Macrophage Activation Syndrome

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.I'm Pradip Kamat and I'm Rahul Damania. We are coming to you from Children's Healthcare of Atlanta - Emory University School of Medicine.Welcome to our Episode of 17-year old with h/o of SLE and now acute liver failure.Here's the case presented by Rahul:A 17-year old teenage female year old presents to the PICU with acute liver failure. Important past h/o includes a diagnosis of SLE on therapy with prednisone, mycophenolate (cellcept), and plaquenil.4 days prior to this admission, patient presented to an OSH with RUQ pain, vomiting (non bloody & no bilious), fever & malaise. Initially due to concern for "lupus Flare" patient was given steroids at the OSH.At the OSH notable initial labs included a mild transaminitis and an INR of 1.5. She suddenly at the OSH developed fluid refractory hypotension and was started on a pressor. Due to continued worsening of her transaminitis well as a rising INR on her repeat labs she was referred to our tertiary PICU for further management.Pertinent history also includes a negative urine pregnancy test. No recreational drug use, and only as needed use of Tylenol.She now is in the PICU. She generally appears tired and ill. She is tachypneic on 4 LPM of nasal canulla and her oxygen saturation is 98%. She has a non-focal lung exam.Her cardiac exam is notable for tachycardia, and pertinently no gallop, rub or murmur.Her abdominal exam is non-focal except for mild discomfort on palpation of the RUQ with a palpable liver edge. Her extremities are cool with 3-4 capillary refill time. She is able to answer questions but intermittently doses off. No rash is noted.To summarize key elements from this case, this patient has:H/o of lupus and is on immunosuppressive medicationsNew onset fever/malaiseThis sounds like a LUPUS flare as she has a clinical picture of generalized inflammation.Rahul: Lets pause right here and take a look at key history and physical exam components in a patient who has a chronic auto-immune condition:Fever, malaise and feeling tired all signs of constitutional symptoms.She has abdominal pain and vomiting that could again be related to systemic inflammation but also an intra-hepatic lesion.Are there some red-flag symptoms or physical exam components which you could highlight?This patient has signs of shock!Tachycardia with delayed cap refill and cool extremitiesTachypnea& hepatomegaly which could indicate increased central venous pressures.Initially her outside presentation of fluid refractory shock is of utmost concern!Fluid refractory shock with multi organ presentation involving liver, kidney and the blood/coagulation systemsAll of these elements bring up a concern for some acute life threatening process such as sepsis, or even immune dys-regulation due to her h/o of LupusTo continue with our case, the patients labs were consistent with:Acute liver dysfunction (Elevated AST and ALT in the thousands, Total bilirubin 1.6, GGT 56) although the total bilirubin is not elevated to a degree I would expect.AKI (creatinine 2.18)An uptrending Coagulopathy with elevated PT and INR: PT 120 and a peak INR of 16Thrombocytopenia: Platelets < 50KShe had a peak lactate 9.2and concurrent Metabolic acidemia: serum HCO3 7, and pH 7.18.A Pertinent negative: Normal serum ammonia <38 micromol/L (nl < 50)Finally, she had an elevated WBC 20.5K/ Hgb 9.7, Platelet 42. CRP 4.2/ESR 5OK to summarize, we have: a 17 yr old female with SLE on mycophenolate (cellcept) who presents with fever, hypotension, AKI and liver dysfunction with severe coagulopathy, although we do not have other labs- This brings up the concern for acute macrophage activation syndrome (MAS) the topic of our discussion today.Let's start with a short multiple choice question:12 year old male with h/o systemic onset juvenile idiopathic arthritis (JIA) presents with fever, rash, hypotension, acute respiratory distress with hypoxia. Mental status is normal. He also has acute kidney injury, transaminitis, coagulopathy, metabolic acidemia as well as anemia and thrombocytopenia. His liver and spleen are enlarged and he has scattered lymphadenopathy. The laboratory findings most suggestive of acute macrophage activation syndrome in this patient is:Erythrocyte Sedimentation Rate > 100ADAMS13 activity < 10%Serum Ferritin > 20, 000ng/mLFibrinogen (> 500mg/dL)The correct answer is serum ferritin > 20,000ng/mL. Any patient with systemic JIA who presents with high fever, heptao-splenomegaly with evidence of multi-organ dysfunction should be considered to have the potentially life threatening complication of systemic inflammatory disorders: acute macrophage activation syndrome (MAS) unless proven otherwise. The 2016 Classification criteria for MAS was published (Ravelli A. et al. Ann Rheum Dis 2016; 75:481-489) requires a Ferritin > 684ng/mL and any two of the following:A platelet count < 181 X 109/L (181K)AST > 48unitsTriglycerides > 156 mg/dLFibrinogen ≤ 360mg/dLOK lets summarize, platelets less than 180K, fibronogen <360, transaminitis >AST 48 and hypertriglcyeridemia! Remember many of these values are acute phase reactantsCorrect Rahul, also the above Laboratory abnormalities should not be otherwise explained by another patient condition, such as concomitant immune-mediated thrombocytopenia, infectious hepatitis, visceral leishmaniasis or familial hyperlipidemia.Are there any other inflammatory mediators or subtleties you would like to highlight with this disease?A falling ESR, especially with a high CRP, is concerning for MAS and is secondary to low fibrinogen in the setting of consumptive coagulopathy.In the question, patient's ESR is elevated. Low or absent ADAMS T-13 activity is more suggestive of thrombocytopenic purpura (TTP), which is not the case here as mental status is preserved indicating no CNS involvement. In MAS there is typically consumption of fibrinogen not its elevation. The elevated ferritin (> 10,000ng/mL) along with other systemic findings in the patient in the question is highly suggestive of MAS. Additional labs that would suggest MAS include demonstration of hemophagocytosis in bone marrow or other tissue, elevated D-dimers, lactic acid dehydrogenase (LDH), triglycerides, low natural killer (NK) cell function, and elevated soluble IL-2 receptor levels.Great highlight of the incorrect answers the pathophysiology of increased immune activation is key along with dysfibrinogenemia — this is likely due to microangiopathic consumptionRahul can you briefly tell us a bit about macrophage activation syndrome?MAS is classified among the group of hemophagocytic lymphohistiocytosis (HLH), so HLH is the umbrella term.HLH includes familial HLH and secondary HLH. Secondary HLH is triggered by several causes, including infection, drugs, malignancy, and rheumatic disorder. Remember in our case the patient had LupusIn MAS A common hypothesis in MAS is that there is a defect in lymphocyte cytolytic activity, which means that lymphocytes are not able to kill cells appropriately.Let's break down the pathophysiology a bit further.There is a genetic predisposition, and that is to having increased macrophage responsivenessThere is some form of background inflammatory activity. What cytokines are elevated?IL-6IL-1IL-18What does IL-6 do?Decreases NK cell functionSo now you have bad T cell cytolytic function and decreased NK cell cytolytic function. What does this lead to?Prolonged cell to cell interactions and amplification of a pro0inflammatory cascade.So now we have genetic predisposition some background cytokine inflammatory activity with cytokine production and now we layer in the third element of the pathophysiology — A trigger!What are triggers: acute on chronic inflammation & especially infection!This trigger will be important to capture in our understand as management will be geared towards reversing this trigger. So where does the hemophagocytosis come about in the term hemophagocytic lymphohistiocytosis? Well, the cytokine storm results in activation of macrophages which are known as hemophagocytes. There's a particular cytokine IFN gamma that make macrophages angry and it is this response that can lead to multi-organ dysfunction.Pradip, now with this summary let's dive into MAS and how it relates to HLH?MAS is a life threatening illness is a form of secondary hemophagocytic lymphohistiocytosis (HLH) and a common complication of rheumatologic conditions, such as systemic JIA. The occurence of MAS has been well reported in other autoimmune or auto-inflammatory conditions, such as, adult-onset and childhood-onset systemic lupus erythematosus, Kawasaki disease, and periodic fever syndromes.Characteristic clinical