Letters to the Editor


12 December 2008

Dear Editor,


Case Report

A 10-year-old girl was admitted into the hospital for high-grade fever (39–40°C), nausea, vomiting, abdominal pain, lethargy, diffuse maculo-papular rash on both arms and legs, and bilateral submandibular lymph nodes enlargement. Ten days before admission, she was diagnosed as having ethmoidal sinusitis and preseptal orbital cellulitis and was successfully treated with full spectrum antibiotics.

On admission, laboratory tests showed progressive pancytopenia (white blood cells count 1.030/mm3 (4.500–11.500), haemoglobin 7.8 g/dL (11.5–13.5), platelet count 40 × 103/mm3 (150–450), erythrocyte sedimentation rate 57 (<30 mm/h), C-reactive protein 14 (<0.6 mg/dL), signs of disseminated intravascular coagulation (DIC) (prothrombin time (PT) 49% (70–130), partial thromboplastin time (PTT) 58 s (27–40), D-dimer 2.700 ng/mL (normal values < 190) Fibrinogen 80 mg/dL (150–350), C3 57 mg/dL (80–170), C4 3 mg/dL (10–40), tryglicerides 226 mg/dL (<170), alanine aminotransferase 55 U/L (<40), aspartate aminotransferase 76 U/L (<40), albumin 2.7 g/dL (3.5–5), ferritin 2508 ng/mL (12–180), urinalysis normal. Antinuclear antibodies were positive (1:1280 with homogeneous pattern), anti-dsDNA antibodies 40 UI/mL (<7), anti-Sm 59 UE/mL (<20), anti-RNP 143 UE/mL (<20). Anti-cardiolipin autoantibodies (IgG, IgM) and anti-beta2 glycoprotein I (IgG, IgM) were all negative.

Over the next 2 days, her general condition progressively worsened with persistence of high fever associated with bilious vomiting, lethargy, tachycardia, tachypnea, hypotension, diffuse exanthema and mild hepatosplenomegaly. Chest X-ray and echocardiography showed bilateral pleural and pericardial effusion. Bone marrow aspirate showed severe dyserythropoiesis but no evidence of haemophagocytosis or malignancy. A diagnosis of juvenile systemic lupus erythematosus (SLE) with macrophage activation syndrome (MAS) was made. The patient was treated with pulse methylprednisolone (20 mg/kg/day) for three consecutive days, followed by oral prednisone (1 mg/kg/day). Symptoms rapidly improved and, 1 week later, full blood count and ferritin level were normal. The patient was discharged after 3 weeks on prednisone (50 mg/day) and hydroxychloroquine (200 mg/day) treatment.


MAS is a rare, life-threatening condition that causes a massive release of proinflammatory cytokines, such as interleukin-1β, interleukin-6 and interferon-γ, which induce increased activation of macrophages. The process results in a DIC associated with hepatosplenomegaly, elevated serum levels of liver enzymes, cytopenia and potentially fatal multi-organ involvement.1

In paediatric patients with rheumatic diseases, MAS is most commonly seen in systemic onset juvenile idiopathic arthritis (soJIA),2, but it has been also rarely described in SLE,3 dermatomyositis4 and Kawasaki disease (KD).5 Two recent case series reported a mortality ranging from 8 to 22%.2,6

The pathogenetic mechanism of MAS is currently not clear, but the process seems to be triggered by viral infections, drugs or change in medication regimen.2,6

A literature search reveals only nine cases of MAS as presenting manifestation of SLE in childhood6–9. At the Department of Paediatrics of Padua, we saw another SLE-related MAS in a 12-year-old girl affected by SLE since the age of 8. She suddenly presented with high-grade fever, abdominal pain, vomiting and diarrhoea. The infectious disease work-up showed evidence of active Epstein–Barr virus (EBV) infection, and the laboratory tests showed pancytopenia, rising liver transaminase, signs of consumption coagulopathy and renal insufficiency. The bone marrow aspirate showed a few haemophagocytic cells. In this case, MAS was not the presenting manifestation of SLE but caused a severe relapse of the disease.

In absence of autoimmune diseases, MAS can be triggered also by virus (i.e. cytomegalovirus, herpes virus, EBV, varicella-zoster virus), bacteria (salmonella, enterobacteria, haemophilus, pneumococcus, etc.), fungi (candida and criptococcus) and also by parasitic infestations such as leishmania or pneumocystis carinii.10

MAS should be differentiated from haemophagocytic lymphohistiocytosis (HLH), a rare life-threatening disease with clinical features similar to MAS but with familial aggregation and worse prognosis. The genetic defects of HLH involve the secretory pathway of natural killer cells and CD4+ T regulatory cells and are due to mutations in the perforin gene. Seven other genetic mutations have been recently discovered and involve integral components of the granule exocytosis pathway which are critical for either the functional secretion of cytotoxic granules, or for the delivery of proteases required for apoptosis of target cells.11,12

When MAS occurs in soJIA or in KD, conditions usually characterised by anemia, leucocytosis, trombocytosis and ESR elevation, a ‘relative drop’ of these parameters, which is likely secondary to the haemophagocytic process, should alert clinicians to this potential complication, and may represent the key to early diagnosis and immediate intervention.

Detecting MAS in SLE may be more complicated, as many features such as fever, rash, lymphadenopathy, hepatomegaly and cytopenia are common to both conditions. In this case, as in our experience, the hallmark features of MAS are hypertriglyceridemia, raised liver enzymes and decreased albumin levels, related to impaired liver function, and hypofibrinogenemia and prolonged aPTT, due to consumption coagulopathy, and responsible for the ESR drop. Increased values of ferritin and lactate dehydrogenase may also help in addressing the diagnosis. The presence of macrophages actively phagocyting erythropoietic elements in the bone marrow aspirate is the most characteristic feature of MAS, but unfortunately is not always evident and not necessarily required to make the diagnosis.2,5

There is no agreement on the optimal therapy for MAS. Most authors suggest the use of parenteral administration of high-dose corticosteroids with supportive management of fluid balance and coagulopathy.6,8 In case of partial or if no response to corticosteroids is obtained, cyclosporine A should be added.2,6

In conclusion, MAS can be the initial presentation or a trigger for relapse in childhood-onset SLE. Prompt recognition and aggressive therapy are crucial, since the prognosis is strongly related to early treatment.