As human civilizations began to flourish, so did the infectious diseases that afflicted them. Over time, an understanding of these contagious sicknesses gradually developed, but not as rapidly as developments in other areas of medicine. Despite major advances in science and medicine that occurred in the first and early second millennia AD in China, India, Persia, and the Islamic world, and more accelerated developments that followed during The Renaissance and the Age of Enlightenment, the specific causes of infectious illnesses defied explanation and remained in the realm of the occult. The Franciscan monk, Roger Bacon, had originally described the fundamental principles of the scientific method in 1269, stressing the formulation of hypotheses based on observations from nature and the primacy of experimentation to confirm such hypotheses. Yet, he and his contemporaries lacked the tools and techniques to adequately study events that could not be observed by the human eye; contagious diseases fell into this category. This remained the major impediment to the advancement of the discipline over the ensuing 400 years.

To the ancients and their descendants well into the second millennium, the cause of infections had been variously ascribed to divine punishment for sins and other human failings; the results of poor hygiene; and the consequences of changes in climate or atmospheric conditions related to cosmic activities—the concept of “bad air” or “miasma”.¹ Although the causes of infections were poorly understood, their contagious nature had been well documented. The Old Testament contains several references—and suggested remedies—regarding contagion.² The kosher food laws from Leviticus may have represented one such remedy, borne out of health concerns as much as anything else. However, the first organized view that microscopic germs may be causes of disease was not articulated until the sixteenth century.

Using his remarkable powers of observation and knowledge of epidemics, the Italian physician Girolamo Fracastoro, also known as Hieronymus Fracastorius, culminated sixteen years of research in 1546 with the publication of “de Contagione,” a treatise that represented the first scientific discussion of the concepts of germs, contagion, transmission, and their application to a variety of infectious diseases. In it he prophetically surmised that tiny, free-living germs exist in nature and are capable of causing disease. Despite being invisible to human eyes, these organisms could be transmitted from person to person directly or via inanimate object intermediaries, thereby spreading illness between people.³

Although penned a century before microscopic germs would actually be seen, Fracastorius’ work remains a landmark of clarity in the field. But it was not his most popular work; he is perhaps best known for naming and characterizing syphilis, disparagingly referred to as “the French Sickness” by the Italians and as “the Italian Disease” by the French. In “Syphilis sive Morbus Gallicus,” written years before his treatise on contagion, he painted in poetic verse a remarkably accurate, detailed picture of the clinical consequences of the “great masquerader”—the disease that mimicked countless others.⁴

More than one hundred years after Fracastorius, the “seeds of disease” were visualized for the first time. Although he did not invent the microscope—that feat having been accomplished late in the sixteenth or early in the seventeenth century—Antony van Leeuwenhoek became the first to use a simple version of the device to actually identify microorganisms, the germs that he likened to “little animals” or “animalcules” in 1676. Leeuwenhoek, a Dutch textile merchant and self-taught amateur scientist, had taken an interest in creating magnifying lenses and building microscopes. He apparently used these to make an enormous variety of observations on natural phenomena, which he duly reported to the most important scientific body of the time—the newly formed Royal Society of London.

In his most famous, 18th letter to the Royal Society, Leeuwenhoek described the little creatures he saw under his microscopes in a sample of rain water left standing for four days, in river water from his hometown of Delft, in well water from his courtyard, in seawater, and in water that he infused with fresh peppercorns, cloves, nutmeg, and ginger.⁵ Despite the likelihood that most of the “animalcules” he noted in these initial observations were not bacteria but protozoa, a subkingdom of microorganisms that are significantly larger in size and more complex in function than bacteria, his findings were still revolutionary. Seven years later, Leeuwenhoek observed and characterized with astonishing accuracy a variety of morphological forms of bacteria found in samples obtained from teeth scrapings of children and adults, including his own.

Although Leeuwenhoek confirmed Fracastoro’s sixteenth century hypothesis,6 and his own findings were subsequently validated by others, the critical significance of these tiny forms to human health would not be fully appreciated until almost 200 years later when an industrial chemist in Paris named Louis Pasteur and subsequently a military physician named Robert Koch in Berlin successfully cultured bacterial organisms from diseased tissues, thus confirming the “germ theory” of disease causation and ushering in the era of modern medical microbiology. Meanwhile, in the time period between Leeuwenhoek and Pasteur, multiple iterations, variations, and opposing views regarding whether germs caused disease were promulgated and debated in enlightened society.⁷ Definitive proof of such theories still awaited the discovery of scientific tools enabling their validation; nonetheless, empiric evidence supporting the concept that microscopic germs caused infectious diseases mounted dramatically with the seminal observations of two European physicians and a holy botanist in the mid-nineteenth century.

By the mid-1800s, childbed or puerperal fever, originally described by the great Hippocrates in his famous Corpus, was well recognized as a highly mortal and all too common complication of obstetrical care on hospital maternity wards. This illness, occurring within days of delivery, resulted from intrauterine infection leading to profound inflammation of the uterus and contiguous organs in the female abdomen and pelvis and, in many cases, to the rapid spread of infection via the bloodstream—leading to death of the mother. While childbed fever was not then known to be an overwhelming bacterial infection as it is today, it was felt by some in the medical profession to be a contagious illness, and it was the most common cause of maternal mortality at the time. The rising number and growth of hospitals that accompanied nascent industrialization in Europe in the eighteenth and nineteenth centuries meant that more women were giving birth on maternity wards; a greater concentration of postpartum women translated to more opportunities for lethal outbreaks of childbed fever.

Allgemeine Krankenhaus—Vienna General Hospital with its associated Lying-in or obstetrical hospital—opened in 1784. Like other such hospitals of the time, it became a major venue for the medical care of society’s poor and served an important role in providing a training ground for young men seeking to become physicians. The Lying-in hospital comprised two obstetrical services that alternated admissions on a daily basis: the First Division, operated by physicians and medical students, and the Second, run by midwives. Because of the need to teach the medical students, more internal examinations were performed on each pregnant woman on the First Division. In the mid-1840s, childbed fever was rampant in the hospital; more than fifteen percent of postpartum women on the First Division succumbed to childbed fever, a figure nearly tenfold higher than that of women on the Second, midwife-operated Division. To Ignác Semmelweis, a young Hungarian obstetrician and newly appointed assistant to the head of the Lying-in hospital, finding the cause of the illness involved solving the riddle of the discrepancy between Divisions. The results of his epidemiologic and pathologic investigation would eventually advance the germ theory of disease causation.⁸

The autopsy—dissection of the dead—was a critically important component of nineteenth century medicine and medical education. It was the primary tool used to teach anatomy and pathology to medical students, and in the absence of X-rays and other techniques of imaging the internal body during life, it represented the best opportunity to make identifiable links between altered anatomy—structure—and clinical manifestations of diseases. Unlike medicine of today, where autopsies have become an uncommon event and medical trainees rarely get the chance to learn from the dead, these procedures were routinely performed in European hospitals, especially those in the German-speaking world. Nowhere was this more highly valued than at the Allgemeine Krankenhaus and its Lying-in hospital. Nearly every woman who died of puerperal fever underwent an autopsy, generally by the same groups of doctors and medical students that moved continuously between the autopsy room and the wards of the First Division to examine expectant mothers and perform deliveries. And therein proved to be a clue that allowed Semmelweis to unravel the epidemiologic mystery behind the cause of childbed fever.

Semmelweis made several observations in conjunction with the aforementioned initial one in 1847 that led him to suspect a germ as the cause of the illness that plagued the First Division. He noted that in some cases, the infant delivered of a woman with childbed fever succumbed to a similar illness, suggesting a communicable cause. This idea received further credence by another event, the death of a respected pathologist at the institution, Professor Kolletschka, due to an overwhelming infection resulting from an accidental blade injury during an autopsy; the findings on Kolletschka’s autopsy appeared similar to those of the victims of childbed fever. Semmelweis recognized that the putrid odor associated with women dying of puerperal fever was similar to that emanating from corpses during autopsies and noted that the malodorous smell from the corpses was also found on the hands of the doctors performing the procedures. Additionally, he observed that the attending physicians and medical students did not generally wash their hands after leaving the autopsy room to see their pregnant patients or after attending to patients with other infections. Finally, he observed that the death rate from puerperal fever declined significantly when the medical students were on vacation and no autopsies were being performed. Synthesizing this information, Semmelweis correctly hypothesized that some form of “putrid matter” must be carried on the hands of physicians and students during their rounds between the autopsy and birthing tables or between patients on the wards, and that this might be transmitted to pregnant women resulting in a highly lethal peripartum illness.⁹

To his great credit, Semmelweis made these observations without the benefit of formal training in microbiology; in fact, the discipline did not exist at the time. The idea that invisible germs could be responsible for illness—the “germ theory of disease”—was neither taught in medical schools nor accepted as truth. This situation would not change until the work of Pasteur and his disciples became widely accepted later in the nineteenth century. But for a variety of reasons, some of which were deeply ingrained personality flaws, he failed to follow-up his astute epidemiological observations with the next logical steps expected of the medical scientist and therefore never sought proof, possible with the state of microscopy at the time, that “animalcules” were present in the “putrid matter”—pus—found in the autopsied abdominal and pelvic cavities of childbed fever victims. There were no rigorous laboratory experiments that would have proved his hypothesis, and despite multiple opportunities and the well-intentioned urging of his proponents, no published manuscript emerged to explain his reasoning and thought process. His views on puerperal fever, correct though they turned out to be, also flew in the face of his chain of command at the hospital. By failing to convincingly demonstrate the merits of his ideas to the medical staff, Semmelweis became alienated and marginalized.