A confirmed case of macrophage activation syndrome secondary to spotted fever rickettsiosis: Response to immunomodulation in a pediatric patient in northeastern, Mexico

An 8-year-old girl with a rash and high-grade fever for 6 days arrived at the emergency room. She had an erythematous macular rash on the face, trunk, arms, and legs. Further interrogation called attention to the presence of close contact with stray dogs. Her town had been recognized as a site of a rickettsiosis outbreak in the past year. Spotted fever rickettsiosis was suspected, and doxycycline treatment was initiated. Macrophage activation syndrome (MAS) secondary to Rickettsia rickettsii infection was diagnosed according to the Hemophagocytic lymphohistiocytosis and EULAR/PRINTO/PRES 2016 criteria. As there are no clear guidelines on the treatment of MAS secondary to R. rickettsii. the course of action taken by the pediatric intensive care unit team was to avoid disseminated intravascular coagulopathy and treat MAS, both life-threatening conditions. Directed therapy with high doses of methylprednisolone and intravenous immunoglobulin therapy was initiated. The patient recovered, regaining her functional state before the illness. Few articles have described the association between MAS and rickettsiosis, an illness with high mortality, which makes it paramount to detect and treat promptly.

Polymorphism in cytolytic pathway genes in patients with pediatric inflammatory multisystemic syndrome temporally associated with SARS-CoV-2 / Polimorfismos em genes da via citolítica em pacientes com síndrome inflamatória multissistêmica pediátrica temporariamente associada ao SARS-CoV-2

Introduction: Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) is a systemic hyperinflammatory disease that occurs in a small number of children after being infected with SARS-CoV-2. Macrophage activation syndrome, an aggressive condition characterized by the excessive inflammation and activation of well-differentiated macrophages, has been shown to occur in patients infected by SARS-CoV-2. Considering the clinical and pathophysiological similarities between these diseases, our main objective was to determine whether gene polymorphisms associated with macrophage activation syndrome were also present in patients with PIMS-TS. Methods: DNA from 10 pediatric patients with PIMS-TS (case group) and ten COVID-19 patients without PIMS-TS (control group) were genotyped by Real-time PCR analysis (TaqMan®) for single nucleotide polymorphisms (SNP) in four genes associated with macrophage activation syndrome: perforin 1 (PRF1), granzyme B (GZMB), syntaxin 11 (STX11), and syntaxin binding protein 2 (STXBP2). The SNP analysis was performed using the additive, dominant, and recessive models. Results: A significantly higher frequency of an SNP (C wild allele in rs6573910) in the GZMB gene was observed in both the additive and dominant models in the PIMS-TS group than controls. A borderline significant difference was also observed for the G allele in rs7764017 of the STX11 gene in the PIMS-TS group in the additive model. Conclusions: This study indicated the presence of two polymorphisms in genes associated with macrophage activation syndrome (GZMB and STX11) in patients who developed PIMS-TS. If the presence of these SNPs is validated in a larger number of PIMS-TS cases, they can be used as potential biomarkers for early identification of pediatric patients with a higher probability of developing PIMS-TS associated with SARS-CoV-2 infection.

Introdução: A síndrome multissistêmica inflamatória pediátrica temporariamente associada ao SARS-CoV-2 (SIMP-TS) é uma doença hiperinflamatória sistêmica que ocorre em um pequeno número de crianças após serem infectadas pelo SARS-CoV-2. A síndrome de ativação de macrófagos (SAM), uma condição agressiva caracterizada pela inflamação excessiva e ativação de macrófagos bem diferenciados, demonstrou ocorrer em pacientes infectados por SARS-CoV-2. Considerando as semelhanças clínicas e fisiopatológicas entre essas doenças, neste estudo o nosso principal objetivo foi determinar se polimorfismos gênicos associados à SAM também estavam presentes em pacientes com SIMP-TS. Métodos: DNA de dez pacientes pediátricos com SIMP (grupo caso) e dez pacientes COVID-19 sem SIMP (grupo controle) foram genotipados por análise de PCR em tempo real (tecnologia TaqMan®) para polimorfismos de nucleotídeo único (SNPs) em quatro genes selecionados associados com SAM: perforina 1 (PRF1), granzima B (GZMB), sintaxina 11 (STX11) e proteína de ligação de sintaxina 2 (STXBP2). A análise dos SNPs foi realizada utilizando o modelo aditivo, dominante e recessivo. Resultados: Uma frequência significativamente maior de um SNP (alelo selvagem C em rs6573910) no gene GZMB foi observada pelos modelos aditivo e dominante no grupo SIMP quando comparado aos controles. Além disso, uma significância limítrofe foi observada para o alelo G em rs7764017 do gene STX11 no grupo SIMP pelo modelo aditivo. Conclusões: Nosso estudo indicou a presença de dois polimorfismos em genes associados à SAM (GZMB e STX11) em pacientes que desenvolveram SIMP-TS. Uma vez validada a presença desses SNPs em um número maior de casos de SIMP-TS, eles podem ser usados como potenciais biomarcadores para a identificação precoce de pacientes pediátricos com maior probabilidade de desenvolver SIMP-TS associado à infecção por SARS-CoV-2.

Clinical study of DEP regimen as a salvage therapy for refractory macrophage activation syndrome / 中华风湿病学杂志

Objective:To investigate the efficacy of liposomal doxombicin combined with etoposide and high dose methylprednisolone (DEP) as a salvage therapy for refractory macrophage activation syndrome (MAS).Methods:Totally 38 patients with refractory MAS were enrolled in this study from January 2016 to January 2022 in Beijing Friendship Hospital, including clinical characteristics and laboratory test results before and after DEP treatment, were retrospectively collected. The efficacy was evaluated every 2 weeks according to the United States Midwest Cooperative HLH Group. Relevant samples were statistically analyzed using non-parametric tests.Results:Of 38 refractory MAS patients, 8 males and 30 females were included into this study.The median age was 30(15-69) years old. The underlying disease were adult onset Still's disease in 29 cases, Systemic lupus erythematosus in 6 cases, Rheumatoid arthritis in 1 case and Undifferentiated Connective-Tissue disease in 2. The overall response rate was 95% (36/38), including 9 patients (24%) achieved complete remission and 27 patients (71%) achieved partial remission after 2 weeks of treatment. The overall response rate was 97% (34/35), including 16 (46%) complete remission and 18 (51%) partial remission after 4 weeks of treatment(due to lack of data in some patients). The overall response rate was 97% (34/35), including 17 (49%) complete remission and 17 (49%) partial remission after 6 weeks of treatment. Patients who achieved partial remission or complete remission were actively treated for the underlying diseases after induction, and their conditions were in persistent remission.Conclusion:The DEP regimen may be an effective salvage therapy for the treatment of refractory MAS.

A case of systemic juvenile idiopathic arthritis with an early manifestation of pulmonary ground-glass opacities combined with macrophage activation syndrome / 中国综合临床

Systemic juvenile idiopathic arthritis is one of the common rheumatic and immune diseases in children. It has a sudden onset, obvious systemic symptoms, and lung involvement. However, systemic juvenile idiopathic arthritis with an early manifestation of pulmonary ground-glass opacities combined with macrophage activation syndrome is rare. The clinical data of a child with systemic juvenile idiopathic arthritis with pulmonary ground-glass shadow and macrophage activation syndrome who was admitted to Hubei Maternal and Child Health Care Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology in December 2021 were analyzed retrospectively in order to improve the understanding of rheumatic diseases and pulmonary lesions. The child was admitted to the hospital for 10 days due to rash and fever. Thoracic CT showed scattered ground glass like shadows in both lungs due to the prevention and control screening of COVID-19 pneumonia epidemic situation. After admission, the child was still repeatedly flaccid with high fever, accompanied by dysfunction of both lower limbs. The knee joint MRI found that there was synovitis in the knee joint, and various laboratory indicators suggested macrophage activation syndrome. After that, systemic juvenile idiopathic arthritis was diagnosed. After being treated with methylprednisolone, cyclosporine and topzumab, the clinical remission and the ground-glass shadow of the lung basically disappeared. Through the analysis of this case, it is suggested that clinicians should not ignore other diseases that cause ground glass shadow in the lung during the current epidemic of COVID-19.

Recommendations for the diagnosis and treatment of rheumatic diseases-related hemophagocytic syndrome in China / 中华内科杂志

Hemophagocytic syndrome (HPS), which is currently named as hemophagocytic lymphohistiocytosis (HLH), is a hyperinflammatory syndrome characterized by persistent fever, hepatosplenomegaly, pancytopenia and hemophagocytosis found in bone marrow, liver, spleen and lymph nodes due to excessive activation of macrophages and cytotoxic T cells. Macrophage activation syndrome (MAS) is a specific form of HLH induced by autoinflammatory/autoimmune disorders which can be life-threatening and requires multiple disciplines. In order to improve clinicians′ understanding of MAS and standardize the clinical diagnosis and treatment practice of MAS, the rheumatology branch of Chinese Rheumatology Association organized domestic experts to formulate the diagnosis and treatment standard, in order to improve the diagnosis and treatment level of MAS and improve the prognosis of patients.

Advances in systemic juvenile idiopathic arthritis associated-lung disease / 中华实用儿科临床杂志

Systemic juvenile idiopathic arthritis(sJIA) is one of the most serious critical illnesses in childhood, characterized by high fever, recurrent rash, and arthritis, etc.Children with sJIA associated-lung disease(sJIA-LD) are more severely ill and have a worse prognosis, the correlation between the mechanism and age, disease activity, anti-rheumatic drug therapy, applications of biologics, infection and other factors is worth exploring.This article reviews the research progress on the mechanism, risk factors, treatment methods and prognosis of sJIA-LD, so as to provide a theoretical basis for improving the diagnosis and treatment of sJIA and improving the prognosis.

Advances in the pathogenesis and biomarker of macrophage activation syndrome in children / 国际儿科学杂志

Macrophage activation syndrome is a life-threatening syndrome of multiple causes secondary to rheumatic immune diseases.It is characterized by the continuous activation and proliferation of T lymphocytes and macrophages that leads to overwhelming immune response and excessive release of pro-inflammatory mediators, which eventually causes cytokine storm and multiple organ failure.The main clinical manifestations and laboratory abnormalities include fever, hemocytopenia, hepatomegaly, splenomegaly, lymph node enlargement, coagulation disorders, liver function damage, hyperferritinemia, hypertriglyceridemia and the phenomenon of phagocytosis of blood cells in bone marrow.This article reviews the progress of epidemiology, pathogenesis and biomarkers in macrophage activation syndrome to provide new insights for early diagnosis and identification of the complication which has a rapid progress and high fatality rate.

Metabolic regulation of macrophage function / 白血病·淋巴瘤

Macrophages have plastic and diverse phenotypes and functions, and they play different roles in host defense, tissue homeostasis and repair, development, and various pathologic processes. Although the classically activated macrophage (M1) and alternatively activated macrophage (M2) phenotypes are widely accepted, most macrophages under physiologic and pathologic conditions are polarized to a continuum of states between the M1 and M2 extreme phenotype poles. In recent years, research on the regulatory mechanisms of M1 and M2 macrophages has made great progress, preliminarily elucidating the role of cellular metabolic reprogramming in macrophage polarization and the role of glycolytic enzymes in controlling inflammatory macrophages. The knowledge lays the foundation for elucidating the mechanisms in the regulation of macrophage functional phenotypes. Tumor-associated macrophages play important roles in the development of tumors. The macrophages in the microenvironment of hematologic malignancies have unique features, and a deep study on them will provide new thoughts and clues for clinical diagnosis and therapeutics.

Clinical features of Kawasaki disease complicated by macrophage activation syndrome: an analysis of 27 cases / 中国当代儿科杂志

OBJECTIVES@#To investigate the clinical manifestations and laboratory examination results of children with Kawasaki disease complicated by macrophage activation syndrome (KD-MAS), and to provide a basis for identifying early warning indicators for the early diagnosis and treatment of KD-MAS.@*METHODS@#A retrospective study was performed on 27 children with KD-MAS (KD-MAS group) and 110 children with KD (KD group) who were admitted to Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 2014 to January 2022. Clinical and laboratory data were compared between the two groups. The receiver operating characteristic (ROC) curve was used to investigate the value of laboratory markers with statistical significance in the diagnosis of KD-MAS.@*RESULTS@#Compared with the KD group, the KD-MAS group had significantly higher incidence rates of hepatomegaly, splenomegaly, incomplete KD, no response to intravenous immunoglobulin, coronary artery damage, multiple organ damage, and KD recurrence, as well as a significantly longer length of hospital stay (P<0.05). Compared with the KD group, the KD-MAS group had significantly lower levels of white blood cell count, absolute neutrophil count, hemoglobin, platelet count (PLT), erythrocyte sedimentation rate, serum albumin, serum sodium, prealbumin, and fibrinogen (FIB), a significantly lower incidence rate of non-exudative conjunctiva, and significantly higher levels of C-reactive protein, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase (LDH), and serum ferritin (SF) (P<0.05). The ROC curve analysis showed that SF, PLT, FIB, and LDH had high value in the diagnosis of KD-MAS, with areas under the curve (AUC) of 0.989, 0.966, 0.932, and 0.897, respectively (P<0.001), and optimal cut-off values of 349.95 μg/L, 159×109/L, 3.85 g/L, and 403.50 U/L, respectively. The combination of SF, PLT, FIB, and LDH had a larger AUC than PLT, FIB, and LDH alone in the diagnosis of KD-MAS (P<0.05), but there was no significant difference in the AUC between the combination of SF, PLT, FIB, and LDH and SF alone (P>0.05).@*CONCLUSIONS@#KD-MAS should be considered when children with KD have hepatosplenomegaly, no response to intravenous immunoglobulin, coronary artery damage, and KD recurrence during treatment. SF, PLT, FIB, and LDH are of high value in the diagnosis of KD-MAS, especially SF is of great significance in the diagnosis of KD-MAS.

Hemophagocytic lymphohistiocytosis: presentation and outcome of twenty-one patients at a single institution

ABSTRACT Introduction: Hemophagocytic lymphohistiocytosis comprises a systemic hyperactivation of macrophages that requires prompt recognition of symptoms and early treatment. Objective and Method: In this context, we described clinical and laboratory characteristics, therapeutic modality and outcome of 21 patients with HLH treated at a pediatric oncology hospital between January 2000 and February 2019. Results: HLH mainly affected females, fever was the most frequent clinical sign and hyperferritinemia was the most prevalent laboratory abnormality. All patients were admitted to the intensive care unit (ICU) at some point. Fifteen (71.4%) patients presented resolution criteria and eight (53.3%) of them presented reactivation. The mortality rate was 57.1% and the mean time between diagnosis and death was 9.98 months. The 5-year overall survival (OS) was 36.7%. We observed a significant difference in prognosis associated with reactivation of HLH. These patients demonstrated an estimated 5-year OS of 25%, while all patients that did not reactivate were alive until the end of the follow-up. Conclusion: In conclusion, HLH is a rare disease with a high mortality rate, especially in patients with disease reactivation and those with familial- or immunodeficiency-associated forms, which makes early recognition and genetic testing crucial for appropriate management and prompt SCT indication.

Pediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2

Objectives To know the clinical presentation and outcome of children with pediatric infammatory multisystem syndrome temporally associated with SARS-CoV- 2 (PIMS-TS) at a pediatric tertiary care center in Chennai. Methods Clinical and biochemical parameters of 65 children with PIMS-TS treated between July and October 2020 were studied. All children had their COVID RT-PCR and IgG COVID antibodies tests done. Results Mean age of the study group was 5.65±3.68 y. Fever with red eyes, rash, vomiting, abdominal pain, and shock were common presenting features. Sixty percent of the study group had Kawasaki/incomplete Kawasaki features. Sixty-seven percent of the study group had coronary dilatation, 41% presented with shock, and 25% had left ventricular dysfunction. Coronary aneurysms were documented in 58% of the study group (z score more than 2.5). Respiratory presentation with pneumonia was seen in 10%. Four children presented with acute abdomen. Acute kidney injury, acute liver failure, hemolysis, pancytopenia, macrophage activation syndrome, encephalopathy, and multiorgan dysfunction syndrome (MODS) were other features. Forty-three percent required noninvasive oxygen support and 15.4% required mechanical ventilation. Intravenous immunoglobulin (73.8%) and methylprednisolone (49.8%) were used for therapy. Mortality in the study was 6%, which was due to MODS. Conclusions Acute febrile illness with mucocutaneous and gastrointestinal manifestations should have PIMS-TS as a possible diferential diagnosis and needs evaluation with infammatory markers and SARS-CoV-2 antibodies.

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

ABSTRACT 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.

Relationship between HO-1 and PPARγ during alveolar macrophage polarization in a mouse model of endotoxin-induced acute lung injury / 中华麻醉学杂志

Objective:To evaluate the relationship between heme oxygenase-1 (HO-1) and peroxisome proliferator-activated receptor γ (PPARγ) during alveolar macrophage polarization in a mouse model of endotoxin-induced acute lung injury (ALI).Methods:Thirty clean-grade male C57BL/6 mice (24 wide-type mice and 6 HO-1 knockout mice), aged 6-8 weeks, weighing 18-22 g, were studied.Wide-type mice were divided into 4 groups ( n=6 each) using a random number table method: control group (C group), ALI group, ALI+ HO-1 agonist hemin group (ALI+ H group), and ALI+ hemin+ PPARγ antagonist T0070907 group (ALI+ H+ T group).HO-1 knockout mice in which the ALI model was developed served as ALI+ HO-1 -/- group.ALI model was developed by injecting lipopolysaccharide (LPS) 15 mg/kg via the tail vein in anesthetized animals.T0070907 1.5 mg/kg was intraperitoneally injected at 1 h before LPS administration in ALI+ H+ T group, and hemin 50 mg/kg was intraperitoneally injected at 30 min before LPS administration in ALI+ H group and ALI+ H+ T group.Mice were sacrificed at 12 h after LPS administration, and lung tissues were obtained to measure the wet to dry weight ratio (W/D ratio), to observe pathological changes which were scored, and to determine the F4/80+ /CD86+ labeled M1 alveolar macrophages and the F4/80+ /CD206+ labeled M2 alveolar macrophages (by flow cytometry), contents of M1 macrophage-related genes inducible nitric oxide synthase (iNOS) and M2 macrophage-related genes Arginase-1 (Arg-1) (by enzyme-linked immunosorbent assay), and the expression of HO-1 and PPARγ (by Western blot). Results:Compared with C group, the lung injury score, W/D ratio, levels of CD86 and CD206, and contents of iNOS and Arg-1 were significantly increased, and PPARγ expression was up-regulated in the other four groups ( P<0.05), and HO-1 protein expression was up-regulated in ALI, ALI+ H and ALI+ H+ T groups ( P<0.05).Compared with ALI group, the lung injury score, W/D ratio, and levels of CD86 and iNOS were significantly increased, the levels of CD206 and Arg-1 were decreased, and the expression of HO-1 and PPARγ was down-regulated in ALI+ HO-1 -/- group, the lung injury score, W/D ratio and levels of CD86 and iNOS were significantly decreased, the levels of CD206 and Arg-1 were increased, and the expression of HO-1 and PPARγ was up-regulated in ALI+ H group ( P<0.05), and no significant change was found in the parameters mentioned above in ALI+ H+ T group ( P>0.05).Compared with ALI+ H group, the lung injury score, W/D ratio and levels of CD86 and iNOS were significantly increased, the levels of CD206 and Arg-1 were decreased, the expression of PPARγ was down-regulated ( P<0.05), and no significant change was found in the expression of HO-1 in ALI+ H+ T group ( P>0.05). Conclusions:HO-1 can up-regulate the expression of PPARγ, inhibit the polarization of alveolar macrophages toward M1 phenotype and promote the polarization toward M2 phenotype, thus playing an endogenous protective role in endotoxin-induced ALI in mice.

Síndrome de activación macrofágica como desenlace de enfermedades reumatológicas: reporte de 4 casos / Macrophage activation syndrome as a result of rheumatological diseases: Report of 4 cases

RESUMEN El síndrome de activación macrofágica (SAM) es una grave complicación de varias entidades reumáticas entre las que se encuentran la artritis idiopática juvenil sistémica, enfermedad de Still y lupus eritematoso sistémico. Este síndrome forma parte de las linfohistiocitosis hemofagocíticas adquiridas y constituye una enfermedad potencialmente mortal, con difi cultad en su identificación y carencia de consensos en cuanto a su manejo. Describimos una serie de casos de pacientes con SAM, exponiendo su proceso diagnóstico, su relación con las enfermedades reumáticas de base, su seguimiento y tratamiento, así como los resultados de diferentes esquemas de manejo.

ABSTRACT Macrophage activation syndrome (MAS) is a serious complication of several rheumatic disor ders, among which are the systemic juvenile idiopathic arthritis, Still's disease and systemic lupus erythematosus. This syndrome is part of the Acquired Haemophagocytic Lymphohistiocytoses, and is a potentially fatal disease, with difficulty in its identification and a lack of consensus regarding its management. A series of cases are describe of patients with macrophage activation syndrome, explaining their diagnostic process, their relationship with rheumatic diseases, their monitoring, and treatment, as well as the results of different management schemes.

Síndrome de activación de macrofágica como complicación de la artritis idiopática juvenil sistémica

RESUMEN La artritis idiopática juvenil sistémica, también conocida como enfermedad de Still, se considera un trastorno autoinflamatorio y suele ser la más compleja y grave entre todas las formas clínicas de la enfermedad. Cursa generalmente en forma de brotes de actividad repetidos, intercalados por periodos de remisión. Se presenta el caso de una paciente femenina de 4 años de edad, con diagnóstico de enfermedad de Still a los 2 años. Actualmente tiene tratamiento con triple terapia de inducción: cloroquina, metotrexato y salazosulfapiridina con actividad de la enfermedad persistentemente alta por JADAS 27. Acudió a consulta por presentar fiebre, toma del estado general y manifestaciones respiratorias de tres días de evolución que se interpretó como una infección respiratoria baja. Se prescribió tratamiento con antibióticos sin signos de mejoría. A los 7 días se agravó el cuadro clínico y se planteó el diagnóstico de síndrome de activación macrofágica. Se comenzó protocolo de tratamiento con esteroides en combinación con otros fármacos de probada eficacia para esta situación clínica (etopósido, ciclosporina, metotrexato). Se revaloró política de antibióticos sin lograrse respuesta satisfactoria y se decidió introducir el rituximab que aporta excelentes resultados. Después de 3 meses de difícil manejo, la paciente egresó del hospital recuperada de esta complicación y con bajo nivel de actividad de la enfermedad de base.

ABSTRACT Systemic Juvenile Idiopathic Arthritis, also known as Still's disease, is considered an autoinflammatory disorder and is often the most complex and severe of all clinical forms of the disease. It usually takes the form of repeated bouts of activity, interspersed with periods of remission. We present the case of a 4-year-old female patient, diagnosed with Still's disease at 2 years of age. Currently undergoing treatment with triple induction therapy: chloroquine, methotrexate and salazosulfapyridine with persistently high disease activity due to JADAS 27. He comes to the clinic due to fever, general condition, and respiratory manifestations of three days of evolution interpreted as an infectious respiratory process under. Antibiotic treatment is started without signs of improvement. At 7 days the clinical picture worsens, and the diagnosis of Macrophage Activation Syndrome is raised. A steroid treatment protocol is started in combination with other drugs of proven efficacy for this clinical situation (ethopside, cyclosporine, methotrexate). Antibiotic policy was reassessed without achieving a satisfactory response and it was decided to introduce rituximab, which provides excellent results. After three months of difficult management, the patient was released from the hospital recovered from this complication and with a low level of activity of the underlying disease.

Linfohistiocitosis hemofagocítica secundaria y síndrome de liberación de citoquinas en COVID-19, ¿entidades iguales o diferentes? / Secondary hemophagocytic lymphohistiocytosis and cytokine release syndrome in COVID-19, the same or different entities?

INTRODUCCIÓN: La liberación excesiva de citoquinas en COVID-19 grave se asemeja a la linfohistiocitosis hemofagocítica secundaria (sHLH). OBJETIVO: Comparar las características clínicas y de laboratorio entre sHLH y el síndrome de liberación de citoquinas (CRS) en COVID-19. MÉTODOS: Se realizó una revisión de artículos en la base de datos PubMed, a través de las siguientes palabras clave "HLH and COVID", "HScore in COVID". Se incluyeron las publicaciones disponibles hasta el 16 julio 2020. RESULTADOS: Se elaboró un cuadro comparativo basado en los criterios diagnósticos del protocolo HLH 2004, HScore y características del CRS-COVID-19. Se utilizaron 18 variables para la comparación. DISCUSIÓN: El CRS en COVID-19 grave presenta similitud con el CRS del sHLH; sin embargo, no se puede afirmar que se traten de la misma entidad. Los reportes de sHLH en COVID-19 son escasos. HScore es una herramienta que podría orientar el diagnóstico de HLH secundario a COVID-19 de una manera más práctica que los criterios HLH-2004; sin embargo, su aplicación en COVID-19 se encuentra limitada debido a la ausencia de características claves del estado hiperinflamatorio de COVID-19 que sí destacan en HLH. CONCLUSIONES: El CRS-COVID-19 no es sinónimo de sHLH. Aunque esta última entidad podría o no estar presente en COVID-19 grave.

BACKGROUND: Excessive release of cytokines in severe COVID-19 resembles secondary hemophagocytic lymphohistiocytosis (sHLH). AIM: To compare the clinical and laboratory characteristics between sHLH and cytokine release syndrome (CRS) in COVID-19. METHODS: A review of articles in the PubMed database was performed, using the following keywords "HLH and COVID", "HScore in COVID". Articles available until July 16, 2020 were included. RESULTS: A comparative table was prepared based on the diagnostic criteria of the HLH 2004 protocol, HScore and characteristics of the CRS-COVID-19. Eighteen variables are used for comparison. DISCUSSION: The CRS in COVID-19 presented similarity with the CRS of sHLH; however, it cannot be stated that they are the same entity. Case reports of sHLH in COVID-19 are small. HScore is a tool that could guide the diagnosis of sHLH in the context of CRS-COVID-19, in a more practical way than the classic criteria described in HLH-2004; however, its application in COVID-19 is limited due to the absence of key features of the hyperinflammatory state of COVID-19 that are included in HLH. CONCLUSIONS: CRS-COVID-19 is not synonymous with sHLH. Although this last entity may or may not be present in the severe COVID-19.

Utilidad de la Determinación de CD25 Soluble en Pacientes con sospecha de Síndrome de Activación Macrofágica / Usefulness of the determination of soluble CD25 in patients with suspected macrophage activation syndrome

El síndrome de activación macrofágica (SAM) presenta criterios clínicos y de laboratorio establecidos. Presentamos el caso de un adolescente varón con debut de Lupus eritematoso generalizado pediátrico grave, donde su manifestación principal fue un SAM y el receptor de interleucina 2 soluble en suero (IL-2rs) o CD25 soluble (CD25s) aumentado resultó clave en la confirmación diagnóstica, en el tratamiento y pronóstico de su enfermedad. Sin embargo, este receptor de citocinas no se mide habitualmente en la práctica clínica.

Macrophage activation syndrome (MAS) presents established clinical and laboratory criteria. We present the case of a male adolescent with the onset of severe pediatric systemic Lupus erythematosus, manifested mainly by MAS and how a laboratory marker, serum soluble interleukin-2 receptor (IL-2rs) or altered soluble CD25(CD25s), played a key role in treatment and prognosis of the disease. However, this cytokine receptor is rarely measured in clinical practice.

Analysis of 7 cases of macrophage activation syndrome secondary to systemic juvenile idiopathic arthritis in infants and toddlers / 中华风湿病学杂志

Objective:To investigate the clinical features, diagnosis and treatment of systemic juvenile idiopathic arthritis (SJIA) complicated with macrophage activation syndrome (MAS).Methods:From January 1st, 2018 to January 1st, 2020, 7 cases of SJIA-MAS were diagnosed. Their clinical and laboratory data were collected and summarized.Results:In these 7 cases, 2 were males and 5 were females, the ratio of male to female was 2∶5. The age range was 11 months to 2 years old. The course of disease was 14 to 32 days. The clinical manifestations included fever and rash in 7 without arthritis; hepatomegaly, splenomegaly and lymphadenopathy in 7; hematological involvement in 7; nervous system involvement in 2; digestive system involvement in 7; respiratory system involvement in 7; cardiovascular involvement in 3. White blood cell was decreased in 1 case, platelet was decreased in 1 case and hemoglobin was decreased in 7 cases. Ferritin, triglyceride, alanine transaminas and aspartate aminotransferase were increased in 7 cases, fibrinogen was significantly decreased in 7 cases, and direct bilirubin was increased in 4 cases. IL-2R was significantly increased. Hemophagocytosis was observed in bone marrow of 4 cases. Cerebrospinal fluid protein was 2 005 mg/L in 1 case. All the 7 cases were tested for exon genes, and no pathogenic mutation was found. All of the 7 cases showed lung lesions in chest CT scan. Multiple demyelinating lesions were found in 1 case by head magnetic resonance imaging. One case was treated with high-dose intravenous methylprednisolone combined with IL-6 receptor antagonist(tocilizumab). The other 6 cases were treated with high-dose intravenous methylprednisolone combined with cyclosporine A (CsA). Two cases were treated with Janus kinases inhibitor(tofacitinib). After treatment, 7 cases got relieved, no death, no recurrence oocurred during the follow-up.Conclusion:Acute onset, multiple organ involvement and no joint inflammation are prominent in MAS of infants and toddlers. High fever, proressive reduction of blood cells and increase of SF are significant in SJIA-MAS. High dose glucocorticoid combined with CsA can benefit in most cases, and some severe cases need to be treated with biological agents.

Significance of cytokine imbalance in systemic onset juvenile idiopathic arthritis combined with macrophage activation syndrome / 中国医师进修杂志

Objective:To analyze cytokine pattern of systemic onset juvenile idiopathic arthritis (SOJIA) combined with macrophage activation syndrome (MAS) in children, and study the early diagnostic value in MAS.Methods:The clinical data of 157 children with SOJIA from January 2013 to March 2018 in Taizhou Hospital of Zhejiang Province were retrospectively analyzed. Among them, SOJIA combined with MAS was in 15 cases (SOJIA combined with MAS group), and simple SOJIA was in 142 cases (simple SOJIA group). The peripheral blood levels of interleukin (IL)-2, IL-4, IL-6, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were measured by flow cytometry cytometric beads array. The characteristics of cytokine pattern was analyzed.Results:The IL-10 and IFN-γ in SOJIA combined with MAS group were significantly higher than those in simple SOJIA group: 40.5 (7.9, 236.9) ng/L vs. 4.1 (2.0, 98.7) ng/L and 55.8 (18.5, 500.0) ng/L vs. 4.4 (1.4, 30.1) ng/L, and there were statistical differences ( P<0.01); there were no statistical difference in IL-2, IL-4, IL-6 and TNF-α between 2 groups (P>0.05). Pearson correlation analysis result showed that IL-10 was positive correlated with IFN-γ in SOJIA children with MAS ( r = 0.638, P = 0.011). Receiver operating characteristic curve analysis result showed that the area under the curve (AUC) of IFN-γ in predicting MAS was 0.991, 95% CI 0.974 to 1.000, the optimal critical value was 18.45 ng/L, the sensitivity was 92.5%, and the specificity was 95.1%; the AUC of IL-10 in predicting MAS was 0.944 (95% CI 0.893 to 0.996), the optimal critical value was 7.75 ng/L, the sensitivity was 91.7%, and the specificity was 81.7%. Conclusions:The significant increased IL-10 and IFN-γ is helpful for the early diagnosis MAS in children with SOJIA.

Evaluation of clinical effects of the early warning scale on systemic juvenile idiopathic arthritis complicated with macrophage activation syndrome / 中华实用儿科临床杂志

Objective:To compare the disease outcome, quality of life score [evaluated by child health assessment questionnaire - disability index(CHAQ-DI)] and medical expenses of children with systemic juvenile idiopathic (sJIA) combined with macrophage activation syndrome (MAS) diagnosed by two different criteria.And to analyze the impacts of early MAS diagnosis criteria on the prognosis of sJIA combined with MAS in children.Methods:From January 2016 to December 2020, children with high disease activity of sJIA who were diagnosed and initially treated in the Department of Rheumatology of Beijing Children′s Hospital were enrolled in this study.Clinical characteristics on admission were recorded as baselines.Patients were divided into 2 groups according to different diagnostic criteria.Children diagnosed as MAS based on the 2016 The European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation MAS diagnostic criteria were included in MAS control group(38 cases), and those diagnosed as early MAS based on the sJIA combined MAS early warning scale but did not meet the 2016 diagnostic criteria were included in MAS early warning group(38 cases). Basic information, clinical manifestations and laboratory test results were collected.According to the clinical manifestations and laboratory results in different periods of follow-up at 4 weeks, 8 weeks, 12 weeks, 6 months and 12 months after treatments, the di-sease activity, CHAQ-DI and medical expenses were compared between the two groups.Results:There were no signi-ficant differences in the disease activity, duration of sJIA and medical expenses between the two groups (all P>0.05). In terms of laboratory results, serum ferritin in MAS early warning group were significantly lower than that of MAS control group at 4 weeks after treatment[(333.97±186.66) μg/L vs.(389.66±221.76) μg/L]( t=-83.47, P<0.05). In terms of disease activity, after 12 months of treatment, the evaluation of American College of Rheumatology pediatric indexes 70 in MAS early warning group was better than that in MAS control group [34.2%(13/38 cases) vs.7.9% (3/38 cases)]( χ2=6.067, P<0.05). In terms of CHAQ-DI, at 4 weeks, 8 weeks, 12 weeks and 6 months of treatment, CHAQ-DI in MAS early warning group were better than those in MAS control group, and the difference were statistically significant ( t=-0.34, -0.27, -0.23, -0.09; all P<0.05). In terms of cumulative medical expenditure at 12 months of treatment, the MAS early warning group was lower than the MAS control group [(114.3±80.7) thousand yuan vs.(157.9±111.7) thousand yuan]( t=-3.97, P<0.05). Conclusions:Quickly judge the condition through the quantitative integral of clinical examination and test indexes, screening and treatment of MAS in early stage are helpful to improve the prognosis and reduce the medical consumption.