Differentiating Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis from Other Forms of Hemophagocytic Lymphohistiocytosis

doi:10.1016/j.jpeds.2012.11.081

The Journal of Pediatrics

Volume 162, Issue 6, June 2013, Pages 1245-1251

https://doi.org/10.1016/j.jpeds.2012.11.081 Get rights and content

Objectives

To identify measures distinguishing macrophage activation syndrome (MAS) in systemic juvenile idiopathic arthritis (sJIA) from familial hemophagocytic lymphohistiocytosis (FHL) and virus-associated hemophagocytic lymphohistiocytosis (VA-HLH) and to define appropriate cutoff values. To evaluate suggested dynamic measures differentiating MAS in patients with sJIA from sJIA flares.

Study design

In a cohort of patients referred for evaluation of hemophagocytic lymphohistiocytosis, we identified 27 patients with sJIA and MAS (MAS/sJIA) fulfilling the criteria of the proposed preliminary diagnostic guideline for the diagnosis of MAS in sJIA. Ten measures at diagnosis were compared between the MAS/sJIA group and 90 patients with FHL and 42 patients with VA-HLH, and cutoff values were determined. In addition, 5 measures were analyzed for significant change from before MAS until MAS diagnosis.

Results

Neutrophil count and C-reactive protein were significantly higher in patients with MAS/sJIA compared with patients with FHL and patients with VA-HLH, with 1.8 × 10⁹/L neutrophils (sensitivity 85%, specificity 83%) and 90 mg/L C-reactive protein (74%, 89%) as cutoff values. Soluble CD25 <7900 U/L (79%, 76%) indicated MAS/sJIA rather than FHL/VA-HLH. Platelet (−59%) and white blood cell count (−46%) displayed a significant decrease, and neutrophil count (−35%) and fibrinogen (−28%) showed a trend during the development of MAS. However, a substantial portion of patients had values at diagnosis of MAS within or above the normal range for white blood cells (84%), neutrophils (77%), platelets (26%), and fibrinogen (71%).

Conclusion

Readily available measures can rapidly differentiate between MAS/sJIA and FHL/VA-HLH. The findings substantiate that a decline of measures may facilitate the distinction of MAS from flares of sJIA.

Section snippets

Methods

Patient data were retrieved from the database of the German national HLH study center, to which patients are referred from Germany, Austria, and Switzerland. Patients with rheumatic disease are not routinely reported, but patients are registered if the center is contacted due to uncertainty about the diagnosis and/or treatment of MAS or if MAS is the presenting feature of a condition, such as sJIA. Diagnosis of MAS or HLH was made between 1992 and 2010. Data were obtained at diagnosis before

Characteristics of Patients with MAS and sJIA

The median age at the time of diagnosis of MAS in patients with MAS/sJIA was 10.0 years, and 59% were girls. In 22 of the 27 patients of the cohort, MAS was the first manifestation of sJIA. Arthritis was present initially in 17 and appeared only later in the course of disease in 5 of 22. In 5 patients, MAS manifested in previously diagnosed sJIA. The mean time between manifestation of sJIA and MAS in this subgroup was 5 years (range 0.75-10 years). Acute EBV infection was identified in 3

Discussion

MAS and FHL/VA-HLH share several features that not only comprise the substantial clinical overlap but include genetic and functional abnormalities, such as low perforin expression, perforin, and Munc13-4 sequence variants and reduced NK cytotoxicity.7, 14, 15, 16, 17 However, current treatment recommendations for MAS and FHL/VA-HLH differ substantially.1, 5, 10, 18, 19, 20, 21, 22 Thus, as the main focus of this study, measures were analyzed for their potential to discriminate between MAS in

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Excessive IL-10 and IL-18 trigger hemophagocytic lymphohistiocytosis–like hyperinflammation and enhanced myelopoiesis
2022, Journal of Allergy and Clinical Immunology
Citation Excerpt :
The Dual-tg mice develop symptoms recapitulating an HLH-like disease, meanwhile showing HSPC compartment shifting toward enhanced myelopoiesis. Although lineage biases of the cytopenia presented in HLH are less commonly discussed, higher neutrophil numbers were reported in MAS than pHLH, with the former setting being more rationally represented by the Dual-tg model.59 In other entities of hyperinflammatory diseases, such as severe COVID-19, lineage biases (monocytosis, granulopoiesis, and increased neutrophil-to-lymphocyte ratios) are frequently noted and considered to play critical roles in driving disease pathogenesis.55,60
Hyperinflammation is a life-threatening condition associated with various clinical disorders characterized by excessive immune activation and tissue damage. Multiple cytokines promote the development of hyperinflammation; however, the contribution of IL-10 remains unclear despite emerging speculations for a pathological role. Clinical observations from hemophagocytic lymphohistiocytosis (HLH), a prototypical hyperinflammatory disease, suggest that IL-18 and IL-10 may collectively promote the onset of a hyperinflammatory state.
We aimed to investigate the collaborative roles of IL-10 and IL-18 in hyperinflammation.
A comprehensive plasma cytokine profile for 87 secondary HLH patients was first depicted and analyzed. We then investigated the systemic and cellular effects of coelevated IL-10 and IL-18 in a transgenic mouse model and cultured macrophages. Single-cell RNA sequencing was performed on the monocytes/macrophages isolated from secondary HLH patients to explore the clinical relevance of IL-10/IL-18–mediated cellular signatures. The therapeutic efficacy of IL-10 blockade was tested in HLH mouse models.
Excessive circulating IL-10 and IL-18 triggered a lethal hyperinflammatory disease recapitulating HLH-like phenotypes in mice, driving peripheral lymphopenia and a striking shift toward enhanced myelopoiesis in the bone marrow. IL-10 and IL-18 polarized cultured macrophages to a distinct proinflammatory state with pronounced expression of myeloid cell–recruiting chemokines. Transcriptional characterization suggested the IL-10/IL-18–mediated cellular features were clinically relevant with HLH, showing enhanced granzyme expression and proteasome activation in macrophages. IL-10 blockade protected against the lethal disease in HLH mouse models.
Coelevated IL-10 and IL-18 are sufficient to drive HLH-like hyperinflammatory syndrome, and blocking IL-10 is protective in HLH models.
Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study
2020, The Lancet Rheumatology
A subset of patients with COVID-19 develops a hyperinflammatory syndrome that has similarities with other hyperinflammatory disorders. However, clinical criteria specifically to define COVID-19-associated hyperinflammatory syndrome (cHIS) have not been established. We aimed to develop and validate diagnostic criteria for cHIS in a cohort of inpatients with COVID-19.
We searched for clinical research articles published between Jan 1, 1990, and Aug 20, 2020, on features and diagnostic criteria for secondary haemophagocytic lymphohistiocytosis, macrophage activation syndrome, macrophage activation-like syndrome of sepsis, cytokine release syndrome, and COVID-19. We compared published clinical data for COVID-19 with clinical features of other hyperinflammatory or cytokine storm syndromes. Based on a framework of conserved clinical characteristics, we developed a six-criterion additive scale for cHIS: fever, macrophage activation (hyperferritinaemia), haematological dysfunction (neutrophil to lymphocyte ratio), hepatic injury (lactate dehydrogenase or asparate aminotransferase), coagulopathy (D-dimer), and cytokinaemia (C-reactive protein, interleukin-6, or triglycerides). We then validated the association of the cHIS scale with in-hospital mortality and need for mechanical ventilation in consecutive patients in the Intermountain Prospective Observational COVID-19 (IPOC) registry who were admitted to hospital with PCR-confirmed COVID-19. We used a multistate model to estimate the temporal implications of cHIS.
We included 299 patients admitted to hospital with COVID-19 between March 13 and May 5, 2020, in analyses. Unadjusted discrimination of the maximum daily cHIS score was 0·81 (95% CI 0·74–0·88) for in-hospital mortality and 0·92 (0·88–0·96) for mechanical ventilation; these results remained significant in multivariable analysis (odds ratio 1·6 [95% CI 1·2–2·1], p=0·0020, for mortality and 4·3 [3·0–6·0], p<0·0001, for mechanical ventilation). 161 (54%) of 299 patients met two or more cHIS criteria during their hospital admission; these patients had higher risk of mortality than patients with a score of less than 2 (24 [15%] of 138 vs one [1%] of 161) and for mechanical ventilation (73 [45%] vs three [2%]). In the multistate model, using daily cHIS score as a time-dependent variable, the cHIS hazard ratio for worsening from low to moderate oxygen requirement was 1·4 (95% CI 1·2–1·6), from moderate oxygen to high-flow oxygen 2·2 (1·1–4·4), and to mechanical ventilation 4·0 (1·9–8·2).
We proposed and validated criteria for hyperinflammation in COVID-19. This hyperinflammatory state, cHIS, is commonly associated with progression to mechanical ventilation and death. External validation is needed. The cHIS scale might be helpful in defining target populations for trials and immunomodulatory therapies.
Intermountain Research and Medical Foundation.
Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome
2018, Blood
Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4^T337S mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4^T337S-induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4^T337S intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-γ–induced genes. Assessing cellular and tissue expression, classical inflammasome components such as Il1b, Nlrp3, and Mefv predominated in neutrophils, whereas Nlrc4 and Il18 were distinctly epithelial. Demonstrating the importance of free IL-18, Il18 transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4^T337S mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18–driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS.
Development and Initial Validation of the Macrophage Activation Syndrome/Primary Hemophagocytic Lymphohistiocytosis Score, a Diagnostic Tool that Differentiates Primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome
2017, Journal of Pediatrics
Citation Excerpt :
Aspartate aminotransferase and bilirubin did not discriminate well between the 2 conditions. Our results are similar to those reported by Lehmberg et al39 in a smaller sample. They found that higher neutrophil count and C-reactive protein and lower soluble CD25 indicated MAS rather than pHLH.
To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis.
The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples.
Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from <1% for a score of <11 to >99% for a score of ≥123. A cutoff value of ≥60 revealed the best performance in discriminating pHLH from MAS.
The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing.
Primary Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome: The Importance of Timely Clinical Differentiation
2017, Journal of Pediatrics
Similar but not the same: Differential diagnosis of HLH and sepsis
2017, Critical Reviews in Oncology/Hematology
Citation Excerpt :
In HLH it is associated with plasminogen activator released by macrophages (plasmin cleaves fibrinogen) (Janka, 2007a). In one study HLH was accompanied by coagulopathy in almost 95% (Palazzi et al., 2003) of pediatric patients, with a median fibrinogen concentration of 105 mg/dl; values from other studies ranged from 72 to 193 (Lehmberg et al., 2013; Niece et al., 2010; Ramachandran et al., 2011). In other pediatric (Janka and Schneider, 2004; Koh et al., 2015) and adult (Li et al., 2014b; Otrock and Eby, 2015; Parikh et al., 2014; Schram et al., 2016; Wang et al., 2015) groups hypofibrinogenemia was present in only 38–62%, which represents a low sensitivity; however higher percentages of 78–79% were described in other cohorts (Li et al., 2014a; Meeths et al., 2014).
Differential diagnosis of hemophagocytic lymphohistiocytosis (HLH; hemophagocytic syndrome) and sepsis is critically important because the life-saving aggressive immunosuppressive treatment, required in the effective HLH therapy, is absent in sepsis guidelines. Moreover, HLH may be complicated by sepsis. Hyperinflammation, present in both states, gives an overlapping clinical picture including fever and performance status deterioration. The aim of this review is to provide aid in this challenging diagnostic process.
Analysis of clinical features and laboratory results in multiple groups of patients (both adult and pediatric) with either HLH or sepsis allows to propose criteria differentiating these two conditions. The diagnosis of HLH is supported by hyperferritinemia, splenomegaly, marked cytopenias, hypofibrinogenemia, low CRP, characteristic cytokine profile and, only in adults, hypertriglyceridemia. In the presence of these parameters (especially the most characteristic hyperferritinemia), the other HLH criteria should be assessed. Genetic analyses can reveal familial HLH. Hemophagocytosis is neither specific nor sensitive for HLH.

View all citing articles on Scopus

: The authors declare no conflicts of interest.

^∗: Contributed equally.

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Original ArticleDifferentiating Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis from Other Forms of Hemophagocytic Lymphohistiocytosis

Objectives

Study design

Results

Conclusion

Section snippets

Methods

Characteristics of Patients with MAS and sJIA

Discussion

Blood

J Pediatr

An Pediatr (Barc)

J Pediatr

Blood

Lancet

Macrophage activation syndrome and rheumatic disease in childhood: a report of four new cases

Clin Exp Rheumatol

Macrophage activation syndrome in juvenile systemic lupus erythematosus: a multinational multicenter study of thirty-eight patients

Arthritis Rheum

Reactive hemophagocytic syndrome complicating the treatment of inflammatory bowel disease

Inflamm Bowel Dis

Hemophagocytic lymphohistiocytosis and Kawasaki disease: combined manifestation and differential diagnosis

Pediatr Blood Cancer

Reactive haemophagocytic syndrome in children with inflammatory disorders. A retrospective study of 24 patients

Rheumatology (Oxf)

The expanding spectrum of hemophagocytic lymphohistiocytosis

Curr Opin Allergy Clin Immunol

Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society

Leukemia

Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders

Arch Dis Child

HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis

Pediatr Blood Cancer

Original Article
Differentiating Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis from Other Forms of Hemophagocytic Lymphohistiocytosis