Macrophage activation syndrome (MAS)

​​What is MAS/HLH

The immune system is the body’s natural defense system to fight infection. It has several groups/families of cells that work together and send signals to one another to help fight against these infections. One family of cells is called macrophages, which work by destroying/ingesting infectious cells (e.g. viruses and bacteria). Macrophages can also control other cells in the immune system to help fight infection. Another family of cells in the immune system is called T cells (or T lymphocytes), which can send signals to gather and control macrophages to help fight infection as one part of their role in the immune system.

Normally, when the immune system is activated, it fights the infection in a coordinated and controlled manner. In individuals with macrophage activation syndrome (MAS), the immune system is uncontrolled and works in overdrive, leading to too much inflammation in the entire body. The inflammation can be in any organ system including the bone marrow, liver, and spleen. This inflammation is very serious and can often make children very ill - it may also result in organ damage.

MAS is classified as part of a group of conditions called Hemophagocytic Lymphohistiocytosis (HLH for short). HLH also results in over activation of the immune system and dangerous inflammation of the body. There are two forms of HLH. Primary HLH, the genetic form (as it is caused by gene abnormalities), usually presents early in life. Secondary HLH, a ‘reactive’ form, usually presents after a trigger (i.e. infection, autoimmune/rheumatic disease, or cancers) causing the immune system to stay in a hyperactive state. MAS is part of the Secondary HLH family. The treatments of MAS and secondary HLH are similar; therefore your healthcare provider may mention the word HLH when discussing treatment options for MAS.

MAS is equally common in girls and boys, and can happen at any age (even as early as one year old).

Signs and symptoms of MAS

The following symptoms can be associated with MAS:

  • Continuous fevers (persistent fevers)
  • Feeling tired and low energy
  • Headaches, feeling confused or ‘foggy’ (mental status changes)
  • Large lymph nodes (lymphadenopathy)
  • Large liver and spleen (hepatosplenomegaly)
  • Bleeding and clotting problems (coagulopathy) seen by nose bleeds, easy bruising, vomiting blood
  • Rash
  • Changes in blood pressure and heart rate
  • Abnormal functioning of the liver
  • Low blood counts

Causes of MAS

We do not know the exact cause of MAS just yet, but active research is being undertaken. There have been several triggers, genes, and proteins linked to the diseases that are being studied.

MAS can be triggered by infection, cancer, changes in medications, and by rheumatic/autoimmune diseases. Rheumatic/autoimmune disease is when the immune system attacks itself accidentally. The most common rheumatic/autoimmune diseases associated with MAS include systemic lupus erythematosus, systemic juvenile idiopathic arthritis and Kawasaki disease.

In certain cases, your medical team may approach you for genetic testing if your physician thinks MAS/HLH may be of a genetic (inherited) for and wishes to exclude that.

Diagnosis of MAS

There are different diagnostic criteria available for MAS. The symptoms and clinical signs listed above, as well as blood work abnormalities, are taken together to make the diagnosis.

Blood work may include the following:

  • Complete blood counts (CBC)
    • Hemoglobin or Red Blood Cells (Carries oxygen in the blood)
    • White Blood Cells Count (Cells that fight infection)
    • Platelets (Cells that help with clotting)
  • High markers of inflammation
    • CRP, Ferritin to name a few
  • High Liver Markers:
    • AST, ALT, GGT, LDH, Bilirubin (jaundice pigment)
  • Clotting abnormalities
    • High INR, PTT
    • Low Fibrinogen
    • High D-Dimer
  • Lipid/Fat abnormalities

In addition to looking at the overall levels of these tests, your child’s doctor will keep an eye on the direction of these levels – whether they are increasing or decreasing, by how much, and how quickly. Your child’s doctor will monitor these values very closely. As a result, blood work may need to be done quite frequently; potentially even several times in the same day.

Bone marrow aspirate (bone marrow sampling) can also be useful in trying to find diagnoses that could be underlying triggers for MAS, and can help us to look at cells that we know are a part of MAS.

Your child may also need imaging tests to monitor their organs (e.g. X-rays, ultrasound, CT scan or MRI). These additional tests are done on an as needed basis.

Your child will be seen by a team of different specialists who will work together to make this diagnosis; this team may include hematologists, rheumatologists, immunologists, infectious disease specialists, liver disease specialists and their pediatrician, among others.

Treatment of MAS

If your child is suspected of having MAS, they will be admitted to hospital for further monitoring and treatment.

The goals of treatment are to:

  • Reduce body inflammation
  • Stop fevers
  • Prevent organ damage

As mentioned above, your child’s blood work and symptoms will be monitored very closely. Blood tests will be repeated often to see if your child is responding to treatment, and to monitor for side effects of the medications listed below.

Since MAS is a dangerous and potentially fatal disease if not treated, we use very strong medications to try and stop the immune system over-activity. The medications normally used include:

  • Steroids (High dose, usually through an IV initially, and then by mouth)
  • Intravenous immune globulin (pooled antibody transfusion)
  • Cyclosporin (a medication that suppresses the immune system)
  • Biologic therapy (another class of medications that suppress different aspects of the immune system than Cyclosporin does). A common example of this type of medication that we use is called Anakinra (Kineret).

In some cases, an anti-cancer drug, etoposide​ has been shown to be useful when treating HLH, and may be considered in severe cases of MAS. A specialist in MAS/HLH may be consulted to help with the treatment.

Outlook for children with MAS

In recent years, there has been increased awareness of MAS, which means that it is being diagnosed much earlier, and children have been receiving appropriate treatments. As a result, most children recover and experience less organ damage than in the past. However, since it is a serious and potentially fatal condition, we treat it very seriously from the onset of symptoms.

Follow-up care

We will only discharge your child from the hospital once we are sure that the inflammation is under control. MAS has been known to recur, therefore we will monitor your child regularly in clinics after discharge. Blood work will be taken at every visit following the episode to ensure that the blood values continue to improve, and are not showing abnormalities.

Once your child is discharged, you will be asked to monitor your child closely for recurrent signs of the disease (fevers, feeling unwell) and seek prompt medical attention if these occur. Blood tests may be done urgently to determine if there is a recurrence of MAS.

Key Points

  • MAS is severe inflammation of the immune system and is a very serious condition.
  • MAS is usually associated with known rheumatologic conditions, infections, and cancers.
  • MAS, when diagnosed, will be monitored closely and treated aggressively.
  • If treated appropriately, most children respond well to therapy.

Evelyn Rozenblyum MD, FRCPC

Andrea Human MD, FRCPC

Shirley Tse MD, FRCPC

Sheila Weitzman, MB ChB, FRCPC

James Whitlock, MD

Ahmed Naqvi MBBS, MRCP

Rayfel Schneider MBBCH, FRCPC

Ronald Laxer MDCM, FRCPC