included. The median age of patients with MIS-C were higher than those with KD while lower than those with sJIA-MAS (8.2, 3, 12 years, respectively). Myalgia (39.6%), cardiac (50.6%), gastrointestinal (72.7%), and neurological (22.1%) involvements were more common in patients with MIS-C compared to others. MIS-C patients had lower levels of lymphocyte (950 vs 1700 cells/µl) and thrombocyte (173,000 vs 355,000 cells/µl) counts and higher pro-BNP (1108 vs 55 pg/ml) levels than KD. Ferritin levels were higher in patients with MIS-C compared to patients with KD while they were lower than patients with sJIA-MAS (440, 170, 10,442 ng/ml, respectively). Patients with MIS-C had a shorter duration of hospitalization than sJIA-MAS (p = 0.02) while they required intensive care unit admission more frequently (55 vs 8 patients, p < 0.001). The median MAS/sJIA score of MIS-C patients was - 1.64 (- 5.23 to 9.68) and the median MAS/sJIA score of sJIA-MAS patients was -2.81 ([- 3.79] to [- 1.27]). MIS-C patients displayed certain differences in clinical and laboratory features when compared to KD and sJIA-MAS. Definition of the differences and similarities between MIS-C and the other intense inflammatory syndromes of childhood such as KD and MAS will help the clinicians while making timely diagnosis.

Discrimination of COVID-19 From Inflammation-Induced Cytokine Storm Syndromes Using Disease-Related Blood Biomarkers.

OBJECTIVE: Infection with the novel coronavirus SARS-CoV-2 triggers severe illness with high mortality in a subgroup of patients. Such a critical course of COVID-19 is thought to be associated with the development of cytokine storm, a condition seen in macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (HLH). However, specific data demonstrating a clear association of cytokine storm with severe COVID-19 are still lacking. The aim of this study was to directly address whether immune activation in COVID-19 does indeed mimic the conditions found in these classic cytokine storm syndromes. METHODS: Levels of 22 biomarkers were quantified in serum samples from patients with COVID-19 (n = 30 patients, n = 83 longitudinal samples in total), patients with secondary HLH/MAS (n = 50), and healthy controls (n = 9). Measurements were performed using bead array assays and single-marker enzyme-linked immunosorbent assay. Serum biomarker levels were assessed for correlations with disease outcome. RESULTS: In patients with secondary HLH/MAS, we observed pronounced activation of the interleukin-18 (IL-18)-interferon-γ axis, increased serum levels of IL-1 receptor antagonist, intercellular adhesion molecule 1, and IL-8, and strongly reduced levels of soluble Fas ligand in the course of SARS-CoV-2 infection. These observations appeared to discriminate immune dysregulation in critical COVID-19 from the well-recognized characteristics of other cytokine storm syndromes. CONCLUSION: Serum biomarker profiles clearly separate COVID-19 from MAS or secondary HLH in terms of distinguishing the severe systemic hyperinflammation that occurs following SARS-CoV-2 infection. These findings could be useful in determining the efficacy of drugs targeting key molecules and pathways specifically associated with systemic cytokine storm conditions in the treatment of COVID-19.

Macrophage Activation Syndrome in a Child with Juvenile Idiopathic Arthritis Secondary to SARS-CoV-2.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a pandemic affecting many countries and millions of people. Physicians have encountered some rare and challenging cases related to SARS-CoV-2, a novel virus with still many unknowns. In order to share our experience of a such clinical picture, we present here a child with SARS-CoV-2-induced macrophage activation syndrome in the setting of juvenile idiopathic arthritis.

Cytokine storm in severe COVID-19 pneumonia.

In this study, laboratorial parameters of hospitalized novel coronavirus (COVID-19) patients, who were complicated with severe pneumonia, were compared with the findings of cytokine storm developing in macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis (sHLH). Severe pneumonia occurred as a result of cytokine storm in some patients who needed intensive care unit (ICU), and it is aimed to determine the precursive parameters in this situation. Also in this study, the aim is to identify laboratory criteria that predict worsening disease and ICU intensification, as well as the development of cytokine storm. This article comprises a retrospective cohort study of patients admitted to a single institution with COVID-19 pneumonia. This study includes 150 confirmed COVID-19 patients with severe pneumonia. When they were considered as severe pneumonia patients, the clinic and laboratory parameters of this group are compared with H-score criteria. Patients are divided into two subgroups; patients with worsened symptoms who were transferred into tertiary ICU, and patients with stable symptoms followed in the clinic. For the patients with confirmed COVID-19 infection, after they become complicated with severe pneumonia, lymphocytopenia (55.3%), anemia (12.0%), thrombocytopenia (19.3%), hyperferritinemia (72.5%), hyperfibrinogenemia (63.7%) and elevated lactate dehydrogenase (LDH) (90.8%), aspartate aminotransaminase (AST) (31.3%), alanine aminotransaminase (ALT) (20.7%) are detected. There were no significant changes in other parameters. Blood parameters between the pre-ICU period and the ICU period (in which their situation had been worsened and acute respiratory distress syndrome [ARDS] was developed) were also compared. In the latter group lymphocyte levels were found significantly reduced (p = 0.01), and LDH, highly sensitive troponin (hs-troponin), procalcitonin, and triglyceride levels were significantly increased (p < 0.05). In addition, there was no change in hemoglobin, leukocyte, platelet, ferritin, and liver function test levels, including patients who developed ARDS, similar to the cytokine storm developed in MAS/sHLH. COVID-19 pneumonia has similar findings as hyperinflammatory syndromes but does not seem to have typical features as in cytokine storm developed in MAS/sHLH. In the severe patient group who has started to develop ARDS signs, a decrease in lymphocyte level in addition to the elevated LDH, hs-troponin, procalcitonin, and triglyceride levels can be a predictor in progression to ICU admission and could help in the planning of anti-cytokine therapy.

Multisystem Inflammatory Syndrome in a Child with Scrub Typhus and Macrophage Activation Syndrome.

LAY SUMMARY: Clinical and laboratory parameters of multisystem inflammatory syndrome in children (MIS-C) mimic Kawasaki disease (KD). KD has been described in association with dengue, scrub typhus and leptospirosis. However, MIS-C with concomitant infection has rarely been reported in literature. A 14-year-old-girl presented with fever and rash with history of redness of eyes, lips and tongue. Investigations showed anemia, lymphopenia, thrombocytosis with elevated erythrocyte sedimentation rate, C-reactive protein, pro-brain natriuretic peptide, Interleukin-6, ferritin and d-dimer. Scrub typhus immunoglobulin M was positive. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) level was also elevated. A diagnosis of MIS-C with concomitant scrub typhus was proffered. Child received azithromycin, intravenous immunoglobulin and methylprednisolone. After an afebrile period of 2.5 days, child developed unremitting fever and rash. Repeat investigations showed anemia, worsening lymphopenia, thrombocytopenia, transaminitis, hypertriglyceridemia, hyperferritinemia and hypofibrinogenemia which were consistent with a diagnosis of macrophage activation syndrome (MAS). KD, MIS-C and MAS represent three distinct phenotypes of hyperinflammation seen in children during coronavirus disease pandemic. Several tropical infections may mimic or coexist with MIS-C which can be a diagnostic challenge for the treating physician. Identification of coexistence or differentiation between the two conditions is important in countries with high incidence of tropical infections to guide appropriate investigations and treatment.

COVID-19 and cytokine storm syndrome: are there lessons from macrophage activation syndrome?

Although interest in "cytokine storms" has surged over the past decade, it was massively amplified in 2020 when it was suggested that a subset of patients with COVID-19 developed a form of cytokine storm. The concept of cytokine storm syndromes (CSS) encompasses diverse conditions or circumstances that coalesce around potentially lethal hyperinflammation with hemodynamic compromise and multiple organ dysfunction syndrome. Macrophage activation syndrome (MAS) is a prototypic form of CSS that develops in the context of rheumatic diseases, particularly systemic juvenile idiopathic arthritis. The treatment of MAS relies heavily upon corticosteroids and cytokine inhibitors, which have proven to be lifesaving therapies in MAS, as well as in other forms of CSS. Within months of the recognition of SARS-CoV2 as a human pathogen, descriptions of COVID-19 patients with hyperinflammation emerged. Physicians immediately grappled with identifying optimal therapeutic strategies for these patients, and despite clinical distinctions such as marked coagulopathy with endothelial injury associated with COVID-19, borrowed from the experiences with MAS and other CSS. Initial reports of patients treated with anti-cytokine agents in COVID-19 were promising, but recent large, better-controlled studies of these agents have had mixed results suggesting a more complex pathophysiology. Here, we discuss how the comparison of clinical features, immunologic parameters and therapeutic response data between MAS and hyperinflammation in COVID-19 can provide new insight into the pathophysiology of CSS.

Comparison of baseline laboratory findings of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis and multisystem inflammatory syndrome in children.

AIMS: Recently, multisystem inflammatory syndrome in children (MIS-C) has been recognized in association with coronavirus disease 2019 as a cytokine storm syndrome. MIS-C presents with symptoms similar to Kawasaki disease and macrophage activation syndrome (MAS). We aimed to better understand this cytokine storm syndrome by comparing the initial laboratory findings of MIS-C and MAS. METHODS: Patients who were diagnosed with MAS due to systemic juvenile idiopathic arthritis in our clinic between March 2002 and November 2020 and with MIS-C between 20 September and 20 October 2020 were enrolled into the study. The medical files of all patients were reviewed retrospectively. RESULTS: A total of 13 MAS (9 boys, 4 girls) and 26 MIS-C (16 boys,10 girls) patients were included in the study. Hemoglobin, absolute neutrophil and lymphocyte counts, C-reactive protein (CRP), ferritin, fibrinogen and lactate dehydrogenase (LDH) levels showed significant differences between the two groups (P < 0.05). Patients with MAS had lower hemoglobin (10.10 g/dL) and fibrinogen (2.72 g/dL), but higher ferritin (17 863 mg/dL) and LDH (890.61 U/L) at the time of diagnosis. Patients with MIS-C had higher absolute neutrophil count (12 180/mm3 ) and CRP (194.23 mg/dL) values, but lower absolute lymphocyte count (1140/mm3 ) at the time of diagnosis. Left ventricle ejection fraction was significantly lower in the MIS-C group in echocardiographic evaluation (P < 0.001). CONCLUSION: Ferritin, hemoglobin, LDH, and fibrinogen levels were significantly changed in MAS compared with MIS-C. However, patients with MIS-C have more severe signs than MAS, such as cardiac involvement.

Hemophagocytic lymphohistiocytosis: a review inspired by the COVID-19 pandemic.

Hemophagocytic syndrome (HPS) or hemophagocytic lymphohistiocytosis (HLH) is an acute and rapidly progressive systemic inflammatory disorder characterized by cytopenia, excessive cytokine production, and hyperferritinemia. Common clinical manifestations of HLH are acute unremitting fever, lymphadenopathy, hepatosplenomegaly, and multiorgan failure. Due to a massive cytokine release, this clinical condition is considered as a cytokine storm syndrome. HPS has primary and acquired (secondary, reactive) forms. Its primary form is mostly seen in childhood and caused by various mutations with genetic inheritance and, therefore, is called familial HLH. Secondary HLH may be caused in the presence of an underlying disorder, that is, secondary to a malignant, infectious, or autoimmune/autoinflammatory stimulus. This paper aims to review the pathogenesis and the clinical picture of HLH, and its severe complication, the cytokine storm, with a special emphasis on the developed classification criteria sets for rheumatologists, since COVID-19 infection has clinical symptoms resembling those of the common rheumatologic conditions and possibly triggers HLH. MED-LINE/Pubmed was searched from inception to April 2020, and the following terms were used for data searching: "hemophagocytic syndrome" OR "macrophage activation syndrome" OR "hemophagocytic lymphohistiocytosis", OR "cytokine storm". Finally, AND "COVID-19" was included in this algorithm. The selection is restricted to the past 5 years and limited numbers of earlier key references were manually selected. Only full-text manuscripts, published in an English language peer-reviewed journal were included. Manuscript selection procedure and numbers are given in Fig. 2. Briefly, the database search with the following terms of "Hemophagocytic syndrome" OR "Macrophage activation syndrome" OR "Hemophagocytic lymphohistiocytosis" OR "Cytokine storm" yielded 6744 results from inception to April 2020. The selection is restricted to the past 5 years and only limited numbers of earlier key references were selected, and this algorithm resulted in 3080 manuscripts. The addition of (AND "COVID-19") resulted in 115 publications of which 47 studies, together with four sections of an online book were used in the final review. No statistical method was used. HLH is triggered by genetic conditions, infections, malignancies, autoimmune-autoinflammatory diseases, and some drugs. In COVID-19 patients, secondary HLH and cytokine storm may be responsible for unexplained progressive fever, cytopenia, ARDS, neurological and renal impairment. Differentiation between the primary and secondary forms of HLH is utterly important, since primary form of HLH requires complicated treatments such as hematopoietic stem cell transplantation. Further studies addressing the performance of HScore and other recommendations in the classification of these patients is necessary.

Haemophagocytic syndrome and COVID-19.

Primary and secondary haemophagocytic lymphohistiocytosis (HLH) are hyperferritinaemic hyperinflammatory syndromes with a common terminal pathway triggered by different etiopathogenetic factors. HLH is characterised by a decreased capacity of interferon gamma production with an activated NK phenotype profile similar to other hyperinflammatory syndromes. Viruses are closely linked to the development of HLH as infectious triggers, and the break of tolerance to self-antigens is considered a critical mechanism involved in the development of immune-mediated conditions triggered by viral infections. Emerging studies in patients with COVID-19 are suggesting a key role of monocytes/macrophages in the pathogenesis of this viral infection, and there is a significant overlap between several features reported in severe COVID-19 and the features included in the HLH-2004 diagnostic criteria. Therefore, SARS-Cov-2, as other respiratory viruses, may also be considered a potential etiological trigger of HLH. The frequency of HLH in adult patients with severe COVID-19 is lower than 5%, although this figure could be underestimated considering that most reported cases lacked information about some specific criteria (mainly the histopathological criteria and the measurement of NK cell function and sCD25 levels). Because HLH is a multi-organ syndrome, the diagnostic approach in a patient with severe COVID-19 in whom HLH is suspected must be carried out in a syndromic and holistic way, and not in the light of isolated clinical or laboratory features. In COVID-19 patients presenting with persistent high fever, progressive pancytopenia, and hepatosplenic involvement, together with the characteristic triad of laboratory abnormalities (hyperferritinaemia, hypertriglyceridaemia, and hypofibrinogenaemia), the suspicion of HLH is high, and the diagnostic workup must be completed with specific immunological and histopathological studies.

Case Report: Systemic Inflammatory Response and Fast Recovery in a Pediatric Patient With COVID-19.

We report a case of an 8-year-old girl who underwent a SARS-CoV-2 infection manifesting with atypical symptoms spearheaded by abdominal discomfort and systemic inflammation and partially mimicking hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS), which however did not fulfill the HLH/MAS diagnostic criteria. In this case of what has since been described as Pediatric Inflammatory Multisystem Syndrome Temporally associated with SARS-COV-2 (PIMS-TS) we documented excellent clinical response to immunosuppression with systemic corticosteroids and intravenous immunoglobulins. We show a detailed longitudinal development of neutrophil immunophenotype which suggests activation and engagement of neutrophils during PIMS-TS with compensatory contraction of the response and contra-regulation of neutrophil phenotype during recovery.

Macrophage activation syndrome as an unusual presentation of paucisymptomatic severe acute respiratory syndrome coronavirus 2 infection: A case report.

RATIONALE: Macrophage activation syndrome (MAS) is a rare life-threatening condition characterized by cytokine-mediated tissue injury and multiorgan dysfunction. PATIENT CONCERNS: We describe the unique case of young man who developed MAS as the sole manifestation of an otherwise paucisymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. DIAGNOSES: Clinical and biological criteria led to the diagnosis of MAS; cytokine profile was highly suggestive reverse transcription polymerase chain reaction for SARS-CoV-2 in nasopharyngeal swabs was negative, but serum anti-SARS-CoV-2 immunoglobulin A and immunoglobulin G resulted positive leading to the diagnosis of SARS-CoV-2 infection. INTERVENTIONS: The patient was treated with empiric antibiotic and hydroxychloroquine. OUTCOMES: Clinical improvement ensued. At follow-up, the patient is well. LESSON: SARS-CoV-2 infection may trigger develop life-threatening complications, like MAS. This can be independent from coronavirus disease 2019 gravity.

Distinct clinical and immunological features of SARS-CoV-2-induced multisystem inflammatory syndrome in children.

BACKGROUNDPediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail.METHODSWe retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS).RESULTSTwenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort.CONCLUSIONMIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.FUNDINGThis work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; Rheumatology Research Foundation Investigator Awards and Medical Education Award; Boston Children's Hospital Faculty Career Development Awards; the McCance Family Foundation; and the Samara Jan Turkel Center.