Genetic studies suggest that M. tuberculosis has been present for at least 15,000 years. Evidence of tuberculosis in humans dates back to 2400-3400 B.C where mummies have been shown to have evidence of disease in their spines. Hippocrates created the term phithis, or consumption, in 460 BC, because of the significant weight loss associated with the disease. Despite its frequency at the time, the cause of tuberculosis was unknown.
Searching for a Cause
By the 17th century, anatomical and pathological descriptions of tuberculosis began to appear in the medical literature. The contagious nature of the disease was suspected as early as 1546 when Girolamo Tracastoro wrote that bed sheets and clothing of a consumptive could contain contagious particles. In 1720, Benjamin Marten, an English physician, was the first to suspect that tuberculosis could be caused by "minute living creatures" and that by coming into contact with a consumptive an individual could contract the disease.
In a landmark study, the French army physician Jean-Antoine Villemin demonstrated in 1865 that tuberculosis could be transmitted from humans to animals and hypothesized that a specific organism caused the disease. It was not until 1882, however, that Robert Koch convincingly demonstrated that M. tuberculosis was the cause of tuberculosis.
Evolution of Treatment
National Jewish Health and 'Consumption'
The sanatorium movement, which had begun slowly in the mid 19th century, became widespread during the early to mid 20th century. In addition to bed rest and clean air, some patients had their lungs collapsed or surgically resected (partially removed).
TB was rampant among Europeans including those who had immigrated to the US in the 17th, 18th and 19th centuries. In the absence of effective treatment, roughly 2 in 3 died within 5 years of diagnosis. A theory emerged in the later 1800s that fresh mountain air and sunshine were helpful in controlling the disease. Sanatoriums sprung up in the Alps and in 1885 Edward Livingston Trudeau founded the first facility in America at Lake Saranac in upstate New York.
Unfortunately, the Adirondacks had little sunshine nor altitude. Thus, the sanatorium movement gravitated to the Rocky Mountains. More people came to Denver to seek “the cure” than for the gold rush.
Many of these poor, desperate souls had no assets and begged to be taken in or slept in the city parks. Francis Wisebart Jacobs, a leading member of Denver’s Jewish Community saw the need to provide shelter and care for the destitute consumptives and led the movement that resulted in the National Jewish Hospital for Consumptives opening in 1899. Focusing on the needy, its motto was “None who enter shall pay; none who can pay shall enter.” Our 20th century National Jewish Health emerged as a preeminent center for TB care and research with special focus on drug-resistant varieties of TB in the last half century.
The Search for the Cure
The ancient Greeks had pursued remedies for “phthisis” (the Greek equivalent of consumption). For 2,000 years no effective medicines were found. However, in an historic anomaly, scientists in Europe and the U.S. in a short period identified three drugs which, when taken together, proffered the long-thought Holy Grail – a cure!
In 1943 Selman Waksman discovered a compound that acted against M. tuberculosis, called streptomycin. The compound was first given to a human patient in November 1949 and the patient was cured. Subsequently, it was noted that some patients who received streptomycin improved only to become ill again because the tubercle bacillus had developed resistance to the drug. It was not until the development of additional anti-tuberculosis drugs that truly effective therapy became a reality.
A chemical related to aspirin, para-aminosalicylate or PAS, another chemical isonicotinic acid hydrazide or INH, and a compound released by a fungus-like microbe to inhibit other organisms from competing with it in the soil (streptomycin), were all discovered between 1943 and 1951.
By the late 1950s it was observed that if all three drugs were given to TB patients, cure rates of 80-90% could be achieved. However, the side effects and toxicity were formidable and required 18-24 months treatment.
Other new drugs were discovered in ensuing decades and by 1990, cure could be achieved in 6 months. Unfortunately, the human propensity for non-compliance had resulted in rising levels of resistance to these medications. When patients took fewer than the prescribed drugs or dose, the TB bacilli could undergo mutations which then made them drug resistant. TB resistance to the two major agents, INH and rifampin, were deemed “multi-drug resistant” or MDR-TB. The next layer of complexity were MDR-TB strains which acquired further resistance to important second-line drugs, deemed “Extensive drug resistance” or XDR-TB.
The outbreak of MDR-TB and XDR-TB were prominently associated with the AIDS epidemic (many of the cases were transmitted in hospitals where AIDS patients were receiving care). The lethality of MDR and XDR took TB back to the status of the White Plague centuries before.
National Jewish Health, by virtue of being a referral center for the U.S., had become the primary source for treatment and laboratory diagnosis of highly resistant TB in the world.
Clinical Trials