Pyrexia of unknown origin 90 years on: a paradigm of modern clinical medicine.

In 1925, Sir Thomas Horder, a leading physician of his day, gave a lecture, published in this journal, entitled 'Some cases of pyrexia without physical signs'. The paper highlighted what was already a familiar clinical presentation "which taxes our resources to the utmost". Fast-forward through 90 years of careful clinical description, technological innovation in diagnosis and treatment, emergent infections, novel diagnoses, demographic shifts, and radical changes in the health economy. Sir Thomas would find certain aspects familiar, and others revolutionary, in the differential diagnosis and management of the 21st century patient with pyrexia of unknown origin (PUO). Within high-income settings, the proportion of cases due to infection has declined, albeit unevenly. The era of untreated HIV, and the consequences of iatrogenic intervention and immunosuppression, led to Durack and Street's subclassification of the condition in the early 1990 s into classic, nosocomial, neutropenic and HIV-associated PUO. Shifts towards ambulatory care have driven a change in the definition of many diseases. An era of observant clinicians, who lent their names to eponymous syndromes, followed by meticulous serological, genetic and clinicopathological correlation, generated a battery of diagnoses that, along with malignancy, form a large proportion of diagnoses in more recent clinical care. In the current era, universal access to cross-sectional imaging and an infinite array of laboratory tests has undermined the attention paid to history and examination. In some areas of the clinical assessment, such as assessing the fever pattern, this shift is supported by research evidence. The issues that need to be addressed in the next 90 years of technological innovation, information sharing and health service transformation are likely to include: transcriptomic approaches to diagnosis; the place of positron emission tomography (PET) in the diagnostic pathway; the optimal management of high ferritin states; and the most cost-effective diagnostic environment, in the face of this era of specialisation and fragmentation of care. In the meantime, this review covers some important early 21st century lessons to be shared in avoiding diagnostic pitfalls and choosing empirical therapy.

[The autumn crocus: two millenniums of actuality]. / Le colchique: deux millénaires d'actualité.

Colchicum holds a singular place in the History of Medicine. Many names were given through the ages: "ephemera", "finger of Hermes", "pater noster", "tue-chiens". Modern phytonyms clearly refer to the land of Colchis, a mythical place close to Armenia. Several centuries were needed to understand that, despite a frightening reputation, colchic was an elective treatment for the gout. In its long story, appears famous personages as Theophraste, Paulus Aeginata, Gilbertus Anglicus, the baron Storck and Benjamin Franklin. In modern times, colchicum has received besides gout, a wide array of new indications, among others: Behcet disease, collagen diseases and malignancies. A scarcely known chapter of genetics is the findings in 1889, by B. Pernice, an obscure physician from Palermo, of the major mitoic changes observed on gastric and intestinal mucosa of two dogs which had received large doses of colchicum. In spite of their scientific value, the works of Pernice remained largely ignored until 1949. Recent advances in colchiocotheraphy have shown fascinating new fields for research: thus in the familial Mediterranean fever, close to periodic disease, genetic disorder elective for subjects originated from all over Mediterranean and around Black Sea... the mythical country of Colchis. No other medicinal plant than colchic, except poppy, can give such records of perennial use in such a wide range of disorders.

New genetic interpretation of old diseases.

The title of this section, "New genetic interpretation of old diseases," perfectly reflects the unique history of our understanding of autoinflammatory diseases (AIDs). Indeed, the main clinical feature of most AIDs is the recurrent fever, a symptom that has been extensively documented for centuries. However, the first clear description of a patient suffering from the AID prototype, familial Mediterranean fever (FMF), has only been reported in 1908, although dating studies have shown that ancestral mutations appeared in biblical times. FMF and 11 other AID genes were identified between 1997 and 2011. The patient's care has dramatically benefited from the elucidation of the molecular defect underlying similar diseases of the innate immune system. However, accumulation of present and future sequence data let us anticipate that interpretation of genetic diagnosis will be increasingly difficult.

Marcel Proust (1871-1922): reassessment of his asthma and other maladies.

Marcel Proust endured severe allergies and bronchial asthma from early childhood. Those who suffer from the frightening and recurrent pangs of asthma often become dependent on their parents particularly mother; Proust was no exception. In his time asthma was poorly understood by physicians who considered the illness to be a type of hysteria. Decades later, we now understand that the severe, poorly controlled, suffocating episodes of asthma were responsible for the complex persona that Marcel Proust had assumed.