The Forgotten Plague | Part 2

TB Book coverWelcome to Part 2 of a review of the captivating book The Forgotten Plague: How the Battle Against Tuberculosis was Won – and Lost by Frank Ryan, M.D. In many ways this story parallels the struggle that is being waged against Crohn’s disease, though the death toll of tuberculosis was far greater. The research presented on this site points to the involvement of a mycobacterial species in Crohn’s disease, the same genus of the bacteria that causes tuberculosis. Therefore, the lessons learned in the battle against tuberculosis could have some applicability in the modern day war on Crohn’s disease. If you missed Part 1, you may want to give it a quick read before starting in on this concluding post.

We rejoin the story where we left off: On the eve of the tuberculosis antibiotic revolution. In 1943, despite most of the world being consumed in a war, Jorgen Lehmann, chief of a chemical pathology laboratory in Gothenburg, Sweden had an inspired deduction. He proposed that a derivative of aspirin would act against tuberculosis due to competitive inhibition. (An oversimplified explanation of  competitive inhibition is where Chemical 1 cannot bind to an enzyme to complete a reaction because Chemical 2 blocks its way by binding to the same slot. Generally the two chemicals are similar in nature, so they occupy the same slot in a chemical reaction. This can be important where a pathogen like TB needs Chemical 1 to replicate, but instead is flooded with Chemical 2, so it cannot survive.)

Lehmann struggled through personal crises, the effects of war, supply shortages, ridicule of his colleagues and eventually ended up living in his laboratory, but against all odds PAS was born. Like other researchers, he tested it on himself before he determined it was fit for human trials. Because exaggerated claims prior to completion of the research could jeopardize PAS’ reputation, trial sites were sworn to secrecy. Miraculous stories of patients brought back from the brink of death followed, and when the discovery could be kept secret no longer, it was revealed to a physician’s conference in June 1946.

One would imagine that the news of any therapy having a positive effect on TB would be heralded, and indeed it was, but by the wrong party. The press had been given a conservatively prepared statement that was to be held until after the conference, but instead released it the morning of. The effect was that the attendees of the conference saw exaggerated claims in their morning newspapers before hearing Lehmann’s presentation. PAS’ reputation was marred, and the audience was not kind. One prominent sanatorium doctor, intending to mock Lehmann in a series of articles, made an unintended but insightful comment: “On the back of a little PAS you add a little streptomycin here, a little Conteben, or penicillin, or aureomycin, or chloromycetin there. The doses and the duration of treatment changes from year to year and from artist to artist.” (1) Interestingly, that is exactly what would be needed a decade later when resistant strains developed.

Across the Atlantic, streptomycin was first cultured from the throat of a sick chicken by Albert Schatz, the doctoral graduate student of Selman Waxsman at Rutgers University in October 1943. As with PAS, dramatic results in human trials at the Mayo Clinic by Feldman and Hinshaw (of failed Promin fame) showed streptomycin had a powerful anti-tuberculosis effect. The long term human results were presented to the National Tuberculosis Association meeting, coincidentally also in June 1946. Unlike the PAS reception, the audience was enthralled and streptomycin was overwhelmingly endorsed. This could be due to the well known Mayo Clinic researchers conducting the human trials, the pre-existing link between Waxsman and Merck Pharmaceuticals who generously provided an immediate supply of streptomycin for testing, or maybe it was because doctors were loathe to accept that a miracle cure could come from the well known drug aspirin. Regardless of the reason, streptomycin was heralded, PAS was criticized. Rene Dubos highlighted this cruel law of scientific life: “The sign of the truth is general acceptance…In science the credit goes to the man who convinces the world, not to the man to whom the idea first occurs.” (2)

Despite the lukewarm reception by the medical community of these discoveries, the patients would do anything to get their hands on some of these medications in limited supply. Streptomycin got to the Russian black market. One patient in a sanatorium made a miraculous recovery with a secret stash of PAS, even though he knew his doctor was against it. He eventually had to tell his doctor when he made an inexplicable recovery, who then relented but warned him not to tell the other patients, fearing for his life. Even Eleanor Roosevelt interrupted a shipment of streptomycin for a friend, which was ironic due to her eventual death from an undiagnosed case of TB.

Back in post-war ravaged Germany, Gerhard Domack was picking up the pieces of his interrupted TB research in 1945, which was desperately needed due to an outbreak.  Three derivatives had been isolated that showed promise, and with the war over, he had an opportunity to test them. One, Conteben, was tested in many manifestations of tuberculosis and performed well. In November 1947, Domagk brought 5 patients treated with Conteben to a new hospital to convince sanatorium doctors of its worth. Although the patients could attest to the severity of their disease and the miraculous cure, Domack was met with accusations. Sadly, this had become a predictable response.

A little fortune came Domagk’s way in 1947, when he was invited to Sweden to accept the Nobel prize he was awarded in 1939 for Prontosil, which he was forced to decline by the Nazi regime. After jumping through hoops to get the necessary documentation in time, and a harrowing train ride with his wife, he arrived thinking he was being attacked when he saw the press cameras and flashlights. He humbly accepted the Nobel prize in his tattered wedding suit jacket, which surprisingly fit him due to so many lean years of war. The new suit he had planned to wear was discovered in his house by the Americans occupying Germany, who played football in it.

It appeared that the war against tuberculosis was won with the advent of these three antibiotics, until George Orwell (and many like him) died from TB in 1950. Orwell had been previously treated with streptomycin and recovered, but the disease came back and a single dose of therapy almost killed him. While Orwell had developed a true allergy, hundreds of thousands of sufferers worldwide were experiencing a recurrence of TB which had become resistant to streptomycin. Studies showed that resistant germs developed after 4 weeks of therapy, and after 4 months 90% of patients had streptomycin resistant bacteria. In the end, a trial proved that streptomycin and PAS were far more effective against TB when combined. However, the combination therapy could only be administered if the patient was not resistant to either of the antibiotics.

Since Conteben was developed during the war by the German company Bayer, the United States would not honor the patent, and immediately began to study it, synthesizing promising derivatives. In an astonishing coincidence, the most promising derivative, isoniazid, would be simultaneously discovered in 1952 by Bayer in Germany and two pharmaceutical companies in America. In a familiar pattern, one of the researchers first tested isoniazid on himself. This powerful new drug proved as effective as PAS and streptomycin combined, but still TB became resistant to it with ease. While Isoniazid is still used as a first-line tuberculosis drug today, the world’s researchers were beginning to see that combination therapy was likely the only hope of a cure.

In the 1960’s researchers began combining all three drugs in an attempt to cure tuberculosis. Their results were so startling that no one believed them. When TB was initially treated with a combination of all three drugs and people meticulous adhered to the protocol, all of the patients were cured. A plan was presented to rid the world of tuberculosis at last. This included hunting down every TB patient, administering triple antibiotic therapy, instituting isolation periods for the contagious and using the BCG vaccine for the uninfected. While this was accomplished in the developed world, it was a failure in the poorer Third World countries. A golden opportunity was lost.

In the 1980’s, developed nations began to see a rise in tuberculosis cases after it had been mostly obliterated. Although a small number of experts warned of the danger, their words fell on deaf ears. As funding dropped, TB hospitals had closed and care was switched to outpatient clinics. The consequence was that an astounding 89% of patients never completed the full course of their treatment, and bred resistant bacteria. In 1985, as predicted by some, the first case of multi-drug resistant (MDR) tuberculosis was documented in the United States. All first and second-line tuberculosis drugs were ineffective against these new MDR bacteria.

In 1990 tuberculosis caused 2.9 million deaths worldwide and approximately 1.7 billion people were infected based on skin test results. The rise of cases in developed countries was alarming. Although factors such as poverty were involved, the main cause of this rise coincided with the emerging AIDS virus. AIDS and TB deliver a double danger to patients. To fight TB, the body calls on monocytes to act as a “jail” for the bacteria. The HIV virus damages those monocytes, making infected patients extremely vulnerable to rapid decline from either a new case of TB or the reactivation of an existing one. Additionally, tuberculosis has the capacity to activate HIV into full blown AIDS. Each disease triggers the other in terrifying synergy.

In a twist that may relate to the latest Crohn’s disease research, AIDS has triggered an infection virtually unknown until recently: Mycobacterium Avium Complex. MAC is a bird strain of mycobacteria commonly found in the environment and is responsible for the wasting, exhaustion, fever and diarrhea in end-stage AIDS patients. While the First World nations struggled to combat these new threats, in the poorer nations they have swarmed to epidemic proportions.

How would the world win this new war? The author suggests that we must know our enemy. “The germ that causes tuberculosis is not only one of the most awesome of enemies that humanity has ever faced, it is also one of the most unpredictable.” (3) New anti-tuberculosis drugs are being developed, like rifabutin, which is also included in the Crohn’s AMAT protocol. The BCG vaccine, or possibly a newly developed vaccine, may provide partial protection. Facilities and methods to prevent the spread of the disease are critical as is monitoring of patients to assure protocol compliance. Developed nations must provide resources to aid the Third World.

Since this book was published in 1994, I was left wondering what had happened in the intervening 10 years. The WHO statistics showed that TB is still alive and well, predominately in Third World countries like India, Pakistan, Indonesia, China, Nigeria and South Africa. In 2014, 1.5 million people died of the disease. One in three HIV deaths were due to TB. Almost half a million people worldwide have MDR TB. Ending the TB epidemic is a goal set for 2030. While the toll of Crohn’s disease is not comparable to that of tuberculosis, some believe that MAP or a related mycobacteria are at its heart. If a mycobacterial species is found to play a key role in Crohn’s disease, the doctors and researchers of the world may wish to review the fascinating and terrible history of The Forgotten Plague.

(1) Ryan, F. (1993). The forgotten plague: How the battle against tuberculosis was won–and lost. Boston: Little, Brown. p. 274.
(2) Ryan, F. (1993). The forgotten plague: How the battle against tuberculosis was won–and lost. Boston: Little, Brown. p. 298.
(3) Ryan, F. (1993). The forgotten plague: How the battle against tuberculosis was won–and lost. Boston: Little, Brown. p.411.

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