Development Of Macrophage Activation Syndrome Research Articles

The NLRP3 inflammasome is essential for IL-18 production in a murine model of macrophage activation syndrome.

Hyperinflammatory disease is associated with an aberrant immune response resulting in cytokine storm. One such instance of hyperinflammatory disease is known as macrophage activation syndrome (MAS). The pathology of MAS can be characterised by significantly elevated serum levels of interleukin-18 (IL-18) and interferon gamma (IFNγ). Given the role for IL-18 in MAS, we sought to establish the role of inflammasomes in the disease process. Using a murine model of CpG-oligonucleotide-induced MAS, we discovered that the expression of the NLRP3 inflammasome was increased and correlated with IL-18 production. Inhibition of the NLRP3 inflammasome or the downstream caspase-1 prevented MAS-mediated upregulation of IL-18 in the plasma but, interestingly, did not alleviate key features of hyperinflammatory disease including hyperferritinaemia and splenomegaly. Furthermore blockade of IL-1 receptor with its antagonist IL-1Ra did not prevent the development of CpG-induced MAS, despite being clinically effective in the treatment of MAS. These data demonstrate that, during the development of MAS, the NLRP3 inflammasome was essential for the elevation in plasma IL-18 - a key cytokine in clinical cases of MAS - but was not a driving factor in the pathogenesis of CpG-induced MAS.

An antibody to IL-1 receptor 7 protects mice from LPS-induced tissue and systemic inflammation.

Interleukin-18 (IL-18), a pro-inflammatory cytokine belonging to the IL-1 Family, is a key mediator ofautoinflammatory diseases associated with the development of macrophage activation syndrome (MAS).High levels of IL-18 correlate with MAS and COVID-19 severity and mortality, particularly in COVID-19patients with MAS. As an inflammation inducer, IL-18 binds its receptor IL-1 Receptor 5 (IL-1R5), leadingto the recruitment of the co-receptor, IL-1 Receptor 7 (IL-1R7). This heterotrimeric complex subsequentlyinitiates downstream signaling, resulting in local and systemic inflammation. We reported earlier the development of a novel humanized monoclonal anti-human IL-1R7 antibody whichspecifically blocks the activity of human IL-18 and its inflammatory signaling in human cell and wholeblood cultures. In the current study, we further explored the strategy of blocking IL-1R7 inhyperinflammation in vivo using animal models. We first identified an anti-mouse IL-1R7 antibody that significantly suppressed mouse IL-18 andlipopolysaccharide (LPS)-induced IFNg production in mouse splenocyte and peritoneal cell cultures. Whenapplied in vivo, the antibody reduced Propionibacterium acnes and LPS-induced liver injury and protectedmice from tissue and systemic hyperinflammation. Importantly, anti-IL-1R7 significantly inhibited plasma,liver cell and spleen cell IFNg production. Also, anti-IL-1R7 downregulated plasma TNFa, IL-6, IL-1b,MIP-2 production and the production of the liver enzyme ALT. In parallel, anti-IL-1R7 suppressed LPSinducedinflammatory cell infiltration in lungs and inhibited the subsequent IFNg production andinflammation in mice when assessed using an acute lung injury model. Altogether, our data suggest that blocking IL-1R7 represents a potential therapeutic strategy to specificallymodulate IL-18-mediated hyperinflammation, warranting further investigation of its clinical application intreating IL-18-mediated diseases, including MAS and COVID-19.

Investigation on the relationship between serum periostin, MMP-7, TGF-β, and IL-18 levels and the clinical course and prognosis of COVID-19.

Cytokines are involved in the inflammatory/anti-inflammatory balance and have been shown to play an important role in the course of COVID-19. This study aimed to evaluate the relationship of periostin, transforming growth factor-beta (TGF-β), interleukin-18 (IL-18), and matrix metalloproteinase 7 (MMP-7) levels with clinical course and mortality in patients with early COVID-19 pneumonia. A total of 150 hospitalized patients were diagnosed with COVID-19 between June and October 2021, and a control group of 30 healthy individuals were included in our study. The COVID-19 patients were divided into those who developed macrophage activation syndrome (MAS) in Group 1 and those who did not in Group 2. Serum periostin, MMP-7, TGF-β, and IL-18 levels were measured from blood samples obtained at admission using enzyme-linked immunosorbent assay (ELISA). Periostin, MMP-7, and IL-18 levels were significantly higher in COVID-19 patients compared to the control group (p<0.001 for all). Periostin and MMP-7 levels were also significantly higher in Group 1 than in Group 2 (p<0.001 for both). Periostin, MMP-7, IL-18, and TGF-β levels were significantly higher in non-surviving patients compared to survivors (p=0.04, p<0.001, p<0.001, and p<0.001, respectively). In the receiver operating characteristic (ROC) curve analysis, MMP-7 was found to have high sensitivity (90%) at a predictive value of 2.66 ng/mL. It is still not possible to predict which patients with early COVID-19 pneumonia will go on to develop MAS despite receiving standard treatment. The results of our study suggest that elevation of periostin and MMP-7 levels in the early period may predict the development of macrophage activation syndrome.

Neutrophil extracellular trap-induced intermediate monocytes trigger macrophage activation syndrome in adult-onset Still’s disease

BackgroundAdult-onset Still’s disease (AOSD) is a systemic autoinflammatory disease characterized by innate immune system activation, with a high risk for macrophage activation syndrome (MAS). MAS development is associated with monocyte/macrophage activation and cytokine storm. Monocytes consist of three different subsets, classical monocytes (CMs, CD14brightCD16 −), intermediate monocytes (IMs, CD14brightCD16 +), and non-classical monocytes (NCMs, CD14dimCD16 +), each has distinct roles in inflammatory regulation. However, the frequencies and regulatory mechanism of monocyte subsets in AOSD patients have not been identified.MethodsWe performed flow cytometry, RNA sequencing, phagocytosis analysis, and enzyme-linked immunosorbent assay to evaluate monocyte subsets, cell functions, and potential biomarkers. The effect of neutrophil extracellular traps (NETs) on monocytes was determined by evaluating mRNA levels of DNA sensors, surface CD16 expression, and inflammasome pathway activation.ResultsHigher proportions of intermediate monocytes (IMs) were identified in active AOSD patients. IMs displayed higher expression of CD80, CD86, HLA-DR, and CD163 than CMs and NCMs. CD163 upregulation was noted on AOSD IMs, accompanied by increased phagocytic activity and elevated cytokine/chemokine production, including IL-1β, IL-6, CCL8, and CXCL10. The frequencies of IMs were correlated with disease activity and higher in AOSD patients with MAS (AOSD-MAS). CCL8 and CXCL10 were highly expressed in RNA sequencing of monocytes from AOSD-MAS patients and plasma CXCL10 level could serve as a potential biomarker for AOSD-MAS. Moreover, DNA-sensing pathway was activated in monocytes from AOSD-MAS patients. Stimulation with NETs derived from AOSD induced DNA sensor expression, the expansion of IMs, and inflammasome pathway activation. These effects can be abrogated by DNase I treatment.ConclusionsOur results demonstrated that the proportions of IMs were elevated in AOSD and associated with MAS. The DNA component in NETs from AOSD plays an important role in the formation of IMs, shedding new light for the therapeutic target.

Clinical and laboratory features associated with macrophage activation syndrome in Still’s disease: data from the international AIDA Network Still’s Disease Registry

To characterize clinical and laboratory signs of patients with Still’s disease experiencing macrophage activation syndrome (MAS) and identify factors associated with MAS development. Patients with Still’s disease classified according to internationally accepted criteria were enrolled in the AutoInflammatory Disease Alliance (AIDA) Still’s Disease Registry. Clinical and laboratory features observed during the inflammatory attack complicated by MAS were included in univariate and multivariate logistic regression analysis to identify factors associated to MAS development. A total of 414 patients with Still’s disease were included; 39 (9.4%) of them developed MAS during clinical history. At univariate analyses, the following variables were significantly associated with MAS: classification of arthritis based on the number of joints involved (p = 0.003), liver involvement (p = 0.04), hepatomegaly (p = 0.02), hepatic failure (p = 0.01), axillary lymphadenopathy (p = 0.04), pneumonia (p = 0.03), acute respiratory distress syndrome (p < 0.001), platelet abnormalities (p < 0.001), high serum ferritin levels (p = 0.009), abnormal liver function tests (p = 0.009), hypoalbuminemia (p = 0.002), increased LDH (p = 0.001), and LDH serum levels (p < 0.001). At multivariate analysis, hepatomegaly (OR 8.7, 95% CI 1.9–52.6, p = 0.007) and monoarthritis (OR 15.8, 95% CI 2.9–97.1, p = 0.001), were directly associated with MAS, while the decade of life at Still’s disease onset (OR 0.6, 95% CI 0.4–0.9, p = 0.045), a normal platelet count (OR 0.1, 95% CI 0.01–0.8, p = 0.034) or thrombocytosis (OR 0.01, 95% CI 0.0–0.2, p = 0.008) resulted to be protective. Clinical and laboratory factors associated with MAS development have been identified in a large cohort of patients based on real-life data.

Systemic Juvenile Idiopathic Arthritis and Secondary Macrophage Activation Syndrome in Latvia from 2009 to 2020: A Nationwide Retrospective Study.

Background and Objectives: Systemic juvenile idiopathic arthritis (sJIA) is a distinctive JIA subtype with mostly nonspecific systemic clinical features, which can be a diagnostic challenge. This study aimed to analyze our experience with sJIA in Latvia for twelve years: assessing clinical and epidemiological characteristics, the efficacy of therapy, and disease outcomes, including the development of macrophage activation syndrome (MAS). Materials and methods: This is a descriptive study in which we conducted a retrospective case review of all patients with sJIA diagnosis admitted to the only pediatric tertiary centre in Latvia during the period 2009-2020. Results: sJIA was diagnosed in 35 patients with a mean annual incidence rate of 0.85 patients per 100,000 children. Major clinical signs at the first visit were: fever, rash, arthritis, and lymphadenopathy. Almost half of the patients, 48.5%, had a monocyclic disease course, and only 20% of patients had persistent disease. MAS developed in 28.6% of patients. Biological therapy was administered to 48.6% of patients, mostly by tocilizumab, which induced remission in 75% after one year, and in 81.2% after two years without any serious therapy-related complications. In our study, none of the patients had interstitial lung disease, drug reaction with eosinophilia and systemic symptoms (DRESS)-like syndrome, or fatal disease. Conclusions: The incidence and clinical characteristics of sJIA correlate with the literature findings, although MAS was more common than described in other studies. There is a tendency for the persistent disease to decrease with the use of biological therapy. Tocilizumab is an efficient choice of treatment with a good safety profile.

Narsoplimab for severe transplant-associated thrombotic microangiopathy

BackgroundTransplantation-associated thrombotic microangiopathy (TA-TMA) is an endothelial injury syndrome linked to the overactivation of complement pathways. It manifests with microangiopathic hemolytic anemia, consumptive thrombocytopenia, and microvascular thrombosis leading to ischemic tissue injury. Mannose residues on fungi and viruses activate the mannose-binding lectin complement pathway, and hence activation of the lectin pathway could be one of the reasons for triggering TA-TMA. Narsoplimab, a human monoclonal antibody targeting MASP-2 is a potent inhibitor of the lectin pathway. We describe the transplant course of a pediatric patient who developed TA-TMA following Candida-triggered macrophage activation syndrome and was treated with Narsoplimab. The data collection was performed prospectively.Case presentationThe six-year-old girl underwent a human leucocyte antigen (HLA) haploidentical hematopoietic stem cell transplant using post-transplant Cyclophosphamide for severe aplastic anemia. In the second week of the transplant, the patient developed macrophage activation syndrome necessitating treatment with steroids and intravenous immunoglobulin. Subsequently, USG abdomen and blood fungal PCR revealed the diagnosis of hepatosplenic candidiasis. Candida-triggered macrophage activation syndrome responded to antifungals, steroids, intravenous immunoglobulin, and alemtuzumab. However, the subsequent clinical course was complicated by thrombotic microangiopathy. The patient developed hypertension in the 2nd week, followed by high lactate dehydrogenase (1010 U/L), schistocytes (5 per hpf), low haptoglobin (< 5 mg/dl), thrombocytopenia, and anemia in the 3rd week. Ciclosporin was stopped, and the patient was treated with 10 days of defibrotide without response. The course was further complicated by the involvement of the gastrointestinal tract and kidneys. She had per rectal bleeding with frequent but low-volume stools, severe abdominal pain, and hypoalbuminemia with a rising urine protein:creatinine ratio. Narsoplimab was started in the 5th week of the transplant. A fall in lactate dehydrogenase was observed after starting Narsoplimab. This was followed by the resolution of gastrointestinal symptoms, proteinuria, and recovery of cytopenia. The second episode of TA-TMA occurred with parvoviraemia and was also successfully treated with Narsoplimab.ConclusionLectin pathway inhibition could be useful in treating the fatal complication of transplant-associated thrombotic microangiopathy.

Metrnl, COVID-19 Hastalarında Makrofaj Aktivasyon Sendromunun Gelişimini Tahmin Etmek için Yeni Bir Biyobelirteç Olabilir mi?

Introduction: Failure to maintain the inflammatory and anti-inflammatory balance during COVID-19 treatment may result in a severe clinical course. In our study, we aimed to determine the relationship between the meteorin-like protein (metrnl), which plays a role in the anti-inflammatory balance, and the clinical course. Materials and Methods: Between October 2021 and December 2021, 160 patients who were hospitalized in our hospital and whose delta variant COVID-19 infection was confirmed and 80 healthy controls, were enrolled in the study. Patients were divided into two groups according to the severity degree of COVID-19 (Group 1: Moderate COVID-19, Group 2: Severe COVID-19 MAS). Results: When comparing the metrnl levels of the groups, it was observed that the metrnl level was statistically significantly lower in Group 2 patients (p&lt; 0.001). While no statistically significant difference was observed between the healthy control group and Group 1, it was observed that the metrnl level of Group 2 patients was statistically significantly lower than the healthy control group (p= 0.77, &lt;0.001 respectively). In the ROC curve analysis of Metrnl level performed in Group 1 and 2 patients, the cut-off value was taken as 17.54 ng/mL, its sensitivity was observed as 80% and the specificity was observed as 60% in predicting the development of severe COVID-19 in patients whose levels were below this value. Conclusion: The low level of metrnl, which is thought to play a key role in anti-inflammatory balance, contributes to the development of macrophage activation syndrome, which leads to the severe clinical course in COVID-19 patients.

Efficacy and safety of canakinumab as a second line biologic after tocilizumab treatment failure in children with systemic juvenile idiopathic arthritis: A single-centre cohort study using routinely collected health data.

A significant number of systemic juvenile idiopathic arthritis (sJIA) patients discontinue biologic disease-modifying antirheumatic drugs (bDMARDs) due to lack of efficacy or safety concerns. Studies of biologic therapy switch regimens in sJIA are required. Patients with sJIA who switched from tocilizumab (due to lack of efficacy or safety) to canakinumab (4 mg/kg every 4 weeks) and were hospitalized at the rheumatology department from August 2012 to July 2020 were included. Primary efficacy outcomes were 30% or greater improvement based on the paediatric criteria of the American College of Rheumatology (ACR30), achievement of inactive disease (JADAS-71 = 0) and clinical remission (ACR sJIA clinical inactive disease criteria). Follow-up from time first canakinumab dose administered was 12 months or the closest time point (not less than 6 and not more than 18 months). Data were extracted from electronic outpatient medical records. During the study period, 46 patients with sJIA switched from tocilizumab to canakinumab. Median age at baseline was 8.2 [interquartile range (IQR) 4.0-12.9] years, with the median sJIA duration being 1.8 (IQR 0.8-5.8) years; 37 (80%) patients received at least one conventional DMARD (cDMARD; oral corticosteroids, methotrexate and/or cyclosporine A). Study outcomes were followed up in 45 patients (one patient did not attend the follow-up for an unknown reason); median follow-up was 359 (IQR 282-404) days. During the follow-up, 1 patient discontinued canakinumab due to tuberculosis detection and the dose was reduced or the injection interval increased in 4 (9%) patients. In total, 27 (60%) patients continued to receive at least one cDMARD. Improvement according to the ACR30 criteria was achieved in 43 patients [96%; 95% confidence interval (CI) 85-99], inactive disease in 42 (93%; 95%CI 82-98), and remission in 37 (82%; 95% CI 69-91); after adjustment for actual time-at-risk, the rates were 83, 85 and 73 events per 100 person-years, respectively. During follow-up, 23 AEs (most frequently infections) were reported in 19/45 (42%) patients; 5/45 (11%) patients developed macrophage activation syndrome, with a favorable outcome in all cases. One-year canakinumab therapy was found to be potentially effective as second-line biologic therapy after discontinuation of tocilizumab in patients with sJIA.

Platelet and ferritin as early predictive factors for the development of macrophage activation syndrome in children with Kawasaki disease: A retrospective case-control study.

To investigate the early predictive factors for Kawasaki disease complicated with macrophage activation syndrome (KD-MAS). We performed a retrospective case-control study in children with KD from August 2017 to August 2022, involving 28 cases with KD-MAS and 112 cases not developing KD-MAS. Based on the univariate analysis, binary logistic regression was used to identify the early predictive factors for KD-MAS development, and the receiver operating characteristic curve (ROC) analysis was carried out to obtain the optimal cut-off value. Two predictive factors were associated with the development of KD-MAS, which were PLT (OR = 1.013, 95%CI, 1.001-1.026), and serum ferritin (OR = 0.991, 95%CI, 0.982-0.999). The cut-off value of PLT was 110 × 109/L, and the cut-off value of serum ferritin was 548.4 ng/ml. Children with KD who had a PLT count under 110 × 109/L, and a serum ferritin level over 548.4 ng/ml are more likely to develop KD-MAS.

Immunomodulation in Sepsis-Induced Macrophage Activation Syndrome in Children

Background: Sepsis is a state of systemic inflammation due to an infectious etiology that may lead to multisystem dysfunction, hemodynamic instability, and even death. It has been postulated that there may be an underlying immunomodulatory process resulting from rapid and exaggerated activation of macrophages that results in a cytokine storm and the development of macrophage activation syndrome (MAS). Adding immunomodulation to standard therapy (antibiotics and supportive care) can improve the prognosis. Clinical Description: We present a series of three young children who presented with the clinical features of sepsis. All three showed poor clinical response to management with timely antibiotics and supportive care, even after 48–72 h of initiation. In addition, there was the development of thrombocytopenia and transaminitis. The suspicion of MAS prompted us to order ferritin, triglyceride, and fibrinogen levels and applies the 2016 diagnostic criteria for MAS. These were satisfied, thus establishing the diagnosis. Management: In all three cases, immunomodulatory agents (intravenous immunoglobulin with or without pulses of methylprednisolone) were added, after which there was a clinical improvement, normalization of biomarkers, and complete recovery. Conclusion: Early immunomodulatory therapy, in addition to antibiotics, is beneficial in the successful treatment of children presenting with sepsis-induced MAS, thus preventing further morbidity and mortality and improving outcomes.

P19 A case of pyrexia of unknown origin - wrong way round!

P19 A case of pyrexia of unknown origin - wrong way round!

Pathogenic roles and diagnostic utility of interleukin-18 in autoinflammatory diseases.

Interleukin (IL)-18 is a pleiotropic, pro-inflammatory cytokine involved in the regulation of innate and adaptive immune responses. IL-18 has attracted increasing attention as a key mediator in autoinflammatory diseases associated with the development of macrophage activation syndrome (MAS) including systemic juvenile idiopathic arthritis and adult-onset Still’s disease. In these diseases, dysregulation of inflammasome activity and overproduction of IL-18 might be associated with the development of MAS by inducing natural killer cell dysfunction. Serum IL-18 levels are high in patients with these diseases and therefore are useful for the diagnosis and monitoring of disease activity. In contrast, a recent study revealed the overproduction of IL-18 was present in cases of autoinflammation without susceptibility to MAS such as pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. The pathogenic and causative roles of IL-18 remain unclear in these autoinflammatory diseases. Further investigations are necessary to clarify the role of IL-18 and its importance as a therapeutic target in the pathogenesis of autoinflammatory diseases.

Challenges in diagnostic research of multisystem inflammatory syndrome in children associated with COVID-19 in combination with the early stage of Epstein-Barr virus infection

Multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 is a rare life-threatening immunopathological complication of COVID-19 that develops 1-6 weeks after the acute coronavirus infection. MIS-C is characterized by fever and multiorgan inflammation.We present a clinical case of a 10-year-old boy with skin lesions at the onset of MIS-C (erythematous malar rash, lacelike rash on the trunk and extremities and petechiae) with macrophage activation syndrome development and the early stage of primary Epstein-Barr virus infection (EBV infection) which required the exclusion of X-linked lymphoproliferative disease.This clinical case demonstrates the complexity of diagnosis in MIS-C with skin manifestations at the onset of the disease, especially with concurrent activation of other infections, particularly EBV infection.

Is There an Association Between Initial Clinical Manifestations and the Development of Macrophage Activation Syndrome in Patients with Systemic Juvenile Idiopathic Arthritis?

Is There an Association Between Initial Clinical Manifestations and the Development of Macrophage Activation Syndrome in Patients with Systemic Juvenile Idiopathic Arthritis?

Role of Distinct Macrophage Populations in the Development of Heart Failure in Macrophage Activation Syndrome.

Macrophage activation syndrome (MAS) is one of the few entities in rheumatology with the potential to quickly cause multiple organ failure and loss of life, and as such, requires urgent clinical intervention. It has a broad symptomatology, depending on the organs it affects. One especially dangerous aspect of MAS’s course of illness is myocarditis leading to acute heart failure and possibly death. Research in recent years has proved that macrophages settled in different organs are not a homogenous group, with particular populations differing in both structure and function. Within the heart, we can determine two major groups, based on the presence of the C-C 2 chemokine receptor (CCR2): CCR2+ and CCR2−. There are a number of studies describing their function and the changes in the population makeup between normal conditions and different illnesses; however, to our knowledge, there has not been one touching on the matter of changes occurring in the populations of heart macrophages during MAS and their possible consequences. This review summarizes the most recent knowledge on heart macrophages, the influence of select cytokines (those particularly significant in the development of MAS) on their activity, and both the immediate and long-term consequences of changes in the makeup of specific macrophage populations—especially the loss of CCR2− cells that are responsible for regenerative processes, as well as the substitution of tissue macrophages by the highly proinflammatory CCR2+ macrophages originating from circulating monocytes. Understanding the significance of these processes may lead to new discoveries that could improve the therapeutic methods in the treatment of MAS.

Macrophage activation syndrome in a patient with adult-onset Still\u2019s disease following first COVID-19 vaccination with BNT162b2

BackgroundAdult-onset Still’s disease (AOSD) is an autoinflammatory multi-systemic syndrome. Macrophage activation syndrome (MAS) is a potentially life-threatening complication of AOSD with a mortality rate of 10–20%. Especially viral infection is thought to be a common trigger for development of MAS. On the other hand, the occurrence of MAS following vaccinations is extremely rare and has been described in a few cases after measles or influenza vaccinations and more recently after ChAdOx1 nCoV-19 (COVID-19 viral vector vaccine, Oxford-AZ).Case presentationWe report the case of a twenty-year-old female with adult-onset Still’s disease (AOSD), who developed a MAS six days after receiving her first COVID-19 vaccine dose of BNT162b2 (mRNA vaccine, BioNTech/Pfizer) with ferritin levels of 136,680 µg/l (ref.: 13–150 µg/l).ConclusionsTo the best of our knowledge, this is the first case report of development of MAS in a patient with preexisting AOSD after vaccination in general, and SARS-CoV-2 vaccination in particular. The new mRNA vaccines have generally shown a reassuring safety profile, but it has been shown that nucleic acids in general, including mRNA can act as pathogen-associated molecular patterns that activate toll-like receptors with extensive production of pro-inflammatory cytokines and further activation of immune cells. Proving an interferon 1 response in our patient directly after vaccination, we think that in this particular case the vaccination might have acted as trigger for the development of MAS. Even if it remains difficult to establish causality in the case of rare adverse events, especially in patients with autoimmune or autoinflammatory conditions, these complications are important to monitor and register, but do not at all diminish the overwhelming positive benefit-risk ratio of licensed COVID-19 vaccines.

Exploring Macrophage Activation Syndrome Secondary to Systemic Lupus Erythematosus in Adults: A Systematic Review of the Literature.

Among the autoimmune (AI) diseases, systemic lupus erythematosus (SLE) is known to mimic various disease processes and this can lead to under-diagnosis of macrophage activation syndrome (a dire complication). We aimed at performing a systematic review to identify trigger factors that could lead to the development of macrophage activation syndrome (MAS) in patients with SLE as well as identify factors that can affect mortality. We searched the following databases to extract relevant articles: PubMed, ScienceDirect, Cochrane library, Pro-Quest, and Google Scholar. We used search terms including but not limited to hemophagocytic syndromes OR hemophagocytic lymphohistiocytosis OR macrophage activation syndrome OR HLH OR secondary hemophagocytic lymphohistiocytosis AND systemic lupus erythematosus OR SLE. We screened the articles first by titles and abstracts and later by full text. After the application of our eligibility criteria, we identified eight studies to include in our final synthesis. The studies showed that lupus flare itself, as well as, time to onset and high systemic lupus erythematosus disease activity index (SLEDAI) scores, were major risk factors that led to the development of MAS. In addition, infections followed by drugs, underlying malignancy, and pregnancy were other potential trigger factors identified. Studies also detected that MAS development led to high intensive care unit (ICU) admissions and in-hospital mortalities with C-reactive protein (CRP) levels, age, presence of infection, leukopenia, thrombocytopenia, MAS throughout the hospital stay, and high liver function tests (LFTs) as signs of poor prognosis. Additionally, ferritin levels, LFTs, and triglyceride levels formed an important part of diagnostic criteria. However, our review was limited due to the absence of prospective studies and heterogeneity in the studies seen. More studies need to be done to identify various factors leading to hemophagocytic lymphohistiocytosis (HLH) in autoimmune diseases with validated criteria for MAS secondary to autoimmune diseases.

СИНДРОМ АКТИВАЦИИ МАКРОФАГОВ ПРИ РЕВМАТИЧЕСКИХ ЗАБОЛЕВАНИЯХ У ДЕТЕЙ: РЕТРОСПЕКТИВНОЕ ИССЛЕДОВАНИЕ

Macrophage activation syndrome (MAS) is a rare life-threatening complication of rheumatic diseases (RD) that requires early recognition and adequate immediate treatment. Objective of the study: to identify the features of onset of RD in patients who developed MAS, the clinical and laboratory characteristics of the MAS, possible trigger factors and the timing of development. Materials and methods of research: 57 patients (20 boys and 37 girls) with RD who developed MAS were included in a retrospective continuous non-randomized study: 36 (63%) with systemic juvenile idiopathic arthritis (sJIA), 19 (33%) with Systemic lupus erythematosus (SLE), 1 (2%) – with juvenile dermatomyositis (JDM), one (2%) – with overlapping syndrome. Results: in the structure of patients with sJIA, patients with a history of MAS accounted for 28%, among patients with SLE – 7,6%. The median age at the time of sJIA debut in the study group was 2,6 years [1,5; 5,75], patients with SLE – 11,8 years [8,6; 13,95]. The ratio of boys and girls in the study group was 1:1,85. 70 MAS episodes were recorded: 48 – with sJIA, 20 – with SLE, one episode each for JDM and crossover syndrome. A single episode of MAS at the onset had 22% of patients with sJIA, 47% – with SLE, MAS during the course of the disease – 55% and 47%, repeated episodes of MAS – 25% and 5% of patients, respectively. Clinical manifestations of MAS included fever in 91% of children, hepatomegaly in 54%, pericarditis in 51%, skin lesions in 68%, CNS damage in 44%, lung damage in 33%, hyperferritinemia in 96%, thrombocytopenia – in 79%, increased aminotransferases – in 89%, hypertriglyceridemia – in 53%. Patients with sJIA and MAS had statistically significantly earlier onset (p=0,047), a greater number of systemic manifestations (p=0,012), a typical exanthema (p&lt;0,0001), and a smaller number of active joints (p=0,041). 83% of them had episodes of MAS before the initiation of therapy with biological disease-modifying antirheumatic drugs (bDMARDs). There was no statistically significant relationship between the development of MAS with the use of bDMARDs with a clear positive relationship with the violation of the therapy regimen. 19% of patients with sJIA and MAS had a history of infusion reaction to tocilizumab, 8% later had interstitial lung damage. Patients with SLE and MAS at the onset were statistically significantly more likely to have serositis (p=0,0028), ulcers of the oral mucosa (p&lt;0,0001), neuropsychiatric disorders (p=0,0024), positive Coombs' test (p=0,026). All patients received glucocorticoid therapy; experience with the use of GIBP in the study group was limited. Conclusion: MAS in children develops more often with sJIA; the dominant provoking factor is the activity of the underlying disease. The overwhelming majority of patients developed MAS during the course of the disease, less often at the onset. Patients with a history of MAS with sJIA are characterized by an earlier age of onset, a predominance of systemic manifestations, the need for early administration of bDMARDs therapy, and a tendency to infusion reaction to tocilizumab. Against the background of bDMARDs, a subclinical course of MAS with the absence of fever is possible. The risk of developing MAS along with SLE is higher in patients with onset of serositis, ulcers of the oral mucosa, neuropsychiatric disorders, and a positive Coombs' test. MAS cases were detected with high SLE activity at the onset, violation of the treatment protocol.

Same Virus, Different Course: The Relationship Between Monocyte Chemoattractant Protein-1 and Surfactant Protein-A Levels And Clinical Course and Prognosis of COVID-19

Introduction: To date, over 165 million people have been infected in the COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 which emerged in Wuhan, China in December 2019. This study examined the relation between serum monocyte chemoattractant protein-1 and surfactant protein-A levels and the clinical course and prognosis of COVID-19. Materials and Methods: The study included a total of 108 subjects. Those in the patient group (n= 88) were diagnosed with COVID-19 using real-time PCR analysis of nasopharyngeal swab samples and treated in the Pulmonary Diseases Intensive Care Unit and the Infectious Diseases Department between March 24 and May 20. The control group (n= 20) included asymptomatic healthcare workers whose real-time PCR results during routine COVID-19 screening in our hospital were negative. Results: The COVID-19 patient group had significantly higher monocyte chemoattractant protein-1 and SP-A levels compared to the control group (p= 0.001, p= 0.001). Patients who developed macrophage activation syndrome had significantly higher monocyte chemoattractant protein-1 and surfactant protein-A levels than those who did not both at admission (p= 0.001, p= 0.001) and on day 5 of treatment (p= 0.05, p= 0.04). Similarly, monocyte chemoattractant protein-1 and surfactant protein-A levels were significantly higher in patients who developed acute respiratory distress syndrome compared to those who did not at both time points (p= 0.001 for all). Both parameters were significantly higher in non-surviving COVID-19 patients compared to survivors (p= 0.001 for both). Conclusion: Monocyte chemoattractant protein-1 and surfactant protein-A are on opposing sides of the inflammatory balance, and SP-A may be a pneumoprotein of importance in the presentation, course, prognosis, and possibly the treatment of COVID-19 in the future.