Macrophage activation syndrome (MAS)

What is MAS?

Macrophage activation syndrome (MAS) occurs when the immune system is overactivated, leading to severe inflammation in the body.

The immune system is the body’s natural defense system to fight infection. It has many families of cells that work together and send signals to each other to help fight infections. One family of cells is called macrophages, which work by destroying/ingesting infectious cells (e.g., viruses and bacteria). Macrophages communicate with other cells in the immune system, including T cells (or T lymphocytes). Normally, these cells work together in a controlled and coordinated way to fight infection.

In someone with MAS, the immune system is uncontrolled and works in overdrive, leading to too much inflammation in the body. The inflammation can affect any organ, including the bone marrow (which produces the body's blood cells), liver and spleen. This inflammation is very serious and can often make children very ill.

MAS and hemophagocytic lymphohistiocytosis

MAS is classified as part of a group of conditions called hemophagocytic lymphohistiocytosis (HLH). HLH also results in overactivation of the immune system and dangerous inflammation of the body. There are two forms of HLH:

1. Primary HLH, the genetic form (as it is caused by gene abnormalities), usually presents early in life.
2. Secondary HLH, a ‘reactive’ form, usually presents after a trigger (e.g., infection, autoimmune/rheumatic disease or cancers), causing the immune system to stay in a hyperactive state.

MAS is part of the secondary HLH family. Because the treatments of MAS and secondary HLH are similar, your child's health-care provider may mention the term HLH when discussing treatment options for MAS.

A newer term that is often applied to MAS/HLH is "cytokine storm syndrome", which refers to the molecules that keep the inflammation high if the condition is not treated.

Signs and symptoms of MAS

The following symptoms can be associated with MAS:

• continuous fevers (persistent fevers)
• feeling tired and having low energy
• headaches, feeling confused or ‘foggy’ (mental status changes), seizures
  
• large lymph nodes (lymphadenopathy)
• large liver and spleen (hepatosplenomegaly)
• bleeding and clotting problems (coagulopathy) seen by nose bleeds, easy bruising, vomiting blood
• rash
• low blood pressure and fast heart rate
  

Causes of MAS

There is no known single cause of MAS. There are numerous triggers, gene cell types and molecules that are being studied to better understand how and why MAS occurs.

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 are systemic juvenile idiopathic arthritis, systemic lupus erythematosus and Kawasaki disease.

MAS is rare; however, it is more common in people with the rheumatic conditions above. MAS is equally common in females and males and can happen at any age.

Diagnosis of MAS

There is no single test available to make a diagnosis of MAS. There are different sets of criteria that incorporate the symptoms and clinical signs listed above. These are used together with blood work abnormalities and other test results to diagnose MAS.

Blood work abnormalities may include the following:

• decreased values of complete blood counts (CBC)
• hemoglobin or red blood cells (carry oxygen in the blood)
  
• white blood cells (cells that fight infection)
• platelets (cells that help with clotting)
• high markers of inflammation
• CRP, ferritin
  
• high liver markers:
• AST, ALT, GGT, LDH
  
• clotting abnormalities
• high INR, PTT
• low fibrinogen
• high D-Dimer
• lipid/fat abnormalities
  
• high triglycerides, high cholesterol

In addition to looking at the overall levels of these tests, your child’s health-care provider will monitor the trend of these levels. They will check whether the values are increasing or decreasing, by how much and how quickly. As a result, your child may need to have blood work 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. This can also help the health-care team to look at cells that they 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).

Your child's health-care provider may also recommend genetic testing to look at changes in genes that are linked to a higher risk of developing MAS.

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 hospital-based paediatricians.

Treatment of MAS

If your child's health-care team suspects MAS, your child will likely be admitted to hospital for further monitoring and treatment and will remain in hospital until the goals of treatment are met.

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.

Your child's health-care team will use very strong medications to try to stop the immune system overactivity. The medications may include:

• corticosteroids (which work to quiet down the many different parts of the immune system)
• intravenous immune globulin (pooled antibody transfusion)
• anakinra (a biologic therapy that targets a specific inflammation molecule called interleukin-1, which is very active in MAS)
• cyclosporin (a medication that suppresses the immune system's T-cells)
• other therapies including some new biologic therapies that target specific inflammation molecules

Rarely, an anti-cancer drug, etoposide, which has been shown to be useful when treating HLH, may be considered in the most severe cases of MAS. 

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, it is treated very seriously from the onset of symptoms.

Follow-up care

Your child's health-care team will only send your child home from the hospital once they are sure that the inflammation is under control. MAS can recur, so the health-care team will monitor your child closely after discharge. Blood work will be taken frequently following the episode to ensure that the blood values continue to improve.

Once your child is discharged, you will be asked to monitor your child closely for recurrent signs of the disease (fevers, rash, 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.

References

Shakoory B, Geerlinks A, Wilejto M HLH/MAS task force, et al. (2023). The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Annals of the Rheumatic Diseases. 82:1270-1285. Retrieved from: https://ard.bmj.com/content/82/10/1271