Secondary HLH or MAS is a severe, potentially life threatening complication of several rheumatic disorders or infections. It is charactrized by proliferation of macrophages, which demonstrate phagocytosis of hematopoetic cells, in bone marrow, liver, spleen etc. It is a broader spectrum disorder, infection associated called sec HLH and chronic rheumatic disorder called MAS. The disease is characterized by high fever, cytopenias, hepatosplenomegaly, CNS dysfunction, coagulopathy. Laboratory features are falling ESR, raised Triglyceride, ferritin and presence of macrophage hemophagocytosis in bone marrow. Main stay of treatment with supportive care, corticosteroids, cyclosporine. Newer advances in treatment are anti thymocyte globulin, IVIg, anti TNF agent etanercept, anti IL 1 receptor antagonist anakinra. Though reported mortality is 15- 60%, early recognition and prompt therapy may give better outcome.
A 15 year old boy with no known co morbidities was admitted with the history of high grade intermittent fever rising up to 103 degrees F, with 3-4 peaks per day, for the last 8 days. Fever was associated with generalised body ache, headache and anorexia. After 4 days of onset of fever, he developed loose stools, occurring 3-4 times a day but without any blood streaking, not associated with any cramps. There was no associated joint pains, cough, sore throat, shortness of breath, urinary symptoms, altered sensorium or seizures. He has no significant past medical history or addictions.
On admission he was conscious, alert but restless. He has obesity with a BMI of 33.46. He has pallor, blanching macular rash over trunks, face and extremities and few palpable anterior cervical lymph nodes. Vitals were stable. He had soft, non tender, smooth hepatomegaly 3 cm below right coastal margin at mid clavicular line and just palpable splenomegaly. He has no neurodeficit or meningeal signs. Other system examinations were unremarkable.
Secondary Hemophagocytic Lymphohistiocytosis.
Chronic Rheumatic Disorder, Macrophage Activation Syndrome.
Complete Blood Counts
- Haemoglobin of 8.6gm/dl
- Total WBC counts of 3600 with 65% neutrophils
- Platelet count of 1,15,000
- LFT showed elevated ALT (356 U/L) AND AST (412 U/L)
- ESR was 55 mm 1st hr
- CRP was raised- 24 mg/dl
- MPDA was negative and no malarial parasite seen on peripheral smear.
- Blood Culture was also sent
Initially we proceeded with the clinical diagnosis of Enteric Fever and started treatment with IV antibiotics and fluid replenishment.
- However, on Day 2 since admission, he developed tachypnoea (respiratory rate of 40/min), tachycardia (pulse rate 120/min) and rapidly began to desaturate. With the suspicion of ARDS, he was shifted to the Intensive Care Unit of our hospital.
- Arterial Blood Gas analyses showed:
- PaO2 56 mm Hg
- PaCO2 29 mm Hg
- pH 7.62
- HCO3 23 mEq/L
- Chest X-ray was suggestive of Acute Respiratory Distress Syndrome.
- Thus, he was put on Mechanical Ventilation.
- But Even after two days on mechanical ventilation, and stepping up IV antibiotics, he showed poor response. GCS was dropping and he showed a worsening sensorium. Now he also developed 3 episodes of fresh lower GI bleeding. With such a devastating turn of events, we had to rethink our diagnosis.
Further Investigations Shows:
- WBC count was further decreased to 2900.
- Platelet count dropped to 50,000/cumm.
- Peripheral smear showed microcytic hypochromic anaemia, anisopoikilocytosis, left shift with toxic granules, no malarial parasite.
- ESR was 32 mm Hg (decreasing).
- INR became 2.3 from 1.1.
- Serum ANA, Rheumatoid Factor, Viral markers, Dengue IgM, IgG negative
- Reticulocyte count was 1.2%.
- USG revealed enlarged liver and mild splenomegaly but was otherwise normal.
- Routine urine and stool examinations were normal.
- Echocardiography showed no valvular vegetation.
- CSF studies showed 4 lymphocytes with normal biochemical parameters and ADA 4.1 mg/dl.
- Blood Culture was positive for Salmonella typhi.
In this clinical context with diagnosis of sepsis with multiorgan dysfunction or Intestinal Perforation due to Typhoid Ulceration or Splenic Rupture due to Enteric fever orTyphoid fever with haemolytic uraemic syndrome we think about secondary HLH or MAS.
Serum Ferritin was seen to be highly raised (>6000mg/dl).
- LDH levels>600mg/dl.
- Serum Triglycerides>650mg/dl.
- Coagulation Profiles (PT, APTT) were significantly altered with Fibrinogen < 150mg/dl and detectable fibrin degradation products.
- With pancytopenia, hepatosplenomegaly and lymphadenopathy, with acute GI bleed, we went for a bone marrow biopsy.
- Macrophage Haemophagocytosis seen on Bone Marrow biopsy slides.
- With the diagnosis of HLH we started high dose IV Methylprednisolone therapy at 30mg/kg for 3 days, followed by 2mg/kg IV in 4 divided doses for the next 4 days.
- Supportive management in the form of FFP transfusion given also.
- Antibiotics given and proper nutrition maintained.
- Within 3 days of initiation of said therapy, he showed dramatic response and could be taken off of ventilator support.
- His blood counts improved and he became afebrile by 7th day since admission.
- He was discharged after a few days of close observation in the general ward.
- He attended the Medicine OPD 2 weeks and 1 month after discharge, and continues to be afebrile with no new complaints.
Secondary Haemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome :
- Haemophagocytic Lymphohistiocytosis (HLH) is a rare but potentially fatal disease of normal but overactive histiocytes and lymphocytes, commonly appearing in infancy but also seen in older age groups.
- Primary HLH is an inherited form, with heterogenous autosomal recessive inheritance. Secondary HLH occurs after strong immunologic activation, i.e., with systemic infection, immunodeficiency or underlying malignancy.
- Macrophage activation syndrome (MAS) is a part of the broader spectrum of secondary HLH where it occurs as a life threatening complication of severe chronic rheumatological disorders of childhood.
The diagnosis of HLH may be established by
1. A molecular diagnosis consistent with HLH (for example, pathologic mutations of PRF1, UNC13D or STX11 are identified) OR
2. Fulfilment of five out of the eight criteria listed below:
Fever > 38.5o C
Cytopenias (affecting at least two of three lineages in the peripheral blood):
Hemoglobin < 9g/100ml (in infants < 4 weeks: hemoglobin < 10g/100ml)
Platelets < 100 103/ml
Neutrophils < 1 103/ml
Hypertriglyceridemia (fasting, 265mg/100ml) and/or hypofibrinogenemia (150mg/100ml)
Hemophagocytosis in BM, spleen or lymph nodes
Low or absent NK cell activity
Soluble CD25 (that is, soluble IL-2 receptor) >2400U/ml (or per local reference laboratory)
Primary Diagnostic Guideline for MAS as a Complication of SOJIA :
Laboratory Criteria :
1. Decreased platelet count < 262 x 109 / L
2. Increased AST
3. Decreased WBC Count < 4000/cmm
Clinical Criteria :
1. CNS Dysfunction (i.e irritability, disorientation, lethargy, headache, seizure or coma )
2. Hemorraghe (i.e purpura, easy bruising or mucosal bleeding)
3. Hepatomegaly (3 cm below rt coastal arch)
Histopathological Criteria :
Evidence of macrophage hemophagocytosis in Bone Marrow aspiration
Diagnostic Rule :
The diagnosis of MAS requires the presence of 2 or more laboratory criteria or any 2 or more clinical/ laboratory criteria. A bone marrow aspiration for demonstration of hem phagocytes may be required in doubtful cases.
It is a severe potentially life threatening complication of several chronic rheumatic diseases of childhood caused by activation and uncontrolled proliferation of T lymphocytes and well differentiated macrophages leading to widespread hemophagocytosis and cytokine overproduction. It commonly occurs with Systemic Onset Juvenile Idiopathic Arthritis. It has been commonly described with SLE, Kawasaki disease or Adult Onset Still, s Disease. Secondary HLH is associated with infection and sepsis.
Pathogenesis of MAS or HLH is poorly understood. The cytotoxic activity of NK cells and T lymphocytes is mediated by release of cytolytic granules which contains performing, granulozymes and other serine proteases to the target of cells.
Mutations in several genetic loci related to release of cytotoxic granules (i.e polymorphism or heterozygous mutation in PRF 1 or UNC 13 D) causes decreased activity of cytotoxic granules.
This impairment in cytotoxic functions causes excessive expansion and activation of cytotoxic cells and macrophages.
This causes hyper secretion of proinflammatory cytokines i.e IFN gamma, alpha, IL 6,IL 10,M CSF. These in turn causes tissue necrosis and organ failure.
In a 2014 study by Pilonieta et al, it is stated, "Hemophagocytes, a subset of macrophages, are characteristic of severe acute infection in patients with, for instance, typhoid fever, brucellosis, tuberculosis, and leishmaniasis. Each of these diseases has the potential to become chronic. Hemophagocytes (blood-eatingcells) engulf and degrade red and white blood cells for unknown reasons. The bacterial pathogen Salmonella acquires the essential nutrient iron from murine hemophagocytes.
We report that Salmonella stimulates macrophages to engulf blood cells, indicating that cells of this bacterium actively promote the formation of a specialized cellular niche in which they can acquire nutrients, evade killing by the host immune system, and potentially transition to chronic infection.
Management And Follow up:
- IV Methylprednisolone 30mg/kg for 3 consecutive days, followed by 2-3mg/kg/day in four divided doses or Dexamethasone IV at 6mg/m2.
- Cyclosporine A may be used in Familial or severe or Corticosteroid resistant HLH after 24-48 hours of no response, at 2-7mg/kg/day IV.
- High dose IVIG, cyclophosphamide, plasma exchange, etoposide have been tried with conflicting results Antithymocyte Globulin or anti TNF agent, Etanercept may be used but these may trigger infection susceptibility.
- Supportive treatment with transfusion of RBC, platelets or FFP, antibiotics, may be needed along with proper nutritional support.
- It is related to the severity of infection.
- Such patients require close monitoring as recurrence may occur.
- Mortality may be 15-60% but statistics are improving with early intervention.
- A high index of clinical suspicion is to be maintained due to the swift progression of HLH and possible mortality and morbidity.
In patients with high grade fever, pancytopenia, hepatosplenomegaly and lymphadenopathy, presenting with bleeding manifestations, HLH is to be kept as a differential diagnosis as it shows dramatic response when therapy is started early. Thus an early diagnosis could save lives.