Paediatric UpdateThe histiocytoses: The fall of the Tower of Babel
Introduction
The history of our understanding and treatment of patients suffering from the group of diverse disorders, termed ‘the histiocytoses’, is characteristic of the self-correcting chain of events which often occurs in science and medicine. To this day these disorders remain enigmatic. In nearly all examples we do not understand their aetiology. There is a primitive view of their pathophysiology. Their classification continues to change and their treatment remains empirical at best1, 2, 3, 4, 5. Yet, progress has been made as evidenced both by the level of data-driven discussion and, most importantly, the fact that more patients now survive.
This update will examine: (1) some of the historical developments associated with our understanding of these disorders; (2) issues concerning their classification; (3) data upon which interpretations concerning aetiology and pathogenesis can be made; (4) the successes and failures of different treatment approaches; (5) late sequelae; and (6) future areas of challenge.
Section snippets
Historical nomenclature
When Metchnikov described the reaction of cells of the larval starfish to a rose thorn in the late 1800s, the first building blocks of a system which would eventually be referred to as the Tower of Babel were set[6]. Based on the observations and conceptual framework of Metchinkov's work on phagocytic cells, Aschoff introduced the term ‘reticuloendothelial system’ (RES)[7]. ‘Reticulo’ refers to the characteristic of cells comprising this compartment to form a ‘lattice or reticulum by
A common origin but separate lives
Much debate has occupied the search for the cell of origin of histiocytes from their initial description. Macrophages were first to arise locally from mesenchymal tissue components[8]. Blood monocytes were considered to be circulating progeny of similar tissue resident cells. Other groups believed monocytes to be derived from endothelial precursors[8]. For many years it was not clear that blood cells had a very high turnover in the adult; thus, there was no reason to assume that a common
Discriminating features and classification of the common histiocytic disorders
The critical importance of understanding the distinguishing characteristics of the different types of disorders involving the RES is exemplified by recent improvements in outcome through directed therapeutic approaches to specific subtypes of disease class. Historically this has not always been the case[31].
In 1893 Dr Alfred Hand from Philadelphia published a case report of a 3-year-old boy with failure to thrive, exopthalmos, hepatosplenomegaly, lymphadenopathy, a scabies-like rash, diabetes
LCH–epidemiology
Although epidemiological analyses cannot define a cause, such studies often provide clues to where one should look with cellular and molecular tools. In the case of LCH, several tantalising associations have been observed.
The annual incidence of LCH has been calculated to be between 3 and 7 cases per million people with males being more frequently affected than females49, 50, 51. Although a Danish population based study showed no significant associations of LCH with neonatal and perinatal
Separate treatment approaches for separate diseases
The initial historical lack of distinction of severe LCH and HLH also resulted in these different disorders being treated similarly. However, with the improved understanding of these two disorders in terms of their underlying biology and distinct clinical courses, therapeutic approaches have diverged.
Some thoughts for the present and future
While significant progress has been made in the treatment of histiocytic disorders over the past 100 years, advances have come about through relatively empirical approaches based on successes in what were considered different manifestations of the same disease. For example, when LCH was considered to be due to a type of infection, antimicrobial agents were used. When it was considered to be a disorder of immune dysregulation, then immunosuppressive or immunostimulatory approaches were used. And
Acknowledgements
I am indebted to Drs Lisa Filipovich, Tom Gross and Ted Zwerdling for their input and critique. Special thanks also go to Drs Maarten Egeler, B.E. Favara, M. van Meurs, J.D. Laman and E. Claassen for sharing unpublished results on cytokines, receptors, CD40 and CD40L expression in LCH. My sincerest thanks also go to Dr Jon Pritchard for his continued encouragement and to Paul, Elizabeth and Nikolas Kontoyannis for continuing to challenge all of us to work together to improve the lives of
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