Macrophage Activation Syndrome (MAS)Dz

Synonyms:  Hemophagocytic syndrome,  hemophagocytic lymphohistiocytosis (HLH), histiocytic erythrophagocytosis

ICD-9 code:  288.4

ICD-10 codes: Macrophage activation syndrome D76.1;  Hemophagocytic syndrome, infection-associated D76.2

Definition: MAS is a severe, potentially fatal disease characterized by severe systemic inflammation. In the bone marrow and other lymphoid tissue a characteristic finding in hemophagocytosis.

Etiology: MAS relates to abundant inflammation driven by a dysregulated immune response. A small number of cases are familial (primary MAS); various genetic diseases predispose to MAS, including immunodeficiency syndromes (Chediak-Higashi, etc), primary immunodeficiencies (X-linked lympoproliferative disease, X-linked SCID, etc) and other genetic diseases related to proteins that affect perforin. Perforin is relevant to killing by cytotoxic T cells and NK cels, and deficiencies may allow uncontrolled viral replication and subsequent inflammation. Most cases of MAS are acquired (secondary MAS), with many cases caused by autoimmune, infectious, malignant or other conditions that can drive inflammation. Provocative conditions for MAS include autoimmune disorders (SLE, RA, PAN, MCTD, PSS, Sjogrens syndrome, Sarcoidosis), auto inflammatory disorders (systemic-onset JIA, adult-onset Still’s disease), infectious diseases (bacterial, Viral, mycobacterial), and malignant conditions (non-Hodgkins lymphoma). Some cases are idiopathic. The underlying etiologies cary in prevalence between adults and children.

Pathology:  The characteristic finding seen on bone marrow biopsy is histiocytic erythrophagocytosis.

Demographics:  Systemic-onset JIA is the most commonly associated underlying disorder among children, accounting for nearly 80% of cases. MAS may occur in up to 10% of children with systemic-onset JIA. In adults, the most common causes are SLE (~52% ) AOSD (~27%) and various other autoimmune conditions (~ 20%).

Cardinal Features: Common clinical features include: fever (~90%), lymphadenopathy, hepatomegaly, splenomegaly (~40 – 50%). While features of the underlying associated disorder may dominate the clinical picture, MAS is suspected by an acute change in severity in those diseases, heralded by high fevers, hepatosplenomegaly,  and dramatic laboratory findings (see below).

Uncommon Findings: DIC, hemorrhagic coagulopathy.

Labs: Ÿ anemia, pancytopenia, increased hepatocellular enzymes, highly elevatedŸ acute phase reactants (ESR, CRP), increased serum ferritin, coagulopathy. The ESR may however decrease with the onset of MAS among patients with some other inflammatory condition.

Diagnostic Criteria: Diagnosis is complicated by the lack of unique clinical, biologic or pathologic features. Many MAS features overlap with the conditions with which MAS is associated. Several classification criteria have been proposed, but none is widely accepted as of yet.

Keys to Diagnosis:    The diagnosis should suspected based on the onset or worsening of a systemic illness, high fevers, persistently high CRP, increased ferritin, coagulopathy (e.g. increased d-dimer concentrations), coupled with anemia, thrombocytopenia or leukopenia.

Differential Diagnosis:  Sepsis, other causes of DIC, fulminant worsening of the underlying disorder (SLE, AOSD, SoJIA, infection, lymphoma).

Treatment: Early recognition is vital. Aggressive management of the underlying disorder (infection, lupus, etc) should be also addressed. Most patients will require high dose corticosteroids. Cyclosporine A has been utilized in many cases. Other agents that have been used include: IV IgG, cyclophosphamide, etoposide. More recently, there has been interest in trying biologic agents in MAS, including TNF inhibitors, IL-1 inhibitors, and IL-6 inhibitors. However. there are patients who have developed MAS while on these cytokine inhibitors.

Prognosis:  The occurence of MAS alters the mortality risk significantly and may range from approximately 10% (e.g. in children with SoJIA) to 40% or more (e.g. adults with cancers).

Bibliography

Kumakura S, Murakawa Y. Clinical characteristics and treatment outcomes of autoimmune-associated hemophagocytic syndrome in adults. Arthritis Rheum 2014;66:2297-2307. PMID: 24756912

Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HSCore, a score for the daignosis of reactive hemophagocytic syndrome. Arthritis Rheum 2014;66:2613-20. PMID: 24782338

Dhote R, Simon J, Papo T, et al.  Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum. 2003; 49: 633-9,  PMID: 14558048

Atteritano M, David A, Bagnato G, et al. Haemophagocytic syndrome in rheumatic patients. A systematic review. Eur Rev Med Pharmacol Sci. 2012;16:1414-24. PMID: 23104659