SNOWMASS, COLO. – Macrophage activation syndrome is a challenging diagnosis whose most useful clues are to be found in the laboratory report.
Suspect the life-threatening diagnosis of macrophage activation syndrome (MAS) in a patient with virtually any form of active rheumatologic disease who becomes acutely ill with a sharp drop in both erythrocyte sedimentation rate and platelet count in the presence of a persistently high C-reactive protein and escalating levels of serum D-dimers, urged Dr. Alexei A. Grom.
Dr. Alexei A. Grom
Another suggestive laboratory feature is marked hyperferritinemia. Patients with MAS often have a serum ferritin level in excess of 10,000 ng/mL, Dr. Grom said at a symposium sponsored by the American College of Rheumatology.
Moreover, while normally 60%-80% of serum ferritin is glycosylated, in MAS it’s typically less than 20%. This makes measurement of serum glycosylated ferritin a useful diagnostic tool, noted Dr. Grom, a pediatric rheumatologist at Cincinnati Children’s Hospital Medical Center.
Assessment of serum levels of soluble CD163 and soluble interleukin-2-receptor-alpha chains can also help pin down the diagnosis. They are strikingly elevated in MAS, and not in many other conditions. Extreme hypertriglyceridemia is another characteristic feature.
The central feature of MAS, he continued, is uncontrolled expansion of cytotoxic CD8 cells secreting cytokines that stimulate macrophages to exhibit hemophagocytic activity.
Indeed, hemophagocytic activity on the part of highly activated macrophages is the hallmark of MAS. Identification of hemophagocytic macrophages in the bone marrow confirms the diagnosis. Unfortunately, often this finding is not present early in the course of the disease.
This macrophage hemophagocytosis explains the extreme hyperferritinemia seen in MAS. Free hemoglobin is released as erythrocytes are phagocytized. This creates a need to boost ferritin production in order to sequestrate the free iron, he explained.
Three cardinal features of the massive systemic inflammatory response that defines MAS are liver dysfunction, cytopenias, and coagulopathy consistent with disseminated intravascular coagulation. However, like hemophagocytic macrophages in the bone marrow, these features often are not of much help in making an early diagnosis. Overt cytopenia is seen only in the late stages of MAS.
Abnormal liver function tests and laboratory evidence of coagulopathy can also occur in a flare of systemic juvenile idiopathic arthritis – and since 80% of pediatric MAS occurs in patients with SJIA, hepatic dysfunction and coagulopathy are not useful in making the distinction.
The clinical presentation of MAS includes persistent fever, impressively enlarged lymph nodes, prominent hepatosplenomegaly, and a hemorrhagic rash featuring bruising, then purpura, followed by mucosal bleeding. Many patients also develop mental status changes and/or seizures. These clinical features can be viewed as largely a consequence of a cytokine storm involving increased interferon-gamma, granulocyte macrophage colony–stimulating factor, tumor necrosis factor-alpha, and interleukin-1, -6, and -18.
No trigger is identifiable in the majority of cases of MAS. When a trigger is found, it is most commonly an infection with Epstein-Barr virus or cytomegalovirus.
MAS has a 10%-20% mortality. The death rate is declining in pediatric patients because of increasing awareness of the syndrome and consequent earlier diagnosis and initiation of treatment.
"I think that in adult rheumatology this condition is still relatively unrecognized. My adult rheumatology colleagues in Cincinnati believe that many of these patients end up with a diagnosis of culture-negative sepsis," Dr. Grom said.
It’s crucial to understand that roughly one-third of patients with MAC will experience recurrent episodes. For this reason, Dr. Grom provides patients with a letter explaining their condition in the event they should have a recurrence while out of town, necessitating a visit to an emergency department where physicians may be MAC inexperienced.
Dr. Grom declared having no relevant financial interests.