Hemophagocytic lymphohistiocytosis and macrophage activation syndrome: two rare sides of the same devastating coin

Abstract Hemophagocytic lymphohistiocytosis (HLH) is a rare genetic hyperinflammatory syndrome that occurs early in life. Macrophage activation syndrome (MAS) usually refers to a secondary form of HLH associated with autoimmunity, although there are other causes of secondary HLH, such as infections and malignancy. In this article, we reviewed the concepts, epidemiology, clinical and laboratory features, diagnosis, differential diagnosis, prognosis, and treatment of HLH and MAS. We also reviewed the presence of MAS in the most common autoimmune diseases that affect children. Both are severe diseases that require prompt diagnosis and treatment to avoid morbidity and mortality.

Emphysematous pyelonephritis in patient with hemophagocytic lymphohistiocytosis: A case report

Emphysematous pyelonephritis (EPN) and hemophagocytic lymphohistiocytosis (HLH) are rare, fatal illnesses. The presence of both at once in a patient is extremely rare. The number of reported cases of EPN is <800 cases worldwide to date. Contrarily, the prevalence of adults with HLH is estimated to be 1 in every 2000 adults admitted to a tertiary health center. This case report aims to present the case of a 45-year-old woman who was diagnosed with EPN with a history of HLH and was successfully treated with medication alone. In conclusion, the clinical manifestations of EPN are non-specific and need imaging modalities like computed tomography (CT) scans. Treating EPN is based on CT scan classification. Medical treatment was an option for these patients. There is no direct association between EPN and HLH; it is a challenging decision to treat patients with both.

Hiperferritinemia: Experiencia de un Centro Universitario en Chile / Hyperferritinemia in a Chilean Academic Healthcare Network: A Retrospective Study

INTRODUCTION: The distribution of causes of hyperferritinemia in international series is heterogeneous. Also, the association between ferritin and prognosis is controversial. This study aims to describe the diagnosis associated with hyperferritinemia in a retrospective cohort at an academic healthcare network in Chile. METHODS: A retrospective review of adult patients admitted to our academic medical center from June 2014 to February 2017 with ferritin ≥3,000 ng/mL. All patients were classified into nine diagnostic categories. Then, the association between ferritin level and disease category, as well as mortality, was evaluated. RESULTS: Ninety-nine patients were identified. The mean age was 50.8 ± 19.9 years, 54.5% were men. The most frequent categories were "inflammatory and autoimmune diseases" (21.2%) and "hematological malignancies" (19.2%). The average ferritin was 10,539 ± 13,016.9 ng/mL, while the higher mean was 16,707 ng/mL in the "inflammatory and autoimmune diseases" category. There was a statistically significant association between the ferritin value and age but not between ferritin and diagnostic categories. In the group over 50, hematologic neoplasms (19%) and infections (19%) were more frequent. In those under 50, inflammatory and autoimmune diseases were more frequent (26.8%). There was no association between the ferritin level and mortality at 1, 3, and 12 months. CONCLUSIONS: The most frequent categories were "inflammatory and autoimmune diseases" and "hematological malignancies", but ferritin level was similar in both. Further research could validate a prognostic role.

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.

Hemofagocitose em cultura de sangue periférico precedendo hemofagocitose em biópsia de medula óssea na síndrome hemofagocítica secundária / Hemophagocytosis in peripheral blood culture preceding hemophagocytosis in bone marrow biopsy in secondary hemophagocytic syndrome

A síndrome hemofagocítica é determinada por desregulação do sistema imunológico, caracterizada por ativação excessiva de macrófagos, resultando em fagocitose de células sanguíneas normais no fígado, baço e medula óssea. Pode ser primária (genética) ou secundária (adquirida). Em adultos quase sempre é secundária, tendo infecções, neoplasias e doenças autoimunes como frequentes desencadeadores. Entre as principais manifestações da síndrome estão febre prolongada e hepatoesplenomegalia. O diagnóstico até o momento é confirmado pelo achado de hemofagocitose em biópsia de medula óssea. Entretanto, é descrito que a biópsia de medula óssea é normal nos primeiros dias de manifestações da síndrome. O presente relato tem como objetivo mostrar a observação de hemofagocitose em cultura de células de sangue periférico de paciente de 29 anos precedendo a hemofagocitose em biópsia de medula óssea. A paciente apresentava diferentes infecções, com grave comprometimento do estado geral e sem melhora com o tratamento das infecções. O achado laboratorial permitiu o tratamento precoce da síndrome hemofagocítica e a melhora da paciente. No presente relato a técnica utilizada está descrita detalhadamente para que possa ser reproduzida, além de ser apresentada uma revisão não sistemática da literatura sobre a síndrome.

Hemophagocytic syndrome, which is caused by dysregulation of the immune system, is characterized by excessive macrophage activation, resulting in phagocytosis of normal blood cells in the liver, spleen, and bone marrow. It can be primary (genetic) or secondary (acquired). In adults, it is almost always secondary, with infections, neoplasms, and autoimmune diseases as frequent triggers. The main manifestations of this syndrome are prolonged fever and hepatosplenomegaly. Currently, diagnosis is confirmed through finding hemophagocytosis in a bone marrow biopsy. However, it has been reported that bone marrow biopsy results are still normal on the first day the syndrome manifests. Here we report observing hemophagocytosis in cultured peripheral blood cells from a 29-year-old patient prior to finding hemophagocytosis in bone marrow biopsy. The patient had various infections and a poor general condition, which did not improve after treating the infections. The laboratory findings allowed early treatment of hemophagocytic syndrome and the patient improved. We describe our technique in detail so it can be reproduced, and we provide a non-systematic review of the literature on the syndrome.

Hemophagocytic lymphohistiocytosis: a case series analysis in a pediatric hospital

Abstract Introduction Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical laboratory condition with high mortality rates, resulting from ineffective overactivation of the immune system. Data in the Brazilian literature is scarce, contributing to the challenge in standardizing conducts and performing an early diagnosis of HLH. Objective To describe the clinical, laboratory, and evolutionary findings on HLH patients treated at a pediatric hospital. Methods This is an observational, cross-sectional and retrospective study on children diagnosed with HLH, hospitalized between 2009 and 2019. The diagnostic criteria were those described in the Histiocyte Society protocol. The authors evaluated HLH patient laboratory tests, myelograms and bone marrow biopsies, clinical characteristics and therapy. Results Twenty-three patients were included, 52.2% of whom were males. The age at diagnosis ranged from one to one hundred and eighty months. Four cases were classified as Primary HLH and nineteen, as Secondary HLH. The main triggers were infections and rheumatological diseases. All children had bicytopenia, and 95.4% had hyperferritinemia. Nineteen patients had liver dysfunction, sixteen had neurological disorders and fourteen had kidney injury. Pulmonary involvement was seen in 61.9%, acting as a worse prognosis for death (p= 0.01). Nine patients underwent the immuno-chemotherapy protocol proposed in the HLH 2004. The time to confirm the diagnosis varied from five to eighty days. The lethality found was 56.3%. Conclusions The present study is the most extensive retrospective exclusively pediatric study published in Brazil to date. Despite the limitations, it was possible to demonstrate the importance of discussing HLH as a pediatric emergency.

Hemophagocytic syndrome in a patient with Fanconi anemia and VACTERL association / Síndrome hemofagocítica em paciente com anemia de Fanconi e associação VACTERL

INTRODUCTION: Hemophagocytic syndrome results from hyperactivity of histiocytes and lymphocytes, triggered by infections, mainly viral by cytomegalovirus, Epstein-Barr and herpes. Fanconi anemia (FA) is a rare genetic disease with heterogeneous symptoms common to other diseases such as VACTERL, a disease of unknown etiology in which there are several congenital malformations. The concomitance of Fanconi and VACTERL anemia occurs in 5 to 30% of FA patients. REPORT: A 14-month-old male infant was admitted to investigate fever, hepatosplenomegaly, and granulopenia. The patient was diagnosed with hemophagocytic syndrome due to hyperferritinemia, bone marrow hemophagocytosis, transaminase elevation, decreased fibrinogen, and cytomegalovirus (CMV) infection confirmed by serology and PCR. The test with mitomycin C (MMC) showed chromosomal fragility. The patient was diagnosed with a VACTERL/FA association for having a clinic and a test compatible with both FA and VACTERL. CONCLUSION: The VACTERL/FA association is seldom described, but is present in pediatric medical practice. This study presented the main clinical-laboratory aspects and reviewed the main aspects of the concurrence of this pathology.

INTRODUÇÃO: A síndrome hemofagocítica decorre da hiperatividade de histiócitos e linfócitos e é desencadeada por infeções, principalmente virais por citomegalovírus, Epstein-barr e herpes. A anemia de Fanconi (AF) é uma doença genética rara com sintomas heterogêneos em comum a outras doenças como a associação VACTERL, uma doença de etiologia desconhecida na qual existe diversas mal formações congênitas. A concomitância da anemia de Fanconi e VACTERL é descrita em 5 a 30% dos pacientes AF. RELATO: Lactente de 14 meses, sexo masculino, admitido para investigar um quadro de febre, hepatoesplenomegalia e granulopenia. Os exames laboratoriais mostraram a hiperferritemia, elevação da transaminases, medula óssea com hemofagocitose e, sorologia e PCR positivos para citomegalovírus (CMV). O paciente foi diagnosticado com síndrome hemofagocítica por citomegalovírus. Como havia também hipoplasia do polegar esquerdo, presença de hemivértebra, agenesia renal e teste positivo de fragilidades cromossômicas com mitomicina C (MMC), o paciente foi diagnosticado com associação VACTERL/AF. CONCLUSÃO: O citomegalovírus quando infecta pacientes com problemas de imunidade como AF, apresenta risco de desencadear a síndrome hemofagocítica. A associação VACTERL/AF é pouco descrita, mas presente na prática médica da pediatria. Esse estudo descreveu os principais aspectos clínicos-laboratoriais e revisou os aspectos fundamenais descritos sobre a concomitância dessas patologias.

An elevated HScore is associated with poor clinical outcomes in COVID-19 / Un HScore elevado se asocia a mal pronóstico en pacientes con COVID-19

BACKGROUND: Patients with Coronavirus Disease 2019 (COVID-19) frequently experience a hyperinflammatory syndrome leading to unfavorable outcomes. This condition resembles Secondary Hemophagocytic Lymphohistiocytosis (sHLH) described in neoplastic, rheumatic and other infectious diseases. A scoring system (HScore) that evaluates underlying immunosuppression, temperature, organomegaly, cytopenias, ferritin, triglycerides, fibrinogen and AST was validated for sHLH, and recently proposed to evaluate hyperinflammation in COVID-19. AIM: To assess the presence of sHLH among patients with COVID-19 admitted for hospitalization and to evaluate Hscore as a prognostic tool for poor outcomes. MATERIAL AND METHODS: One hundred forty-three patients aged 21-100 years (64% males) admitted because of COVID-19 were enrolled in a prospective study. HScore was calculated within 72 hours admission. The incidence of sHLH during hospitalization was evaluated. Additionally, the relationship between a HScore ≥ 130 points and either the requirement of mechanical ventilation or 60-days mortality was explored. RESULTS: The median HScore was 96 (33-169). A SHLH was diagnosed in one patient (incidence 0.7%), whose HScore was 169. After adjusting for age, sex, comorbidities and obesity, HScore ≥ 130 was independently associated with the composite clinical outcome (Hazard rartio 2.13, p = 0.022). CONCLUSIONS: sHLH is not frequent among COVID-19 patients. HScore can be useful to predict the risk for poor outcomes.

ANTECEDENTES: Los pacientes con Enfermedad por Coronavirus 2019 (COVID-19), experimentan frecuentemente un síndrome hiperinflamatorio que lleva a resultados desfavorables. Esta situación se asemeja al Síndrome Hemofagocítico Secundario (sHLH) descrito en enfermedades neoplásicas, reumatológicas y por otros agentes infecciosos. Un sistema simple de puntaje (HScore) que evalúa inmunosupresión, temperatura organomegalia, citopenias, ferritina, triglicéridos, fibrinógeno y AST ha sido validado para el diagnóstico de sHLH y ha sido propuesto recientemente para evaluar la hiperinflamación en COVID-19. OBJETIVO: Medir la frecuencia de sHLH entre pacientes con COVID-19 hospitalizados, y evaluar a HScore como una herramienta pronóstica. MATERIAL Y MÉTODOS: Ciento cuarenta y tres pacientes de 21 a 100 años (64% hombres) fueron ingresados en este estudio de cohorte prospectivo, unicéntrico. Se calculó HScore dentro de las primeras 72 horas desde el ingreso, y se midió la incidencia de sHLH durante la hospitalización. Adicionalmente, se evaluó la relación entre HScore ≥ 130 puntos y un desenlace compuesto de ventilación mecánica o muerte a los 60 días. RESULTADOS: La mediana de HScore fue 96 (33-169) puntos. Un paciente fue diagnosticado con sHLH (incidencia 0,7%). Luego de ajustar por edad, sexo, comorbilidades y obesidad, un HScore ≥ 130 se asoció de manera independiente con el desenlace compuesto. CONCLUSIONES: El sHLH no es frecuente en los pacientes con COVID-19. El uso de HScore puede ser útil para predecir el riesgo de desenlaces clínicos desfavorables.

Síndrome hemofagocítico asociado a varicela / Hemofagocytic syndrome associated with varicella

Presentación del caso. Lactante femenina de 14 meses de edad con desarrollo psicomotor normal, sin comórbidos. Con historia de un día de fiebre de 40 °C, intermitente, acompañada de evacuaciones diarreicas y vómitos. Fue llevada por sus padres a una clínica privada sin notar mejoría con el tratamiento médico indicado. Posteriormente, presentó deterioro clínico y fue llevada a un hospital, donde se diagnosticó un síndrome febril agudo, diarrea con deshidratación leve y faringitis. Al cuarto día de evolución inició con máculas y pápulas que progresaron a vesículas y costras. Además, presentó intolerancia a la vía oral, disnea, distensión abdominal, coma y desequilibrio hidroelectrolítico. Intervención terapéutica. Inició el tratamiento con hidratación parenteral, antivirales, esteroides endovenosos y antihistamínicos; se diagnosticó shock séptico con compromiso respiratorio, se proporcionó ventilación mecánica asistida y fue referida al hospital de tercer nivel para atención por medicina crítica. Los estudios reportaron un derrame pleural derecho del 40 % y hepatomegalia. Continuó el tratamiento con antibiótico terapia, hidratación parenteral, antivirales, diuréticos, antipiréticos y hemoderivados, presentó mejoría, continuó el manejo terapéutico. Evolución clínica. El día 18 presentó fiebre, hepatoesplenomegalia, los exámenes reportaron elevación de ferritina, triglicéridos y citopenia se diagnosticó un síndrome hemofagocítico que evolucionó con una falla multisistémica y falleció al siguiente día

Case presentation. A 14-month-old female infant with normal psychomotor development, without comorbidities. With a one-day history of fever of 40 °C, intermittent, accompanied by diarrhea and vomiting. She was taken by her parents to a private clinic without improvement with the indicated medical treatment. Subsequently, she presented clinical deterioration and was taken to a hospital, where she was diagnosed with acute febrile syndrome, diarrhea with mild dehydration, and pharyngitis. On the fourth day of evolution, she started with macules and papules that progressed to vesicles and crusts. In addition, she presented oral intolerance, dyspnea, abdominal distension, coma, and hydro electrolytic imbalance. Therapeutic intervention. She started treatment with parenteral hydration, antivirals, intravenous steroids, and antihistamines; septic shock with respiratory distress was diagnosed, assisted mechanical ventilation was provided, and she was referred to a tertiary hospital for critical care medicine. Studies reported a 40 % right pleural effusion and hepatomegaly. She continued treatment with antibiotic therapy, parenteral hydration, antivirals, diuretics, antipyretics, and hemoderivatives, presented improvement, and continued therapeutic management. Clinical evolution. On day 18 he presented fever and hepatosplenomegaly. Tests reported elevated ferritin, triglycerides, and cytopenia, and was diagnosed with hemophagocytic syndrome that evolved with multisystemic failure and died the following day

Clinical values of morphology of hemophagocytes in infection associated hemophagocytic lymphohistiocytosis / 中华检验医学杂志

Objective:To study the morphology of hemophagocytosis (HPC) in bone marrow smears of patients with infection-associated hemophagocytic lymphohistiocytosis (IAHLH), and further analyse if there were differences in the clinical and laboratory features, the cytokines level and prognosisMethods:24 patients newly diagnosed with IAHLH from 2016-Dec-1 to 2021-Dec-31 in Beijing Friendship Hospital were included as study group, and 20 patients with infectious disease as non-HLH control group. In IAHLH group, mean age was 34±13 years, including 17(71%) males and7(29%) females. In Non-HLH group, mean agewas 43±16 years, including 14 (70%) males and6 (30%) females. Depending on re-checking phagocytic cell type on the initial bone marrow smear, the HPCs were divided into HPC-1, phagocytizing non-nucleated cells (mature erythrocyte or platelets), and HPC-2, phagocytizing nucleated cells. The differences in clinical presentations covered in HLH-2004 criteria, cytokines value(IL-6, IL-10, IL-18, IFN-γ) recommended in HLH-2022-China guideline, and the mortality within 1 year of diagnosis, were compared between IAHLH and non-HLH groups, between patients with or without HPC, and between patients with HPC-2 or only with HPC-1. For categorical variables, two groups were compared with the use of either the chi-square test or Fisher′s exact test. For non-normal distribution continuous variables, the difference between two groups variation was performed by using Mann-Whitney U test, and for normal distribution continuous variables, the difference was by the Independent Samples t-test.Results:The positive rates of fever, hepatomegaly and splenomegalyand the motrtality in IAHLH were 100% (24/24), 63% (15/24), 92% (22/24) and 46% (11/24), respectivelyin non-HLH were 55%(11/20),0(0/20),25% (5/20),0(0/20),and the differences between two groups were all statistically significant( P<0.01), but thedifferences between groups with and without HPC and between IAHLH patients with HPC-2 or only with HPC-1 were no statistically significanlly, ( P>0.05).In IAHLH group, IFN-γ in patients with HPC-2 was 400(246, 532)ng/L, significantly higher than 146(38, 180)ng/L in patients only with HPC-1 [ P=0.02, 95% CI was 233(75.8 to 397)], andthe other test parameters and cytokines level showed no obvious differences ( P>0.05).

Clinical analysis of seven cases of hemophagocytic lymphohistiocytosis secondary to cutaneous T-cell lymphoma / 中华皮肤科杂志

Objective:To investigate clinical and laboratory characteristics of secondary hemophagocytic lymphohistiocytosis (sHLH) associated with secondary cutaneous T-cell lymphoma (CTCL) .Methods:CTCL patients with clinically suspected sHLH were collected from Department of Hematology, Wuhan No.1 Hospital from January 2016 to October 2021, and were evaluated according to the HLH-2004 diagnostic criteria and HScore.Results:Seven CTCL patients were confirmedly diagnosed with sHLH, including 2 with primary cutaneous γδT-cell lymphoma (PC-GDTCL) , 3 with cutaneous extranodal natural killer/T-cell lymphoma (C-ENKTCL) , and 2 with primary cutaneous anaplastic large cell lymphoma (PC-ALCL) . All the 7 patients received chemotherapy, but 6 died finally, and the median overall survival duration was 26.5 days (range: 14 - 60 days) after the confirmed diagnosis of CTCL complicated by sHLH. HLH-related gene mutations, which were located in the PRF1 and LYST genes, were identified in 2 patients; lymphoma-related gene mutations were identified in the KRAS and KMT2D genes in 1 PC-GDTCL patient,and in the JAK3 and SAMHD1 genes in another PC-GDTCL patient.Conclusions:CTCL complicated by sHLH usually progresses rapidly, so early diagnosis and treatment are needed. Bone marrow biopsy and mutation screening of lymphoma- and HLH-related genes at initial diagnosis and during disease progression may facilitate early diagnosis.

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.

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.

Adult hemophagocytic syndrome with mutations in UNC13D and MYO5A genes: a case report and literature review / 中国综合临床

Objective:To explore the pathogenesis of primary hemophagocytic syndrome with UNC13D and MYO5A gene mutations.Methods:A case of adult hemophagocytic syndrome with gene mutation of UNC13D and MYO5A admitted to The 940th Hospital of the Joint Logistic Support Force of the PLA on January 28, 2022 was retrospectively analyzed in terms of laboratory examination, gene atlas of its close relatives and prognosis, and related literature was reviewed.Results:The patient was finally diagnosed with primary hemophagocytic syndrome, and chemotherapy was performed twice with hemophagocytic lymphohistiocytosis(HLH)-2004 regimen. The HLA matching of his cytoplasm was semi-compatible. Considering that his cytoplasm carried blood-macrophage related genes, it was not suitable to be selected as a donor, and there were no other suitable relatives. He was transferred to another hospital for allogeneic hematopoietic stem cell transplantation, but failed to receive allogeneic hematopoietic stem cell transplantation during telephone follow-up, and died.Conclusion:The gene mutation of primary hemophagocytic syndrome is the gold standard for the diagnosis of primary HLH. There may be dual gene inheritance pattern in primary HLH, and the combination of immune disorder caused by viral infection and genetic factors may lead to the pathogenesis of primary HLH.

Clinical features and risk factors for secondary hemophagocytic lymphohistiocytosis in elderly patients with severe SARS-CoV-2 infection: a multicenter retrospective cohort study / 中华危重病急救医学

Objective:To explore the incidence of secondary hemophagocytic lymphohistiocytosis (sHLH) in elderly patients with severe SARS-CoV-2 infection, and to analyze and summarize its clinical features and risk factors for early identification of high-risk groups.Methods:A retrospective cohort study was conducted. From January to May 2020, No. 960 Hospital of People's Liberation Army, the Second Hospital Affiliated to Cheeloo College of Medicine of Shandong Province, the First Rehabilitation Hospital of Shandong Province, the Public Health Clinical Center Affiliated to Shandong University, and Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine received 248 patients over 60 years old who were diagnosed with severe SARS-CoV-2 infection during their assistance to Hubei or support for diagnosis and treatment of SARS-CoV-2 infection in Shandong Province. The clinical data of patients were collected. According to the hemophagocytic lymphohistiocytosis diagnosis scoring (HScore) criteria, the patients were divided into sHLH group (HScore > 169) and non-sHLH group (HScore < 98). The demographic data, clinical features, laboratory results, the proportion of organ failure and 60-day mortality of patients were collected and compared between the two groups. The risk factors of sHLH and 60-day death were evaluated through binary multivariate Logistic regression analysis in elderly patients with severe SARS-CoV-2 infection. The receiver operator characteristic curve (ROC curve) was plotted to analyze the diagnostic value of indicators only or combined for sHLH.Results:Among 248 elderly patients with severe SARS-CoV-2 infection, 82 patients with incomplete data and untraceable clinical outcomes, and 35 patients with HScore of 98-169 were excluded. Finally, 131 patients were enrolled in the final follow-up and statistics, including 25 patients in the sHLH group and 106 patients in the non-sHLH group. Compared with the non-sHLH group, plasma albumin (ALB), hemoglobin (Hb), lymphocyte count (LYM), platelet count (PLT), fibrinogen (Fib) and prealbumin (PAB) in the sHLH group were significantly reduced, while alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), MB isoenzyme of creatine kinase (CK-MB), serum creatinine (SCr), C-reactive protein (CRP), D-dimer, ferritin (Fer), lactate dehydrogenase (LDH), procalcitonin (PCT), cardiac troponin I (cTnI), triglycerides (TG), interleukin-6 (IL-6), total bilirubin (TBil) were significantly higher. The fever and fatigue in the sHLH group were more severe than those in the non-sHLH group, and the patients in the sHLH group had higher rates of shock, acute kidney injury, liver dysfunction, and cardiac injury than the non-sHLH group. The 60-day mortality of patient in the sHLH group was significantly higher than that in the non-sHLH group [84.0% (21/25) vs. 40.6% (43/106), P < 0.01]. Binary multivariate Logistic regression analysis showed that high Fer [odds ratio ( OR) = 0.997, 95% confidence interval (95% CI) was 0.996-0.998], D-dimer ( OR = 0.960, 95% CI was 0.944-0.977), LDH ( OR = 0.998, 95% CI was 0.997-0.999) and TG ( OR = 0.706, 95% CI was 0.579-0.860) were independent risk factors for sHLH in elderly patients with severe SARS-CoV-2 infection (all P < 0.01), while elevated Fer ( OR = 1.001, 95% CI was 1.001-1.002), LDH ( OR = 1.004, 95% CI was 1.002-1.005) and D-dimer ( OR = 1.036, 95% CI was 1.018-1.055) were independent risk factors for 60-day death of patients (all P < 0.01). The death risk of the sHLH patients was 7.692 times higher than that of the non-sHLH patients ( OR = 7.692, 95% CI was 2.466-23.987, P = 0.000). ROC curve analysis showed that a three-composite-index composed of LDH, D-dimer and TG had good diagnostic value for sHLH in elderly patients with severe SARS-CoV-2 infection [area under the ROC curve (AUC) = 0.920, 95% CI was 0.866-0.973, P = 0.000]. Conclusions:Elderly patients with severe SARS-CoV-2 infection complicated by sHLH tend to be critically ill and have refractory status and worse prognosis. High Fer, LDH, D-dimer and TG are independent risk factors for sHLH, and are highly suggestive of poor outcome. The comprehensive index composed of LDH, D-dimer and TG has good diagnostic value, and can be used as an early screening tool for sHLH in elderly patients with severe SARS-CoV-2 infection.

Progress of ruxolitinib in the treatment of hemophagocytic lymphohistiocytosis / 国际儿科学杂志

Hemophagocytic lymphohistiocytosis (HLH) is a rare immune-mediated disorder characterized by hyperactivation of antigen-presenting cells and T cells, massive secretion of inflammatory cytokines, and impaired function of natural killer cells and CD8 + T cells.Ruxolitinib is a Januse kinase(JAK)inhibitor that reduces cytokine release and retards the inflammatory response by competitive binding to the JAK catalytic site, to achieve the goal of curing HLH.In recent years, ruxolitinib has been gradually applied in the treatment of HLH, and its effectiveness has also been verified.However, studies have also found that there are efficacy differences in the treatment of HLH caused by different etiologies.This article reviews the mechanism of ruxolitinib in the treatment of HLH and the differences in the efficacy of ruxolitinib in the treatment of HLH of different etiologies.

Progress of X-linked inhibitor of apoptosis deficiency in hemophagocytic lymphohistiocytosis / 国际儿科学杂志

Hemophagocytic lymphohistiocytosis(HLH)is a systemic hyperinflammation syndrome.XIAP deficiency is an innate immunodeficiency disorder, often combined with HLH, with increased susceptibility to EB virus, mostly in childhood.XIAP deficiency leads to innate immune deficiency, increased apoptosis, and excessive activation of NLRP3 inflammasome, which together lead to impaired clearance of pathogens and excessive release of cytokines, resulting in HLH.The course of HLH in patients with XIAP deficiency is generally mild and the mortality rate is low, but it frequently relapses.In addition to HLH, XIAP deficiency can be combined with some auto-inflammatory disease.Hematopoietic stem cell transplantation is the only curable method and reduced-intensity conditioning is recommended.Some new targeted therapies, such as IFN-γ monoclonal antibodies, IL-18 and IL-6 antagonists may be effective, but the specific efficacy needs more study.

Analysis of clinical characteristics of early death in adult patients with hemophagocytic syndrome / 白血病·淋巴瘤

Objective:To explore the clinical characteristics of early death in adult patients with hemophagocytic syndrome (HPS).Methods:The clinical data of 53 adult HPS patients in Xianning Central Hospital, Huangshi Central Hospital and Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology from September 2016 to November 2021 were retrospectively analyzed, and the patients were grouped according to whether they died within 28 d after diagnosis. The clinical characteristics of the two groups were compared. A multivariate analysis of patients' death within 28 d was performed using logistic regression.Results:In 53 adult HPS patients, the mortality rate within 28 d was 28.3% (15/53). The survival time of patients was related to white blood cell count ( r = 0.324, P = 0.018), total bilirubin level ( r = -0.280, P = 0.042) and albumin level ( r = 0.281, P = 0.042), but there was no linear causality (all P > 0.05). When compared between the death within 28 d group and the non-death within 28 d group, the differences in patients' age, platelet count, albumin level, creatine kinase isoenzyme level, triacylglycerol level, ferritin level, and central nervous system involvement were statistically significant (all P < 0.05). Multivariate logistic regression analysis showed that platelet count <30×10 9/L, albumin <30 g/L, central nervous system involvement, and ferritin ≥10 000 ng/ml were independent risk factors for patients' death within 28 d (all P < 0.05). Conclusions:In adult HPS patients, assessing the risk of early death based on ferritin level, platelet count, albumin level, and neurological symptoms, actively correcting internal environmental disturbances, and enhancing organ support therapy can contribute to survival benefit.

Analysis of High-Risk Clinical Factors of Early Death in Secondary Hemophagocytic Lymphohistiocytosis / 中国实验血液学杂志

OBJECTIVE@#To explore the high-risk clinical factors of early death in patients with secondary hemophagocytic lymphohistiocytosis (sHLH), and further identify the clinical factors related to the rapid progression of sHLH in the short term.@*METHODS@#The clinical manifestations, laboratory examination and prognosis of sHLH patients were retrospectively analyzed. Continuous variables were grouped by median, univariate and multivariate Cox regression analysis and Kaplan-Meier survival curve were used to explore the risk factors affecting early death of sHLH. Then, a nomogram model was established with independent risk factors, Bootstrap resampling method was used for verification, and consistency index (C-index) and calibration curve were used to detect the prediction accuracy.@*RESULTS@#A total of 126 sHLH patients were enrolled, with a median age of 48.5(16-88) years, including 74 males and 52 females. Fifty-five patients (43.6%) died within 30 days, including 39 males and 16 females. Univariate regression analysis showed that lymphocyte count <0.45×109/L, platelet count (PLT) <39.5×109/L, prothrombin time (PT)≥13.3 s, activated partial thromboplastin time (APTT)≥39.7 s, albumin (ALB) <25.9 g/L, lactate dehydrogenase (LDH)≥811 U/L, creatinine (Cr) ≥67 μmol/L and procalcitonin (PCT)≥0.61 ng/ml were risk factors for death within 30 days in sHLH patients. Multivariate regression analysis showed that lymphocyte count <0.45×109/L, APTT≥39.7 s and ALB <25.9 g/L were independent risk factors for death within 30 days in sHLH patients. A nomogram model was established based on the above three risk factors, its C-index was 0.683, and the calibration chart showed good agreement between the observed and predicted values of sHLH.@*CONCLUSIONS@#Lymphopenia, prolonged APTT, and hypoalbuminemia are risk factors for early death of sHLH patients. Early identification and positive intervention are expected to reduce early mortality in sHLH patients. The nomogram model based on the above risk factors provides a method for clinicians to evaluate sHLH.

Investigation of the relationship between red blood cell distribution width and mortality in patients with hemophagocytic lymphohistiocytosis: a retrospective study

ABSTRACT BACKGROUND: Red blood cell distribution width (RDW) is related to sepsis-related mortality. Hemophagocytic lymphohistiocytosis (HLH) is a syndrome caused by severe infection, tumors, or autoimmunity without a specific diagnosis. OBJECTIVE: To explore the correlation between RDW and mortality in patients with HLH. DESIGN AND SETTING: A retrospective study conducted in a hospital in China. METHODS: A total of 101 inpatients with HLH from January 1, 2017 to December 31, 2021 were divided into non-survivor (n = 52) and survivor (n = 49) groups. A non-parametric test was used to analyze demographic, clinical, and laboratory data between groups. Independent variables with P < 0.05 were analyzed using binary logistic regression to screen out mortality-related variables. Selected variables were subjected to multivariate logistic regression analysis, and those with strong correlations were screened. Receiver operating characteristic (ROC) curves of strongly correlated variables and area under curve (AUC) values were obtained. RESULTS: The APACHE II score, RDW, and platelet (PLT) and fibrinogen (FIB) levels (P < 0.05) different significantly. RDW, PLT, FIB were correlated with mortality. The AUC values of RDW, PLT, and FIB were 0.857, 0.797, and 0.726, respectively. RDW was associated with mortality in patients with HLH (P < 0.01, cut-off value: 16.9). The sensitivity and specificity of predicting mortality were 97.96% and 96.1%, respectively. CONCLUSION: Logistic regression analysis showed a correlation between RDW and patients' mortality. Therefore, RDW can be used to predict mortality in patients with HLH.