Fever tree revisited: From malaria to autoinflammatory diseases

Abstract

Over the centuries the idea of recurrent fevers has mainly been associated with malaria, but many other fevers, such as typhoid and diphtheria were cause for concern. It is only in recent times, with the more severe forms of fever from infectious origin becoming less frequent or a cause for worry that we started noticing recurrent fevers without any clear infectious cause, being described as having a pathogenesis of autoinflammatory nature. The use of molecular examinations in many cases can allow a diagnosis where the cause is monogenic. In other cases, however the pathogenesis is likely to be multifactorial and the diagnostic-therapeutic approach is strictly clinical. The old fever tree paradigm developed to describe fevers caused by malaria has been revisited here to describe today’s periodic fevers from the periodic fever adenitis pharyngitis aphthae syndrome to the more rare autoinflammatory diseases. This model may allow us to place cases that are yet to be identified which are likely to be of multifactorial origin.

Keywords: Recurrent fevers, Malaria, Autoinflammatory diseases, Periodic fever adenitis pharyngytis aphthe syndrome, History of medicine, Interleukin-1, Genetics, The fever tree

Core tip: Periodic fevers of autoinflammatory nature have been increasingly recognized in recent decades, in many cases reflecting monogenic disorders of inflammation. However, patients can be encountered in clinical practice who don’t fit in any definite category of periodic fever, despite of extensive molecular analyses. A clinical approach based on the analogy with the well defined monogenic diseases can be reasonable in these cases, which likely represent an heterogeneous group of multifactorial disorders. We propose revising the historical image of the fever tree to figure the possible existence of a disease continuum between multifactorial and monogenic periodic fever syndromes.