The MH Score: Separating primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome

“Sincerity is the key to success. Once you can fake that, you’ve got it made.”

–Groucho Marx

The above quote is not particularly related to this blog post –but I like it.

A recent study (F Minoia et al. J Pediatr 2017; 189: 72-8) provides data supporting a scoring system which helps distinguish primary hemophagocytic lymphohistiocytosis (HLH) from macrophage activation syndrome (MAS).

Background: “By convention, secondary HLH seen in rheumatic disorders is termed macrophage activation syndrome…occurs most commonly in systemic juvenile idiopathic arthritis (sJIA).”  Both HLH and MAS are life-threatening, though HLH tends to be more severe.  The treatment for the two disorders is much different.

HLH typically develops in the first year of life, though some remain asymptomatic until later.  Identification of pathologic mutations (primary HLH is not a single disease) is considered the gold standard, but this “takes weeks to complete and is not available in many resource-limited areas.”

In this study, the authors reviewed clinical features from 362 patients with MAS and 258 patients with HLH to develop a scoring system that more readily distinguished these conditions.The data from 80% of the patients was used to construct the scoring system and then this was validated with the remaining 20%.  MH Score:

  • Age of onset, years:                              0 points if >1.6 yr, 37 points if ≤1.6 yr
  • Neutrophil count, x 10 to the 9th/L:      0 points if >1.4, 37 points if ≤1.4
  • Fibrinogen, mg/dL:                               0 points if >131, 15 points if ≤131
  • Splenomegaly:                                      0 points if no, 12 points if yes
  • Platelet count, x 10 to the 9th/L:           0 points if >78, 11 points if ≤78
  • Hemoglobin, g/dL:                                0 points if >8.3, 11 points if ≤8.3

The age of onset and severe neutropenia are weighted the most heavily as they most heavily influence the odds ratio of having HLH; with multivariate analysis (Table 3), age of onset ≤1.6 yrs had an OR of 40.3, and neutrophil count ≤1.4 had an OR of 39.3.  All of the other parameters had OR between 2.9 and 4.4.  Hepatomegaly favored HLH as well but was not independently associated with the diagnosis.

How to use this scoring system:

  • In this cohort, the MH score ranged from 0 to 123.  The median value was 97 for HLH and 12 for MAS.
  • A cutoff of ≥60 yielded a sensitivity of 91% and specificity of 93% for the diagnosis of HLH.  Higher values increased the probability of HLH further.

Most laboratory studies were more abnormal with HLH; however, both ferritin elevation and LDH elevation were more pronounced with MAS.  Median ferritin was 5353 with MAS and 2910 with HLH.  Median LDH was 1230 with MAS compared with 696 with HLH.

This study validated the MH score for distinguishing HLH from MAS associated with sJIA; this can allow early introduction of aggressive treatment and appropriate genetic/immunologic evaluation.  The applicability of the MH score for distinguishing HLH from other conditions is unclear.  Further prospective evaluation of the MH score is needed.

My take: This is a very helpful study and is likely to influence diagnostic workup and management of these sick patients. Due to the liver and spleen abnormalities, pediatric gastroenterologists need to be able to recognize both HLH and MAS.

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Hemophagocytic Lymphohistioctosis: Advances

A recent medical progress report provides a concise update on hemophagocytic lymphohistiocytosis (HLH) (J Pediatr 2013; 163: 1253-59).

  • Table 1 summarizes the subtypes of HLH.
  • Atypical presentations include colitis and hypogammaglobulinemia.
  • Table 2 provides the diagnostic criteria.
  • The treatment approach is outlined as well.  In the short-term, with primary HLH, the goal is controlling the hyperinflammatory state (often with dexamethasone and etoposide).  The long-term goal aims to definitively correct the underlying genetic defect by allogeneic hematopoietic stem cell transplantation (HCT)

Other points:

  • A genetic diagnosis of familial HLH can be made in 40-80% of HLH cases with the identification of PRF1, UNC13D, STX11, and STXBP2 genes.
  • UNC13D are the predominant defects identified in Caucasians in U.S.
  • PRF1 is most common in African-American patients.
  • Ferritin remains an excellent screening tool.  A level >500 mcg/L is suggestive (but not specific) for HLH; a level >10,000 has much greater specificity (96%) along with fairly high sensitivity (90%).
  • HLH is commonly referred to as macrophage activation syndrome (MAS) in the setting of a rheumatologic illness.
  • There is no broad consensus on management of secondary HLH.  In MAS, therapy often includes pulsed steroids and/or cyclosporine.

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