Fever, jaundice with emerging pancytopenia
Ira Shah
Medical Sciences Department, Pediatric Oncall, Mumbai, India.

Address for Correspondence: Dr Ira Shah, 1, B Saguna, 271, B St Francis Road, Vile Parle {W}, Mumbai 400056, India.

Clinical Problem :
A 7 year old boy born of non-consanguineous marriage presented with fever with chills for 10 days. He had left flank pain and bilateral painful knees along with fever. There was one episode of uprolling of eyes 7 days ago which lasted for 2 minutes. He had received anti-malarials and cotrimoxazole for these complaints. There is no contact with any patient having TB. He had fungal urinary tract infection at 5 years of age and was treated with IV antibiotics, ionotropic support and antifungal agents. His milestones and immunization are normal. On examination, he had tachycardia, bilateral knee effusions with restriction of movement, pallor and insignificant cervical lymphadenopathy with no organomegaly.
His investigations initially revealed leucocytosis which then subsequently developed into pancytopenia. He developed jaundice and elevated transaminases on Day 20 of illness which then subsided by Day 25 of illness. His serial hemograms and liver function tests are depicted in Table 1. His other biochemistries showed elevated LDH and uric acid. Renal tests were normal. Other investigations in form of Widal test, Leptospira tridot, Peripheral smear for malarial parasites, OptiMAL test, Hepatitis A IgM, HBsAg, Anti Hepatitis C, Dengue IgM, HIV ELISA, Parvovirus IgM, Brucella IgM and IgG, Weil Felix test were negative. Blood bactec culture and urine culture did not show any growth. Ultrasound of abdomen and electroencephalogram were normal. Prothrombin time was 17.3 {control = 11.0 sec} and Partial Thromboplastin time = 42.5 {control = 23.6 sec}. Serum immunoglobulins, ANA and dsDNA were normal. Echocardiography did not show any vegetations. Bone marrow examination did not show malignant cells but was diagnostic of the disease.

Question :
What is the diagnosis__?

Expert Opinion :
Bone marrow aspiration and biopsy showed presence of hemophagocytes with large proerythrocytes and no myeloid cells or megakaryocytes. Serum Fibrinogen was 120 mg percent and triglycerides were 457 mg percent. Serum Ferritin was 9,820 IU, dl. Cytomegalovirus PCR and tests for Epstein Barr Virus were not done due to unaffordability. He was treated with IV Antibiotics and G-CSF. In view of persistent high fever and delirium at the height of fever, he was treated with IV Methyl Prednisolone to which the fever responded and hemogram became normal. He was diagnosed as a case of Macrophage Activation syndrome and advised regular follow up. A repeat hemogram and serum ferritin after 15 days were normal. He was suspected to have underlying systemic onset juvenile idiopathic arthritis {JIA} in view of associated arthritis at the onset of fever. He was referred to the rheumatologist for treatment of his JIA.
Macrophage activation syndrome {MAS} is clinically similar to hemophagocytic lymphohistiocytosis {HLH} {1} though in the presence of JIA it is labelled as MAS. MAS is very rare. {2} MAS may present with persistent fever, significant hepatosplenomegaly, icterus, pancytopenia, coagulopathy, hepatic and renal derangement. Though diagnosis may be difficult, measurement of serum ferritin is a useful indicator of disease activity. {3} MAS is postulated to occur due to a defective function of perforin, a protein involved in the cytolytic processes and control of lymphocyte proliferation. {4}
Bone marrow examination may show presence of hemophagocytes. However, presence of hemophagocytes is variable and is dependent on the timing of the aspiration. {5} High dose corticosteroid is the initial treatment of choice in MAS. {4} Other agents used for treatment include cyclosporin A {cy A}and anti-Tumor Necrosis Factor {TNF} therapy. {5,6} Role of high-dose intravenous immunoglobulins, cyclophosphamide, plasma exchange and etoposide has been conflicting. As mortality is very high {6}, early and aggressive treatment is required.

1. Hadchouel M, Prieur AM, Griscelli C. Acute hemorrhagic, hepatic and neurologic manifestations in juvenile rheumatoid arthritis: possible relationship to drugs or infection. J Pediatr 1985`106:561-566.
2. Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome : a potentially fatal complication of rheumatic disorders. Arch Dis Child 2001`85:421-426.
3. Ravelli A. Macrophage activation syndrome. Curr Opin Rheumatol 2002`14:548-52.
4. Hadchouel M, Prieur AM, Gris Celli C. Acute hemorrhagic, hepatic and neurologic manifestations in juvenile rheumatoid arthritis: a possible relationship to drugs or infection. J Pediatr 1985`106:561-566.
5. Mouy R, Stephan JL, Pillet P et al. Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: report of five cases. J Pediatr 1996`129:750-754.
6. Pralahad S, Lovell DJ, Grom AA. Use of etanercept in the treatment of macrophage activation syndrome. Arthritis Rheum 2000`9{s}:S257.

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