Fever and Systemic Features

Amelia is a 7-year old living in rural Brazil and is referred to Paediatric Rheumatology with spiking daily fever for over 40 days. She had weight loss, fatigue, pallor, diffuse hair loss, myalgia and arthralgia. Her past medical history was unremarkable. Investigations for fever of unknown origin which revealed leukopenia and moderate anaemia, positive IgG CMV serology (suggesting previous infection) and high IgG serum levels. She had also a positive ANA test, low titre anti-DNA antibodies and positive Coombs test. Blood film and bone marrow aspirate / biopsy excluded malignancy.

She received NSAIDs and then a short course of oral prednisolone with a presumed diagnosis of connective tissue disease.

During follow up she had a sudden drop of her haemoglobin levels with severe leucopenia with neutropenia and was observed to have moderate splenomegaly. This scenario raised concerns about macrophage activation syndrome (haemophagocytic syndrome) as a serious complication of many multisystem diseases (including connective tissue diseases). Her second bone marrow aspirate and biopsy revealed haemophagocytic macrophages but also on this occasion, amastigote forms of Leishmania sp. intra- and extra-cellular. She was then treated with liposomal amphotericin B and supportive therapy. Her therapeutic response was evaluated clinically in terms of decrease in spleen size, resolution of fever and weight gain. 

Diagnosis: Visceral leishmaniasis

This is a systemic disease affecting the reticuloendothelial system, caused by protozoa of the genus Leishmania.  This infection affects dogs and humans and is transmitted from the bite of female sandflies. Over the last decade, the disease prevalence has increased five fold mainly due to an expansion in global sandfly distribution associated with climate changes.

• This parasitic disease is endemic in many countries including North Africa, Central and South America, the Middle East, the Indian subcontinent and Southern Europe.
• The main manifestations include muscle wasting, prolonged fever, weight loss, splenomegaly and pancytopenia. Musculoskeletal symptoms of myalgia and arthralgia accompanied by fever and systemic features raise suspicion of malignancy and infection: however once excluded, the differential diagnosis will consider multisystem diseases including connective tissue diseases and haemophagocytic lymphohistiocytosis. Consideration of leishmaniasis is important as the clinical scenario of suspected immunological / rheumatic disease may prompt systemic corticosteroid treatments to be given. This would clearly not be appropriate with visceral leishmaniasis infection.  
• The association of haemophagocytic syndrome and visceral leishmaniasis is rarely found in childhood. It is an atypical presentation of a parasitic infection mimicking childhood-onset systemic lupus erythematosus and unspecific autoimmune phenomena.
• Prolonged fever and musculoskeletal complaints are common presenting features of many multisystem diseases; this case highlights the importance of considering infections for those living in, or having travelled to an endemic area. 

Further information is available from the Centre for Disease Control and Prevention 

Reference

Scalzone M, Ruggiero A, Mastrangelo S, Trombatore G, Ridola V, Maurizi P, Riccardi R: Hemophagocytic lymphohistiocytosis and visceral leishmaniasis in children: case report and systematic review of literature. Journal of infection in developing countries 2016, 10(1):103-108.