Macrophage activation syndrome/hemophagocytic lymphohistiocytosis and Kawasaki disease

Abstract

To the Editor: We read with interest the two recent reports on Hemophagocytic Lymphohistiocytosis (HLH) associated with Kawasaki disease (KD) [1,2]. Both are inflammatory conditions and clinical features can overlap, to the point that in one of the two reported cases [1] the diagnosis was uncertain.In patients with rheumatologic disorders, particularly systemic onset Juvenile Idiopathic Arthritis, macrophage activation syndrome (MAS) is sometimes seen. MAS is a systemic inflammatory disorder caused by uncontrolled histiocytic proliferation, hemophagocytosis, activation of macrophages and inflammatory cytokine up-regulation. It can be secondary to several rheumatic diseases, including Kawasaki disease [3][4][5]. It is thought that reactive HLH and MAS may represent the same disorder [6][7][8].We recently diagnosed with KD a patient who at the onset of disease also presented findings suggestive of MAS and would like to add our recent experience. A 20-month-old female presented with a history of fever for 6 days unresponsive to antibiotic treatment. Upon admission she was pale and restless; clinical evaluation showed bilateral conjunctivitis, a diffuse maculopapular rash, oral mucosal changes, and edema of the extremities. Laboratory investigations showed elevation of C-reactive protein (16.3 mg/L) but normal erythrocyte sedimentation rate, hemoglobin of 10.6 g/dl, platelet count 59,000/l, hyponatremia (133 mEq/L), and elevated AST/ALT (185 and 64 UI/L, respectively). Infections were ruled out. Abdominal ultrasound showed splenomegaly, an abdominal effusion and hydrops of the gallbladder, while echocardiography showed abnormalities of all coronary arteries (with brightness of the left and dilatation of the anterior and right vessels) and a pericardial effusion. Diagnosis of KD was made and treatment with IVIG (2 g/kg) performed. Despite treatment she remained febrile and irritable. Laboratory tests showed further increase of C-reactive protein and liver function tests, hypoalbunimenia, persistent thrombocytopenia, as well as increased levels of d-dimers (2076 mg/dl, n.v. 50-250 ng/ml), lactate dehydrogenase, cholesterol, triglycerides, and ferritin. A second course of IVIG was then administered, with resolution of fever and reduction of laboratory abnormalities and coronary dilatations. The child was discharged 7 days after admission and was subsequently followed, up to complete recovery.Although bone marrow aspiration showing hemophagocytosis was not performed, even if she did not fulfill classical HLH criteria, on the basis of clinical and laboratory findings we diagnosed MAS [9]. Apart from nomenclature issues, we think that a practical point is represented by treatment decisions, in that MAS is usually treated with high steroids +/− cyclosporine only, while HLH is initially treated with more potent medications including etoposide [1]. At least some secondary (reactive) cases appear not to need chemotherapy but can be treated with standard high-dose immunosuppression only [10].In conclusion, KD can present with c...

2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative

“…Macrophage activation syndrome (MAS) is the term used to describe a potentially life-threatening complication of systemic inflammatory disorders, which occurs most commonly in systemic juvenile idiopathic arthritis (JIA) and in its adult equivalent, adult-onset Still's disease (1)(2)(3)(4), although its occurrence in patients with other autoimmune or autoinflammatory conditions, i.e., adult-and childhood-onset systemic lupus erythematosus (5,6), Kawasaki disease (7,8), and periodic fever syndromes (9,10), is being reported with increased frequency. MAS is characterized by an overwhelming inflammatory reaction due to an uncontrolled and dysfunctional immune response involving the continual activation and expansion of T lymphocytes and macrophages, which results in massive hypersecretion of proinflammatory cytokines (11,12).…”

A Child With Epstein-Barr Virus-associated Hemophagocytic Lymphohistiocytosis Complicated by Coronary Artery Lesion Mimicking Kawasaki Disease

“…In short, HLH was interpreted as secondary disease induced by KD. 4,5,[7][8][9][10] In contrast, Titze et al 6 reported on the patient who had either HLH secondary to KD, or both as a result of a yet unknown common triggering mechanism. In fact, a number of immunological alterations reported in KD, most of which overlap with HLH, suggest a similar pathophysiology for these conditions, that is, serum levels of IL-6, IL-8, TNF-a, and sIL-2R are found to be elevated in both HLH and KD.…”

“…3 Thus, HLH and KD seem to share the similar pathogenesis and several cases with KD preceding HLH have been reported. [4][5][6][7][8][9][10] We here firstly report a pediatric case of HLH associated with Epstein-Barr virus (EBV-HLH), which fulfilled the diagnostic criteria of KD including the typical complication of CAL, and which also demonstrated increased serum levels of proinflammatory cytokines previously reported in both HLH and KD.…”

2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis

“…Macrophage activation syndrome (MAS) is the term used to describe a potentially life-threatening complication of systemic inflammatory disorders, which occurs most commonly in systemic juvenile idiopathic arthritis (JIA) and in its adult equivalent, adult-onset Still's disease,1–4 although its occurrence in patients with other autoimmune or autoinflammatory conditions, that is, adult-onset and childhood-onset systemic lupus erythematosus,5 6 Kawasaki disease7 8 and periodic fever syndromes,9 10 is being reported with increased frequency. MAS is characterised by an overwhelming inflammatory reaction due to an uncontrolled and dysfunctional immune response involving the continual activation and expansion of T lymphocytes and macrophages, which results in massive hypersecretion of proinflammatory cytokines 11 12…”