A case of haemophagocytic lymphohistiocytosis ( HLH )

Haemophagocytic lymphohistiocytosis (HLH) results from infiltration of various organs and tissues with lymphocytes, natural killer (NK) cells and haemophagocytic histiocytes and reflects a highly stimulated yet ineffective immune response triggered by various stimuli 1 . It is classified as Class 11 Histiocytosis according to Histiocyte Society Classification (Writing Group of the Histiocyte Society 1987) 2 .


Introduction
Haemophagocytic lymphohistiocytosis (HLH) results from infiltration of various organs and tissues with lymphocytes, natural killer (NK) cells and haemophagocytic histiocytes and reflects a highly stimulated yet ineffective immune response triggered by various stimuli 1 .It is classified as Class 11 Histiocytosis according to Histiocyte Society Classification (Writing Group of the Histiocyte Society 1987) 2 .
A high degree of clinical suspicion is needed in the initial diagnosis of this condition as clinical features and laboratory investigations are non specific.If treatment is not established immediately, death supervenes due to severe sepsis and multi organ dysfunction.

Case report
A previously healthy 11 year old boy presented to hospital with fever of 14 days duration associated with respiratory symptoms at the onset.The illness progressed rapidly with jaundice and tea coloured urine appearing on day 5 and a generalized purpuric rash on day 8. Towards the end of the second week, generalized oedema was noticed with deepening of jaundice.He was admitted to the intensive care unit of the Lady Ridgeway Hospital with diffuse mucocutaneous bleeding, deterioration of intellect and circulatory collapse.He is the second born of healthy non consanguineous parents and the family history was insignificant.He was treated with intravenous cefotaxime, amikacin, penicillin and liver failure regime as well as IPPV ventilation.He received IV immunoglobulins, recombinant activated factor V11 injections and several transfusions of platelets, plasma and blood.Despite treatment his condition deteriorated further and he succumbed on day 18 of the illness.

Discussion
HLH occurs in both familial and acquired forms and both can be triggered 1 .The primary familial form has autosomal recessive inheritance and a frequency of 1 per 50 000 births.70% of affected patients manifest symptoms during the first year.There is a preceding symptom free period and HLH is the only clinical manifestation.The secondary familial variety occurs in association with immune deficiency syndromes such as Chediak Higashi syndrome, Griscelli syndrome and X linked lymphoproliferative disease 1 .
The acquired forms are mainly due to infections, most commonly viruses of the herpes group.Epstein Barr virus (EBV) has been isolated in 74% of those with a viral aetiology 3 .Bacteria, fungi and protozoa, especially leishmania are non-viral infective causes.The macrophage activating syndrome (MAS) is a form of acquired HLH occurring in association with autoimmune diseases like rheumatoid arthritis and SLE, and is triggered by infections as well as drugs such as NSAIDs and methotrexate.It occurs during the active phase of the disease and carries a fatality of 10-20%.HLH is also being reported with malignancies, especially lymphomas and metabolic diseases like lysinuric protein intolerance and multiple sulfatase deficiency.
In the pathogenesis of HLH, the infiltrated cytotoxic T cells and NK cells hyper secrete proinflammatory cytokines like interferon gamma, tumor necrosis factor alfa, interleukin-6, 10 and macrophage colony stimulating factor which lead to tissue necrosis and organ failure.Despite the accumulation of these cells at tissues, their cytotoxic activity is impaired due to defective cytolytic granules containing perforin and granzyme as well as improper immunological synapsing 4 .
The 3 cardinal features of HLH are high grade fever, hepatosplenomegaly and pancytopenia.Lymphadenopathy, hepatic impairment with coagulopathy and severe sepsis are additional features.CNS involvement occurs in up to 73% 5 and in 20% is present at the onset 6 .The neurological features include hemiplegia, cranial nerve palsies, focal deficits and seizures, especially myoclonic 7 .