The history of diphtheria is traceable to a period ‘almost contemporary with Homer’. References to ‘malignant sore throat’ among young children can be identified in the writings of the Greek physician Aretaeus who, in the first century C.E., described a condition, which he termed ‘Egyptian’ or ‘Syrian’ ulcer, as it was most prevalent in those countries. Aretaeus traced the spread of these ulcers to the thorax near the windpipe – which occasioned ‘death by suffocation within the space of a day’ – and lamented that ‘children, until puberty, especially suffer’. Macrobius Aurelius recorded an epidemic that swept through Rome in 380 C.E., when sacrifice to the gods failed to liberate the city from the ravages of the suffocating disease ‘angina maligna’. Macrobius's account of this visitation was contemporaneous with the Goth invasion of the Roman Empire, and in the period spanning the fall of Rome to the fall of Constantinople, references to ‘malignant sore throat’ and ‘angina maligna’ remain largely absent from the historical record.

In January 1517, an epidemic disease ‘wholly unknown to medical men’ appeared in Holland. While displaying similar characteristics to ‘angina maligna’, an attendant infectious inflammation of the throat was said to be ‘so rapid in its course’ that unless assistance was procured within the first eight hours ‘the patient was past all hope of recovery […] the threatened suffocation, at length actually produced it’. Outbreaks of disease displaying similar epidemiological characteristics occurred in Paris in 1576 and in Naples in 1618–19, where 5,000 victims perished.