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A Brief History of Tuberculosis

By Candice B. Kissinger, Chao Center for Industrial Pharmacy & Contract Manufacturing

“A THING of beauty is a joy for ever:
Its loveliness increases; it will never
Pass into nothingness…”

These romantic words began the epic poem ‘Endymion’. It was the most famous work of English poet John Keats1 and was published three years before his tragic death from tuberculosis, at the age of 26. Although Keats was trained as a physician, he chose to be a practitioner of literature. He developed his chronic cough as a young adult, a legacy from his mother and brother who had preceded him in death from pulmonary tuberculosis. Awaking one morning in Italy to the sight of a blood-stained pillow, he recognized that the disease had begun to weaken his pulmonary artery. It signaled his doom and he died shortly thereafter in 1821, long before the definitive relationship between ‘germs’ and disease was described by a man born the following year: Louis Pasteur2. However, it wasn’t until 1881, another six decades, before the German physician Robert Koch3 proved conclusively that tuberculosis (TB) was also a bacterial infection and not some mysterious, supernatural curse of humanity.

March 24 is celebrated annually as World TB Day4, the anniversary of Koch’s sensational announcement to the Physiological Society in Berlin (March 24, 1882) proving that tuberculosis was caused by a living organism that could be studied and ultimately treated. Prior to this date, TB was shrouded in mystery. It was almost demonic: a lethal affliction of unknown origin which defied treatment. TB was so pervasive in Europe that the average person faced a 1 in 4 chance of death from this cause. It had many names. It was ‘The White Plague’ and ‘The Captain of Death’. TB also had many manifestations. In ancient times, the primary cause of ‘hunchback5’ was tuberculosis of the bone, observed in mummies from Egypt6 and Peru7, skeletons in European Neolithic gravesites8, and Huron ossuaries9 from prehistoric Ontario. Gross disfiguration of the neck with huge swollen lesions characterized the disease Scrofula10, otherwise known as tuberculosis of the lymphatic system. A myth which persisted in Europe for several hundred years was that the touch of a king or queen was sufficient to cure scrofula, providing another nickname for tuberculosis as ‘The King’s Evil11’. “Consumption” is the disease associated with the demise of heroines in French literature by Victor Hugo and Alexandre Dumas and French Opera (“La Traviata”) but it is otherwise known as pulmonary tuberculosis, the most common form of the disease. Pulmonary TB produces severe and unresolved coughing, night sweats and progressive weight loss. It can progress slowly, with the body wasting away, or it can be a rapid, fulminating infection achieving fatality in a matter of weeks. Every organ system in the body of a human or animal is susceptible to infection by Mycobacterium tuberculosis, the bacterium responsible for the disease, although lung disease is most common because respiratory transmission is highly efficient.

Koch’s work made diagnosis possible. Until such guidance was available, physicians had attributed the disease to some defect in the patient. Since multiple members of one family were often afflicted, it was suggested that TB was an inherited weakness. So many famous writers, musicians, poets and artists succumbed to TB, that it was thought to be linked to their artistic temperament. Koch’s lecture fostered hope. It snatched tuberculosis from the realm of superstition and subjected it to the scrutiny of scientific investigation. With a demonstrable cause, there could be a cure.

The cure was a long time coming. Antibiotics were born in the 20th century, beginning in Germany with Dr. Paul Ehrlich’s discovery in 1909 of the drug Salvarsan12, a “magic bullet” which cured syphilis. Ehrlich had attended Koch’s lecture on tuberculosis and later learned that he was himself infected, but was unable to find a cure. Sulfanilamides, the first broad-spectrum antibiotics, were derived from German Gerhard Domagk’s discovery of Prontosil13 in 1931. While sulfanilamides saved the lives of millions, especially women (“Childbirth Fever14”), they were ineffective against TB.

It wasn’t until 1943 that the first cure was discovered by an American graduate student named Albert Schatz15 working in the laboratory of Selman Waksman at Rutgers. Waksman alone received the Nobel Prize for the discovery, primarily because he had recognized the role of soil bacteria (Actinomyces and Streptomyces) to produce exotoxins which might be useful in treating disease. Schatz not only made the original discovery but more importantly performed heroic work in the laboratory to scale up production of crude streptomycin to provide material for the first animal tests and human clinical trials conducted by veterinarian William Feldman and physician H. Corwin Hinshaw at the Mayo Clinic. The announcement that streptomycin cured tuberculosis was stupendously important. There had never been a cure before. Tuberculosis was a death sentence. To survive was to experience a miracle. People who got the disease went away to remote places, like a state sanitarium, often never to be seen again.

Parallel to the developments at Rutgers was the quiet and careful development of para-aminosalicylic acid (PAS) by Jorgen Lehmann, a Danish pharmacologist working in Gothenberg, Sweden. PAS could also be rightly called the first effective treatment for tuberculosis but Lehmann lacked the support that Waksman had enjoyed, especially from his peers who openly derided the notion that something akin to common aspirin could have any benefit during the treatment of tuberculosis. Lehmann had made an intuitive leap from a single page paper published by American biochemist Frederick Bernheim about the insatiable appetite of M. tuberculosis for salicylates. He rightly predicted that another salicylate might competitively bind to the same site in M. tuberculosis and inhibit its growth. Progressing rapidly from studies in guinea pigs to treatment of TB patients in Denmark and Sweden, Lehman was able to demonstrate a cure.

Within a few years, some of the patients who had previously been cured of TB by one of these two wonder drugs, succumbed to the disease again and then died when the drugs proved ineffective. Drug-resistant tuberculosis had emerged. Researchers in England were the first to successfully combine streptomycin and PAS to overcome resistance, while clinicians in Scotland proved that strict adherence to therapy throughout a much longer term of six months was critically important. More powerful drugs, such as isoniazid, were discovered in the 1950’s and meticulous use of multi-drug therapy was mandatory. Worldwide, death rates from tuberculosis began to fall dramatically and there was a shared sentiment that TB could be ultimately vanquished.

Andrew Grove of the Intel Corporation once said, “Success breeds complacency. Complacency breeds failure. Only the paranoid survive.” He was talking about semiconductor research, not tuberculosis, but his quote describes the reason for the continued global failure to defeat TB. With the advent of drugs that successfully treated tuberculosis, vigilance lagged. Research into new treatments was not supported because the business model was unappealing: TB is cured, why bother? Likewise, financial support for treatment centers and epidemiological surveillance began to be diverted. In spite of all that was already known about the uncanny ability of Mycobacterium tuberculosis to survive various treatments, society became complacent. TB patients, feeling better after a few weeks, would stop taking their medications. TB treatments around the world were not always manufactured or formulated correctly. A dose that was incompletely absorbed would result in a treatment that was incompletely lethal for the bacterium, encouraging the survival of more and more resistant strains of TB.

No immunity to tuberculosis is conferred via prior exposure to the disease. The immune system lacks the long term ‘memory’ to recognize the disease. TB is predominantly an airborne disease, transmitted by a cloud of thousands of tiny droplets expelled when a person, whose lungs or throat is infected, coughs, talks, or even sings. Inhaling these droplets can establish a new pulmonary (lung) infection in susceptible populations, especially those people whose immunity has been weakened by factors such as smoking, malnutrition, another disease (especially HIV-AIDS), or certain treatments (such as anti-cancer drugs, or medications which prevent tissue rejection after organ transplants). In a community where the disease is rampant, repeated infection is possible and with every subsequent treatment, the probability of increased drug resistance increases.

Multi-drug-resistant tuberculosis (MDR-TB) is defined as a strain of Mycobacterium tuberculosis that is resistant to at least two of the best, first-line TB drugs: isoniazid and rifampicin. MDR-TB already exists in North America, although the incidence is far less than in other countries. Citizens and visitors to underdeveloped countries are at a greater risk for tuberculosis. For example, the annual incidence rates were about 356 per 100,000 people in Africa versus about 4.4 per 100,000 individuals in the United States in 2007. In 2005, Swaziland had the highest estimated incidence at 1,262 cases per 100,000 people. With more than 1.8 million cases, India has the largest number of infections. Tuberculosis infections are not increasing globally. However, the incidence of multidrug-resistant tuberculosis, commonly called MDR-TB, is on the rise. The World Health Organization reports that there are nearly 500,000 new cases of MDR-TB each year. In Baku, Azerbaijan, for example, drug resistant strains are responsible for as many 20 percent of all new cases. In 2006, the United States experienced 111 new cases of MDR-TB and three cases of the more dangerous extremely drug-resistant tuberculosis, according to the CDC.16

The number of antibiotics that remain effective against tuberculosis and multidrug-resistant tuberculosis have declined. There are new drugs in the development pipeline, including some in clinical trials, but their approval requires proof of both safety and efficacy and neither outcome is assured. If some of these drugs achieve regulatory approval, their availability is still several years away. This rate of development is at odds with another trend in tuberculosis: the emergence of an even deadlier form called extremely drug-resistant tuberculosis (XDR-TB). Like MDR-TB, XDR-TB is also resistant to the two most powerful and effective antibiotics (isoniazid and rifampicin), but unlike MDR-TB, it is also resistant to at least one fluoroquinoline antibiotic (e.g. ciprofloxacin, levofloxacin, ofloxacin, etc.) plus at least one of the three injectable 2nd-line treatments (amikacin, kanamycin or capreomycin). Bacterial drug resistance implies mutation, and mutation has traditionally been thought to confer some degree of weakness to the organism. Recent research contradicts that notion. MDR-TB and XDR-TB are virulent pathogens. While the origin of the resistant forms of tuberculosis derives from treatment failure (inadequate, incomplete, or inappropriate), this disease is not restricted only to those individuals who have been treated for TB previously. Primary infections with drug-resistant tuberculosis are appearing in the epidemiological data.

Percy Bysshe Shelley, a contemporary of Keats, wrote a poem describing an inscription at the base of a broken statue that was scattered among ruins of a lost civilization: “My name is Ozymandias, king of kings: Look on my works, ye Mighty, and despair!” In the 19th and 20th centuries, medical research made enormous strides. Bacteria were linked to disease, vaccines were developed to control smallpox, anthrax and rabies. Antibiotics were discovered and multiple diseases were actually cured for the first time. Fueled by hubris and armed by science, mankind declared victory over infectious disease, including that most ancient scourge of humanity: tuberculosis. Like Ozymandias, we were premature in this declaration and the emergence of drug resistant TB has toppled our illusion of supremacy. We must never again underestimate tuberculosis, nor rely solely on the power of antibiotics to save us. Only with the combined force of education, surveillance, training, thorough and effective treatment, maintenance of our healthcare network, continuous research, and the willing cooperation of patients will we be able to push back this disease which continues to afflict millions of people worldwide.

Excerpt from a paper originally presented at World TB Day 2008

One of the few effective drugs, Seromycin®, is manufactured by Purdue University's Chao Center for Industrial Pharmacy & Contract Manufacturing.

References

  • 1http://en.wikipedia.org/wiki/John_Keats
  • 2http://louisville.edu/library/ekstrom/special/pasteur/cohn.html
  • 3http://en.wikipedia.org/wiki/Robert_Koch
  • 4http://www.stoptb.org/events/world_tb_day/
  • 5http://books.google.com/books?id=iYXel4RXuU8C&pg=PA125&lpg=PA125&dq=tuberculosis+bone+hunchback&source=web&ots=acAXKeFf1Z&sig=JHUjamzinEqpq6DPN_CET6mHjp0&hl=en&sa=X&oi=book_result&resnum=5&ct=result
  • 6http://jcm.asm.org/cgi/content/full/41/1/359
  • 7http://findarticles.com/p/articles/mi_m1200/is_n12_v145/ai_14947828
  • 8http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003426
  • 9 Paleopathology in an Iroquoian ossuary, with special reference to tuberculosis, Am J Physical Anthropology, Volume 65, Issue 2, October 1984, Pages: 181-189.
  • 10http://www.umm.edu/ency/article/001354.htm
  • 11http://en.wikipedia.org/wiki/Scrofula
  • 12http://books.google.com/books?id=yZwVAAAAYAAJ&dq=Salvarsan+syphilis&printsec=frontcover&source=bl&ots=nib2-mPRPj&sig=IMw0i1lpHguHLMTigArZpFVvTd4#PPP1,M1
  • 13http://www.nationmaster.com/encyclopedia/Prontosil
  • 14http://www.medterms.com/script/main/art.asp?articlekey=7921
  • 15http://en.wikipedia.org/wiki/Albert_Schatz_(scientist)
  • 16http://www.ourjeet.com/Newsletter/tbcapsule_article.asp?nid=N000000335
  • Ryan, Frank, The Forgotten Plague: How the Battle Against Tuberculosis was Won – and Lost, (1992), Little, Brown & Co., Boston, ISBN 0-316-76380-2

    • Lee Reichman, M.D., (Executive Director of the New Jersey Medical School, National TB Center, and author of “Timebomb: The Global Epidemic of Multi-Drug-Resistant Tuberculosis”) with Candice Kissinger (Chao Center and Dept Industrial & Physical Pharmacy, Purdue Univ) during Union Conference on Lung Health, Paris, October-2008.

  • Daniel, Thomas M., Captain of Death: The Story of Tuberculosis, (1997) University of Rochester Press, 668 Mt. Hope Avenue, Rochester, NY 14620, ISBN 1-878822-96-9
  • Coker, Richard J., From Chaos to Coercion: Detention and the Control of Tuberculosis, (2000) St. Martin’s Press, 175 5th Avenue, New York, NY, 10010, ISBN 0-312-22250-5
  • Reichman, Lee B., Tanne, Janice H., Timebomb: The Global Epidemic of Multi-Drug-Resistant Tuberculosis, (2002) McGraw-Hill, New York, NY, ISBN-0-07-135924-9
  • Iseman, M.D., Tuberculosis Therapy: Past, Present and Future, European Respirating Journal (2002) Vol.20: 87s-94s
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