Familial and acquired hemophagocytic lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of severe hyperinflammation caused by the uncontrolled proliferation of activated lymphocytes and histiocytes secreting high amounts of inflammatory cytokines. Cardinal signs and symptoms are prolonged fever, hepatosplenomegaly and pancytopenia. Characteristic biochemical markers include elevated triglycerides, ferritin and low fibrinogen. HLH occurs on the basis of various inherited or acquired immune deficiencies. Impaired function of natural killer (NK) cells and cytotoxic T-cells (CTL) is shared by all forms of HLH. Genetic HLH occurs in familial forms (FHLH) in which HLH is the primary and only manifestation, and in association with the immune deficiencies Chédiak-Higashi syndrome 1 (CHS 1), Griscelli syndrome 2 (GS 2) and x-linked lymphoproliferative syndrome (XLP), in which HLH is a sporadic event. Most patients with acquired HLH have no known underlying immune deficiency. Both acquired and genetic forms are triggered by infections, mostly viral, or other stimuli. HLH also occurs as a complication of rheumatic diseases (macrophage activation syndrome) and of malignancies. Several genetic defects causing FHLH have recently been discovered and have elucidated the pathophysiology of HLH. The immediate aim of therapy in genetic and acquired HLH is suppression of the severe hyperinflammation, which can be achieved with immunosuppressive/immunomodulatary agents and cytostatic drugs. Patients with genetic forms have to undergo stem cell transplantation to exchange the defective immune system with normally functioning immune effector cells. In conclusion, awareness of the clinical symptoms and of the diagnostic criteria of HLH is crucial in order not to overlook HLH and to start life-saving therapy in time.

Macrophage Activation Syndrome in Autoimmune Disease

“…as many as half of the patients with MAS secondary to sJIA may respond to corticosteroids alone [23,24,57]. Additionally, the clinical features of MAS may differ from those seen in other forms of HLH [17,31,80,81], and the features of HLH syndromes in children may differ from those in adults [12], potentially altering the risk/benefit ratio of therapies originally applied to familial and other forms of HLH.…”

“…It is now recognized that MAS is a form of secondary HLH. Some authors suggest that the terms are interchangeable [12,13,14,15], whereas others describe MAS as a distinct subset of secondary HLH [16,17], and still others highlight the heterogeneity of disorders described by both terms and call for revised terminology based more precisely on pathophysiology [18,19,20]. …”

“…Thus, routine testing of all patients with rheumatologic disease and a new clinical feature (such as fever) for each of the HLH-2004 criteria would be cost-ineffective, could confuse the diagnosis if biopsy data were misapplied in isolation, and might expose many patients to unnecessary risks. Similarly, waiting for the delayed results of HLH-2004-directed testing in patients with true MAS prior to initiating therapy could invite catastrophe [17,23], and many patients with true MAS may require treatment initiation prior to the fulfillment of strict criteria when clinical suspicion is high [61], similar to aggressive forms of arthritis [32,62] due to novel mechanisms [63,64]. Lastly, differences in precipitating events, diagnostic parameters, and prognostic factors between adults and children exist [65,66,67,68,69,70,71,72], leading some authors to suggest that the current gold standard of the HLH-2004 criteria cannot be applied in the adult population [12].…”

Artrite Idiopática Juvenil: Atualização

“…Nos casos secundários, como ocorre na AIJ sistêmica, a tempestade de citocinas e hemofagocitose de células sanguíneas pelos macrófagos CD163 é a responsável pelas manifestações clínicas e laboratoriais da HLH. 11 Mais recentemente, a AIJ sistêmica parece ser melhor compreendida como uma doença autoinflamató-ria (DAT) e não autoimune. Nas doenças autoimunes clássicas, como Artrite Reumatoide e Diabetes Mellitus tipo 1, a resposta imune é o mecanismo principal, com antígenos autorreativos contra linfócitos T e altos títulos de autoanticorpos, com forte associação aos alelos MHC classe II.…”

Congenital Hemophagocytic Lymphohistiocytosis in a Preterm Infant

“…1-3 FHL is a rare autosomal recessive disorder in which 3 different gene defects encoding perforin (PRF), Munc (MUNC13D), and syntaxin 11 (STX11) have been identified. [1][2][3] However, in a large number of affected patients the genetic defects are still unknown.…”