• DIC
• sepsis
• thrombocytopenia

• chemotherapy
• immunotherapy
• macrophages
• malignancy
• thrombocytopenia

• Humans
• Interleukin 1 Receptor Antagonist Protein/pharmacokinetics
• Interleukin 1 Receptor Antagonist Protein/administration & dosage
• Critical Illness/therapy
• Extracorporeal Membrane Oxygenation/methods
• Child
• Models, Biological
• Child, Preschool
• Adolescent
• Male
• Female
• Infant
• Continuous Renal Replacement Therapy/methods
• Computer Simulation

• 1R01HD097775 Foundation for the National Institutes of Health

• COVID-19
• HIV
• HLH
• SARS-CoV-2

• Autopsy
• Bone Marrow Diseases
• COVID-19
• LYMPH NODES

• Humans
• COVID-19/pathology
• COVID-19/complications
• Male
• Autopsy
• Female
• Middle Aged
• Lymph Nodes/pathology
• Aged
• Bone Marrow/pathology
• Lymphohistiocytosis, Hemophagocytic/pathology
• Lymphohistiocytosis, Hemophagocytic/virology
• Lymphohistiocytosis, Hemophagocytic/diagnosis
• Aged, 80 and over
• Adult
• SARS-CoV-2

• HLH
• HSV 1 and 2
• epidemiology
• mortality

• Anakinra
• Cytokine storm syndrome
• IL-1 receptor antagonist
• IL-18 binding protein
• Interleukin-1 (IL-1)
• Interleukin-1 receptor-like 1
• Interleukin-18 (IL-18)
• Interleukin-33 (IL-33)
• Macrophage activation syndrome
• Secondary hemophagocytic lymphohistiocytosis

• Humans
• Cytokine Release Syndrome/immunology
• Cytokine Release Syndrome/drug therapy
• Interleukin-1/antagonists & inhibitors
• Interleukin-1/immunology
• Interleukin-1/genetics
• Interleukin-1/metabolism
• Animals
• Interleukin 1 Receptor Antagonist Protein/therapeutic use
• Interleukin 1 Receptor Antagonist Protein/genetics
• Calcium-Binding Proteins/genetics
• Interleukin-18/genetics
• Interleukin-18/immunology
• Macrophage Activation Syndrome/immunology
• Macrophage Activation Syndrome/drug therapy
• Macrophage Activation Syndrome/genetics
• Lymphohistiocytosis, Hemophagocytic/immunology
• Lymphohistiocytosis, Hemophagocytic/genetics
• Lymphohistiocytosis, Hemophagocytic/drug therapy
• CARD Signaling Adaptor Proteins

• anakinra
• continuous renal replacement therapy
• ex vivo
• pharmacokinetics

• R01 HD097775 NICHD NIH HHS

• Hemophagocytic lymphohistiocytosis
• Immune system
• National inpatient sample
• Treatment

• Humans
• Adult
• Time-to-Treatment
• Lymphohistiocytosis, Hemophagocytic/epidemiology
• Lymphohistiocytosis, Hemophagocytic/therapy
• Lymphohistiocytosis, Hemophagocytic/complications
• Multiple Organ Failure/epidemiology
• Multiple Organ Failure/etiology
• Multiple Organ Failure/therapy
• Hospitals
• Hospitalization

• Cancer epidemiology
• Haemophagocytic lymphohistiocytosis
• National Inpatient Sample

• HLH
• LAHS
• hemophagocytic lymphohistiocytosis
• hemophagocytosis
• mHLH
• ruxolitinib

• anakinra
• fever of unknown origin
• hemophagocytic lymphohistiocytosis
• postpartum fevers

• K23 HL148310 NHLBI NIH HHS

• COVID-19
• immune system
• post-COVID-19 syndrome
• systemic inflammatory syndrome

• Humans
• COVID-19/complications
• SARS-CoV-2
• Post-Acute COVID-19 Syndrome
• Pandemics
• Risk Factors

Immune checkpoint inhibitors avoid inhibition of T-cell responses, upregulating antitumor immune response. Moreover, a dysregulation with hyperactive immune response can be caused, some of them underdiagnosed. Hemophagocytic lymphohistiocytosis is a rare and often fatal syndrome of uncontrolled and ineffective hyperinflammatory response that triggers an inflammatory cascade that can lead in many cases to death.

We report the case of a 67-year-old Caucasian man with stage IV lung adenocarcinoma who developed hemophagocytic lymphohistiocytosis after initiation of atezolizumab, an antagonist of programmed death-ligand 1. Even with early diagnosis and proper treatment, death occurs in approximately half of all cases reported.

Key markers are needed to better identify patients at risk of developing severe immune-related adverse events. In addition to key markers, a higher degree of suspicion and early intervention are needed to improve outcomes in acquired hemophagocytic lymphohistiocytosis, especially with the increasingly and expanding use of immune activation.

• HLH
• ICI
• IrAE
• Pharmacovigiliance

• adult onset Still’s disease
• anakinra
• cytokines
• hemophagocytic lymphohistiocytosis
• immunotherapy
• inflammatory mediators
• interleukin-1

• hemophagocytic lymphohistiocytosis
• macrophage activation syndrome

• Humans
• Child
• Macrophage Activation Syndrome/drug therapy
• Macrophage Activation Syndrome/diagnosis
• Lymphohistiocytosis, Hemophagocytic/therapy
• Retrospective Studies
• C-Reactive Protein
• Biomarkers

• K08 AR073339 NIAMS NIH HHS
• K12 HD052896 NICHD NIH HHS
• P30 AR070253 NIAMS NIH HHS
• T32 AI007512 NIAID NIH HHS

Anti-cytokine therapies have been gaining attention as a means of improving outcomes in adult secondary HLH (asHLH), which currently has poor outcomes when treated with standard etoposide-based therapies. Anakinra is an interleukin-1 antagonist that is increasingly being used in the management of asHLH. Here is described a multi-hospital series of 16 adult patients with secondary HLH treated with anakinra. Provoking factors of secondary HLH included hematologic malignancy (n = 7, 44%), bacterial infection (n = 7, 44%), viral infection (n = 5, 31%), rheumatologic disorder (n = 4, 25%), and unknown (n = 1, 6%). Five patients remained alive at time of last follow-up (OS = 31%). Median OS was 1.7 months from initiation of anakinra (range 0.2–59). OS among patients with rheumatologic causes of secondary HLH was 75%, whereas only 17% of patients with other provoking factors survived (p = 0.0293). Anakinra was well tolerated, with only 1 patient experiencing associated toxicity (grade 3 liver injury). Anakinra may be useful in the management of asHLH provoked by rheumatologic conditions, although its benefit in asHLH provoked by other factors may be limited.

• Adult HLH
• Anakinra
• Anti-cytokine therapy
• HLH
• Secondary HLH

• Bone marrow biopsy
• Hemophagocytic lymphohistiocytosis
• Living patient
• Post COVID-19
• SARS-CoV-2
• Trephine biopsy

• Aged, 80 and over
• Biopsy/adverse effects
• Bone Marrow/pathology
• COVID-19/complications
• Humans
• Leukocytosis/complications
• Leukocytosis/pathology
• Lymphohistiocytosis, Hemophagocytic/complications
• Lymphohistiocytosis, Hemophagocytic/etiology
• Male
• SARS-CoV-2

• COVID-19
• bone
• bone marrow

• Autopsy
• Bone Marrow/pathology
• COVID-19/complications
• Humans
• Lymphohistiocytosis, Hemophagocytic/diagnosis
• Lymphohistiocytosis, Hemophagocytic/pathology
• Multiple Organ Failure/pathology

• Instituto de Salud Carlos III co-financed by the European Development Regional Fund. ‘A way to achieve Europe’ (FEDER)
• Instituto de Salud Carlos III- CIBERONC
• IRYCIS

• HES
• HLH
• ONS
• epidemiology

To investigate whether a simplified inflammation-based risk scoring system comprising three readily available biomarkers (albumin, C-reactive protein, and leukocytes) may predict major adverse outcomes in patients with COVID-19.

Upon admission to the emergency room, the inflammation-based risk scoring system was applied and patients were classified as having mild, moderate, or severe inflammation. In-hospital occurrence of thrombosis, need for mechanical ventilation, and death were recorded.

One-hundred patients (55 ± 13 years; 71% men) were included and classified as having mild (29%), moderate (12%), or severe (59%) inflammation. The need for mechanical ventilation differed among patients in each group (16%, 50%, and 71%, respectively; P < 0.0001), yielding a 4.1-fold increased risk of requiring mechanical ventilation in patients with moderate inflammation and 5.4 for those with severe inflammation. On the contrary, there were no differences for the occurrence of thrombosis (10%, 8%, and 22%, respectively; P = 0.142) or death (21%, 42%, and 39%, respectively; P = 0.106). In the multivariate analysis, only severe inflammation (hazard ratio [HR] = 4.1), D-dimer > 574 ng/mL (HR = 3.0), and troponin I ≥ 6.7 ng/mL (HR = 2.4) at hospital admission were independent predictors of the need for mechanical ventilation.

The inflammation-based risk scoring system predicts the need for mechanical ventilation in patients with severe COVID-19.

• Albumin
• C-reactive protein
• COVID-19
• Inflammation
• Leukocytes
• Mechanical ventilation

• Adult
• Aged
• Biomarkers/blood
• COVID-19/blood
• COVID-19/therapy
• Female
• Fibrin Fibrinogen Degradation Products/analysis
• Hospitalization
• Humans
• Inflammation/blood
• Inflammation/therapy
• Male
• Middle Aged
• Proportional Hazards Models
• Respiration, Artificial
• Risk Factors
• SARS-CoV-2
• Severity of Illness Index
• Troponin I/blood

• COVID-19
• SARS-CoV-2
• acute respiratory distress syndrome

• COVID-19/complications
• COVID-19/genetics
• COVID-19/virology
• Cytokines/biosynthesis
• Cytokines/genetics
• Genome, Viral/genetics
• Humans
• Multiple Organ Failure/complications
• Multiple Organ Failure/genetics
• Multiple Organ Failure/virology
• Respiratory Distress Syndrome/complications
• Respiratory Distress Syndrome/genetics
• Respiratory Distress Syndrome/virology
• SARS-CoV-2/pathogenicity

• adults
• macrophage activation syndrome

• Adult
• Arthritis, Juvenile
• Child
• Humans
• Lupus Erythematosus, Systemic
• Macrophage Activation Syndrome/diagnosis
• Macrophage Activation Syndrome/etiology
• Retrospective Studies

• JT and Margaret Talkington Endowment

• Coronavirus disease 2019 (COVID-19)
• cytokine release syndrome
• cytokine storm syndrome
• hemophagocytic lymphohistiocytosis
• hyperinflammation

• COVID-19/blood
• COVID-19/mortality
• COVID-19/prevention & control
• COVID-19/therapy
• Cytokine Release Syndrome/blood
• Cytokine Release Syndrome/mortality
• Cytokine Release Syndrome/prevention & control
• Cytokine Release Syndrome/therapy
• Cytokines/blood
• Humans
• SARS-CoV-2/metabolism
• Therapies, Investigational

• T32 AR048522 NIAMS NIH HHS
• T32 GM007309 NIGMS NIH HHS
• T32 GM136577 NIGMS NIH HHS

• COVID-19
• IL-6
• JAK
• SARS-CoV-2
• STING
• TNF-α
• cytokine storm
• cytokines
• hemophagocytic lymphohistiocytosis
• hyperinflammatory
• proinflammatory
• sepsis

• Betacoronavirus
• COVID-19
• Coronavirus Infections/immunology
• Coronavirus Infections/therapy
• Cytokine Release Syndrome/immunology
• Cytokine Release Syndrome/virology
• Humans
• Immunomodulation
• Interleukin-6/immunology
• Pandemics
• Pneumonia, Viral/immunology
• Pneumonia, Viral/therapy
• SARS-CoV-2
• Sepsis/immunology

• P50 GM115305 NIGMS NIH HHS
• R01 AI152183 NIAID NIH HHS
• R01 HG010863 NHGRI NIH HHS
• R21 AI139021 NIAID NIH HHS

• SARS-CoV-2
• corticosteroids
• disease-modifying anti-rheumatic drugs
• hyperferritinaemia
• immunotherapy
• rheumatology

• CART
• CRS
• chimeric antigen receptor
• immunotherapy
• neurotoxicity

• Animals
• Biomarkers
• Cytokine Release Syndrome/diagnosis
• Cytokine Release Syndrome/etiology
• Cytokine Release Syndrome/prevention & control
• Cytokine Release Syndrome/therapy
• Disease Management
• Disease Susceptibility
• Humans
• Immunotherapy, Adoptive/adverse effects
• Immunotherapy, Adoptive/methods
• Neurotoxicity Syndromes/diagnosis
• Neurotoxicity Syndromes/etiology
• Neurotoxicity Syndromes/prevention & control
• Neurotoxicity Syndromes/therapy
• Receptors, Antigen, T-Cell/genetics
• Receptors, Antigen, T-Cell/immunology
• Receptors, Antigen, T-Cell/metabolism
• Receptors, Chimeric Antigen/genetics
• Receptors, Chimeric Antigen/immunology
• Receptors, Chimeric Antigen/metabolism
• T-Lymphocytes/immunology
• T-Lymphocytes/metabolism

• K12 CA090628 NCI NIH HHS

• HLH
• Hemophagocytosis
• JAK/STAT
• JAK1/2 inhibition
• Malaria tropica

Hemophagocytic syndrome (HPS) is characterized by various clinical and biological data derived from cytokine hyperproduction and cell proliferation. The objectives of this study were to evaluate the epidemiological, etiological, clinical and evolutionary characteristics of patients diagnosed with hemophagocytic syndrome and HIV infection, as well as their comparison with data from the literature.

A retrospective descriptive observational study was performed, including all adult patients with a diagnosis of HPS and HIV infection treated in the Infectious Diseases and Tropical Medicine Unit of the Hospital Universitario Insular, Las Palmas, Gran Canaria from June 1, 1998 to December 31, 2018.

An analysis of this series of case reports of 15 patients showed a higher percentage of males than females, with a mean age of 42 years. With respect to the diagnostic criteria for HPS, presence of fever, cytopenias and hyperferritinemia were a constant in all patients. Clinical neurological manifestations were frequent and clinical respiratory signs and symptoms absent. HPS was confirmed in some patients who were not severely immune-depressed and had undetectable viral loads. Furthermore, 40% of cases were not receiving ART. The most frequent triggering causes of HPS were viral, especially HHV-8. In addition, two new HPS triggers were identified: Blastocystis dermatitidis and Mycobacterium chelonae.

Administration of treatment in HPS is arbitrary. This, together with the high mortality rate and the fact that it is underdiagnosed, indicates the importance of conducting future studies.

• Acquired immunodeficiency syndrome
• Antiretroviral therapy
• HIV
• Hemophagocytic syndrome
• Human herpes virus 8

Dysregulation of inflammation is hypothesized to play a crucial role in the severe complications of COVID-19, with the IL-1/IL-6 pathway being central. Here, we report on the treatment of eight severe COVID-19 pneumonia patients—seven hospitalized in intensive care units (ICUs) in Greece and one non-ICU patient in the Netherlands—with the interleukin-1 receptor antagonist Anakinra. All patients scored positive for the hemophagocytosis score (HScore) and were diagnosed with secondary hemophagocytic lymphohistocytosis (sHLH) characterized by pancytopenia, hyper-coagulation, acute kidney injury, and hepatobiliary dysfunction. At the end of treatment, ICU patients had less need for vasopressors, significantly improved respiratory function, and lower HScore. Although three patients died, the mortality was lower than historical series of patients with sHLH in sepsis. These data suggest that administration of Anakinra may be beneficial for treating severe COVID-19 patients with sHLH as determined by the HScore, and they support the need for larger clinical studies to validate this concept.

•

Anakinra treatment was administered to eight severe COVID-19 patients

• Anakinra
• COVID-19
• HScore
• SARS-CoV-2
• ferritin
• hemophagocytic lymphohistocytosis
• pneumonia
• respiratory function

Macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH) are increasingly recognized as being on a continuum of cytokine storm syndromes, with different initiating pathways culminating in cytotoxic dysfunction and uncontrolled activation and proliferation of T lymphocytes and macrophages. The activated immune cells produce large amounts of proinflammatory cytokines, including interleukin 1β (IL)‐1β. Management depends on the recognized diagnosis. In the setting of a cytokine storm syndrome and infection, collaborative involvement of specialists, including infectious disease and rheumatology is ideal. Anakinra, a recombinant IL‐1 receptor antagonist, has been used subcutaneously and intravenously in pediatric patients and is considered a first‐line treatment for MAS and secondary HLH (sHLH) among many pediatric rheumatologists. Previous reports of anakinra used in adults for treatment of MAS or sHLH are limited to subcutaneous administration. In this issue, Moneagudo et al. present a series of adult patients with sHLH treated with intravenous anakinra, including patients in whom subcutaneous anakinra was insufficient. As the authors suggest, there is a potential therapeutic use for anakinra in sHLH or the cytokine storm syndrome triggered by COVID19. Trial design will be key, with the patient subpopulation, timing of intervention, and doses tested important.

• haematological cancer
• inflammatory diseases
• graft-versus-host disease

• Hematopoietic Stem Cell Transplantation/adverse effects
• Humans
• Lymphohistiocytosis, Hemophagocytic/diagnosis
• Lymphohistiocytosis, Hemophagocytic/etiology
• Lymphohistiocytosis, Hemophagocytic/therapy

Secondary haemophagocytic lymphohistiocytosis (sHLH) is a rare life-threatening condition mainly associated with underlying infections, malignancies, and autoimmune or immune-mediated diseases.

To analyse all sHLH cases that were diagnosed and managed under real-world circumstances in our department focusing on the treatment schedule and the outcome.

Prospectively collected data from all adult patients fulfilling the criteria of sHLH who diagnosed and managed from January 1, 2010 to June 1, 2018, in our department of the tertiary care university hospital of Larissa, Greece, were analysed retrospectively (n = 80; 52% male; median age: 55 years). The electronic records and/or written charts of the patients were reviewed for the demographic characteristics, clinical manifestations, underlying causes of sHLH, laboratory parameters, treatment schedule and 30-d-mortality rate. Most of patients had received after consent intravenous γ-immunoglobulin (IVIG) for 5 d (total dose 2 g/kg) in combination with intravenous steroid pulses followed by gradual tapering of prednisolone.

Seventy-five patients (94%) reported fever > 38.5 °C, 47 (59%) had liver or spleen enlargement and 76 (95%) had ferritin > 500 ng/mL including 20 (25%) having considerably high levels (> 10000 ng/mL). Anaemia and thrombocytopenia occurred in 72% and leucopoenia in 47% of them. Underlying infections were diagnosed in 59 patients (74%) as follows: leishmaniasis alone in 15/80 (18.9%), leishmaniasis concurrently with Coxiella Burnetti or non-Hodgkin lymphoma in 2/80 (2.5%), bacterial infections in 14/80 (17.5%) including one case with concurrent non-Hodgkin lymphoma, viral infections in 13/80 (16.3%), fungal infections in 2/80 (2.5%), infections by mycobacteria in 1/80 (1.3%) and unidentified pathogens in 12/80 (15%). Seventy-two patients (90%) had received combination treatment with IVIG and intravenous steroids. Overall, sHLH resolved in 76% of patients, 15% died within the first month but 82.5% of patients were still alive 6 mo after diagnosis. Univariate analysis showed older age, anaemia, thrombocytopenia, low fibrinogen, disseminated intravascular coagulation (DIC), and delay of diagnosis as factors that negatively affected remission. However, multivariate analysis showed low platelets and DIC as the only independent predictors of adverse outcome.

sHLH still carries a remarkable morbidity and mortality. Underlying infections were the major cause and therefore, they should be thoroughly investigated in patients with sHLH. Early recognition and combination treatment with IVIG and corticosteroids seem an efficient treatment option with successful outcome in this life-threatening condition.

• Haemophagocytic syndrome
• Haemophagocytic lymphohistiocytosis
• γ-immunoglobulin
• Leishmaniasis
• Ferritin

• fever
• haemophagocytic lymphohistiocytosis
• hyperinflammation
• immune suppression
• interleukin 1

• Cause of Death
• Disease Progression
• Female
• Humans
• Inflammation/complications
• Inflammation/diagnosis
• Inflammation/mortality
• Lymphohistiocytosis, Hemophagocytic/complications
• Lymphohistiocytosis, Hemophagocytic/diagnosis
• Lymphohistiocytosis, Hemophagocytic/drug therapy
• Lymphohistiocytosis, Hemophagocytic/mortality
• Male
• Multiple Organ Failure
• Neoplasms/complications
• Neoplasms/diagnosis
• Neoplasms/mortality
• Prognosis
• Rare Diseases
• Risk Assessment
• Survival Analysis
• Syndrome

• dermatomyositis
• hemophagocytic lymphohistiocytosis
• infection
• interstitial lung disease
• outcome
• polymyositis

Die Hämophagozytische Lymphohistiozytose (HLH), in der Literatur auch Hämophagozytosesyndrom oder Makrophagenaktivierungssyndrom im Rahmen einer rheumatologischen Vorerkrankung, wird auf Intensivstationen aufgrund des sepsisähnlichen Krankheitsbildes in über 70 % der Fälle nicht erkannt. Es wird von einem 30-jährigen, zuvor gesunden Patienten berichtet, der nach einer 3‑monatigen Asien- und Südamerikareise mit unklarem Fieber zunächst auf die infektiologische Normalstation der Charité – Universitätsmedizin Berlin aufgenommen und nach 3 Tagen bei respiratorischer Insuffizienz auf die Intensivstation verlegt wurde. Durch die sofortige HLH-Diagnostik mit Initiierung der spezifischen immunsupprimierenden Therapie mittels Dexamethason, Immunglobulinen und Anakinra konnte der Patient nach insgesamt 14-tägigem Krankenhausaufenthalt vollständig genesen in die Häuslichkeit entlassen werden. Es werden weiterhin aktuelle diagnostische und therapeutische Möglichkeiten diskutiert. Ferritin als entscheidender diagnostischer Marker sollte bei jedem Patienten mit unklarem Organversagen bestimmt werden.

• Ferritin
• Hemophagocytic lymphohistiocytosis
• Hemophagocytic syndrome
• Macrophage activation syndrome
• Sepsis

• Evidence-based guideline
• Hemophagocytic lymphohistiocytosis (HLH)
• Macrophage activation syndrome (MAS)
• Quality improvement research