Commentary: Cholera conundrums and proto-epidemiologic puzzles. The confusing epidemic world of John Lea and John Snow

Republication of one of John Lea’s 1849–51 cholera studies1 forces us to admit that our interest in it stems mainly from its influence on John Snow’s ‘Broad Street pump’ and South London studies 5 years later.2 That Snow’s work ultimately survived to become a part of the epidemiological canon,3,4 whereas Lea’s sank quickly into 150 years of obscurity (arguably until 20005), is worth examination. But examination is complicated by a century of Snow-hagiography that may mislead us. The comments below consider men like Lea and Snow in the larger context of their mid-19th century times, in which trying to elucidate the obscure causes of epidemic diseases was among the most important challenges of the day, but an undertaking almost inevitably doomed to failure. To take such a look back in time, we must forget most of what we know about infectious diseases like cholera, and try to accept the mysteries of such diseases as inexplicable in their entirety by any single theory. To fairly review what Lea, Snow and their contemporaries thought about cholera, when they set out to theorize about its occurrence and spread, would take hundreds of pages, and the results would still be incomplete, contradictory, confusing and paradoxical. In Lea’s/Snow’s time there was not a single major epidemic, let alone communicable, disease for which substantial evidence existed for the theoretical concept of infection, as we use the term today: denoting a microbial cause. Whereas communicability of many diseases had long been accepted, infection was merely one of several theories to explain it, and each theory had multiple perplexing variations. Though widely discussed, the idea of infection as an explanation for communicability was crowded out by competing theories; cholera could not even be shown to be communicable, let alone infectious. Theories of cholera communicability were considered to be particularly weak in their failures to explain such clearly observed phenomena as the repeated appearances of new cholera case patients who had never been exposed to ill persons. To posit microbial disease causation of cholera was to go even further out on a limb. Nevertheless, by 1849 suspicions about infectious aetiologies of a number of diseases were slowly growing. (Infection would eventually be established by Koch’s 1876 characterization of the full infectious cycle of Bacillus anthracis). Since the 1820s, greatly improved microscope lenses had led to the association of several skin/mucous membrane diseases with various fungi or protozoans, e.g. candidiasis and trichomoniasis. But aetiological proof of microbe/disease associations was frustratingly elusive: microorganisms were everywhere, in almost every sample from every ill or well patient, and from the environment—water, air, soil etc., and there was (yet) no standardized means of cultivating them to speciate them to identify which were harmless and which pathogenic, or to link specific microorganisms to specific diseases. The pitfalls of over-interpreting microbial associations were many, as Snow’s colleague William Budd (1811–80) learned in 1849 when he unwisely joined colleagues in announcing a fungal cause of cholera. Embarrassingly, it turned out to be a microscopic artefact.6 To complicate matters, the relationship between contagion and infection seemed not to be the same for all diseases, and the few stable clues available were misleading and irreconcilable between those diseases. Indeed, cholera was probably the worst possible potentially infectious disease any theorist could choose to study in the mid-19th century, because evidence about its mode of spread was so maddeningly contradictory.7–12 For example, cholera was seemingly contagious at the population level—it infected only humans and strictly followed the movement of humans over thousands of miles via multiple means of conveyance and, despite wind and weather, never travelled faster than humans travelled. Yet at the individual and local levels, common experiences argued against cholera contagion from person to person or via fomites. As physicians and laymen all knew, intense contact with cholera victims did not normally result in either nosocomial cases or even substantial numbers of secondary cases; yet at the same time, well people at intermediate distances, often lacking any contact with index cases whatsoever, were among cholera’s frequent secondary victims. Quarantine had no evident effect; already-affected troops marching into new locales did not transmit cholera to newly-exposed troops; chains of person-to-person spread could not be found; time intervals between successive cases were seemingly random; sudden outbreaks associated with low attack rates often featured widely dispersed cases with almost simultaneous disease onsets; outbreaks appeared in strictly circumscribed urban, but less commonly in rural locales, and prevailed for only very brief periods of time; cholera tended to recur decades later in the very same locales it had struck earlier (e.g. in 1832 and 1849); and human inoculation with cholera material did not produce disease. Theorists were perplexed. Depending on one’s point of view, cholera appeared simultaneously to be a contagious and a miasmatic disease, or neither contagious nor miasmatic; the American Medical Association hedged that ‘cholera is portable but not contagious’. [The term ‘miasmatic’ refers to hypothesized disease-causing elements in the ambient air, e.g. gases. Many diseases believed to be miasmatic are now known to be infectious by non-miasmatic means, prominently including those with indirect mechanisms of transmission such as waterborne (e.g., cholera, typhoid), insect borne (e.g. yellow fever, malaria) and by other intermediate and environmental means of disease spread (e.g. human gastrointestinal or inhalation anthrax)]. Other missing pieces of the puzzle whose absences confounded disease theorists in the mid-19th century included infectivity before disease onset and after disease resolution, infectivity without recognizable clinical illness, carrier states, environmental persistence of infectious agents, and other epidemiological features that, if known, might have helped make sense of things. But they were not known, and could not be learned without the ability to reliably identify specific aetiological agents or to prove disease associations using standardized reproducible methods and agreed-upon criteria. The brightest minds of science, medicine and public health in the mid-19th century kept going over the facts about cholera occurrence again and again, in thousands of published arguments spanning more than five decades, always to find them irreconcilable. It was into this confusing mix that Lea, Snow and men of their day ventured, certain that any theory could be refuted by any number of observations. Even so, in retrospect we can see that prescient theories and critical observations about the cause of cholera were becoming plentiful when Snow was still a youth. Cholera’s first major appearance in Europe and the western hemisphere, in 1831–32, led to hundreds of studies and multiple/variable/evolving theories about disease occurrence that foreshadowed and greatly influenced thinking about infectious diseases two decades later. Cholera theorists of the 1840s all knew the cholera literature of the 1830s, and in many ways carried on that earlier work where it had left off, as if there had not been a two-decade hiatus. In this writer’s view, it was during the 1831–32 cholera pandemic (Snow was then 18 years old) that recognizably ‘modern’ epidemiology was born, when Parisian physicians and health workers ably characterized cholera occurrence in person, place and time in large open populations, publishing in ‘real time’ line lists of cases (typically, columns of sequentially-appearing cases with associated demographic data such as age, sex and date/place of onset), and calculated morbidity and mortality rates, case-fatality rates and attributable risks, and statistically examined such suspected risk factors as age, sex, socio-economic status, occupation and crowding.13–19