The Diagnosis Dilemma: How Could They Treat It If They Didn’t Know What It Was?

Until the discovery of the antibiotic streptomycin in 1944, sufferers of tuberculosis and their physicians throughout recorded history did not know that the diverse collection of maladies and symptoms they fought were all different manifestations of the same disease¹:

• pulmonary tuberculosis, also known as phthisis (from the Greek word for “wasting”) or consumption, the most common form of the disease affecting the lungs;
• scrofula, TB of the lymph nodes in the neck, also known as “the King’s Evil,” which caused a chronic painless mass in the neck that grew over time and could rupture to form an open abscess;
• tabes mesenterica, TB of the small intestines, lymph nodes and peritoneum, which caused bowl obstruction, abdominal pain, vomiting and diarrhea;
• lupus vulgaris, TB of the skin, causing pink or brown nodules, anywhere on the body but often on the face, that eventually ulcerated and caused permanent disfigurement.

As study of the human body through autopsy progressed, scientists and physicians realized that all of these diseases shared a common characteristic, abscesses and lumps of scar tissue called tubercles, where the immune system attempted to wall off the affected area. Based on their experience and observations, doctors and scientists devised many theories about what caused the most common form, pulmonary tuberculosis. These theories ranged from unlikely to ridiculous to very close to the truth, and eventually to the discovery of Myobacterium tuberculosis in 1882.

Bad Genes, Weak Heart

For many centuries, the primary cause of TB was thought to be heredity – a familial weakness or disposition to develop the disease. Some physicians thought that TB was the failure of an inherited small and weak heart and ineffective circulatory system that could not pump the blood forcefully enough through the body to prevent the tubercles from forming. This school of thought led to the belief that reduced air pressure in higher altitudes could help the heart pump more easily, providing a cure and leading to the sanatorium movement. There was also belief that a wide variety of other environmental factors and behaviors caused TB: poor air quality, rebreathing the same air too many times, depravity and sexual promiscuity, spiritual anguish and alcoholism to name a few.

Tools for Diagnosis

The Thermometer – Though tracking changes in temperature had been used since early Greece, in 1868, Carl Wunderlich, professor of medicine in Leipzig, Germany, published the results of an extensive study in which he recorded and analyzed several million temperature readings in 25,000 patients with a number of diseases over a 20-year period. He devoted 200 pages to the regularly recurring spikes of temperature in tuberculosis patients, but he could not explain the fluctuations. After this study was published, monitoring body temperature became standard. ¹

The Stethoscope – Hearing what was going on in the chest became part of medical exams since the late 1700’s, but when French physician René Laennec had trouble getting clear sound through the layer of fat on an obese patient, he rolled up some paper, held it to her chest and listened, pleased to hear that the tube amplified the sound. He invented the first stethoscope, which was a wooden tube, in 1816, and conducted detailed research in the sounds of tuberculosis and other lung and heart diseases. Unfortunately, along with many of his contemporaries, Laennec did not believe that tuberculosis could be spread easily, and he was known to be careless about contamination. Though there is no way to know for sure how he contracted TB, Laennec died of the disease in 1826.¹

The X-Ray – In 1895, Wilhelm Röntgen, a professor of physics in Bavaria, was conducting a test by passing an electric current through a vacuum tube when he accidentally discovered new rays that he called X-rays, that could pass through many solids.⁵ Using X-rays to examine the chest transformed the diagnosis of tuberculosis, allowing physicians for the first time to see the development and progression of the disease.

Stain Unmasks TB and Breaks the Case for Contagion

It’s hard to believe today, but for many years physicians actively opposed the concept that TB could be caused by a contagious substance that could be spread from person to person.

“In 1546 and Italian named Girolamo Fracastoro noticed that tuberculosis usually attacked the lungs and suggested that it might be contagious, with the causative agent carried on clothing or in the air. Most of the European medical community scoffed at the possibility…”²

The breakthrough that would put these misconceptions to rest came in 1882, when Robert Koch announced his discovery of the bacterium that causes tuberculosis.

Koch, who had already made a name for himself by identifying the cause of anthrax, had been searching for the organism that could be proved to cause TB, probably after following the earlier work of French military physician and veterinarian Jean Antoine Villemin, who had published a paper in 1865 summarizing experiments in which he injected rabbits with the pus from recently deceased TB patients, showing that they always developed widespread tuberculosis while his control subjects did not. Villemin’s findings had not been widely accepted.¹

After several years of trying, Robert Koch was able to isolate the Myobacterium tuberculosis organism, and stain it so it could be seen under the microscope. TB’s hard, waxy shell and very small size made staining a challenge so that it could be easily viewed under a microscope. So Koch developed a method where he first used the standard blue stain called methylene blue and then a second counterstain called vesuvin. After heating the slide thoroughly, the Myobacterium tuberculosis was visible under the microscope.³

However, when Koch tried to recreate his results with a new batch of methylene blue stain, it didn’t work. He repeated the staining with his old batch of stain and the bacterium were visibly again. Koch figured out that the older stain must have absorbed some ammonia from the air of his laboratory, and when he added a small amount of ammonia to the new batch of stain, he could again see the bacterium. What he realized was that the ammonia had damaged the hard shell of the bacterium, allowing the methylene blue to stain it.³

Koch announced his findings to the medical community on March 24, 1882 in Berlin. He brought his laboratory with him and showed hundreds of slides showing Myobacterium tuberculosis taken from humans and many animals with TB to support his findings.³ In their book “Timebomb: The Global Epidemic of Multi-Drug-Resistant Tuberculosis,” authors Lee B. Reichman, MD, MPH and Janice Hopkins Tanne describe the initial reaction:

“At first, the shocked scientific establishment, in Germany and elsewhere, refused to believe that bacteria caused tuberculosis. How could well-meaning, good, dedicated physicians have been wrong for so many years? How could tiny, invisible bacteria cause this devastating disease that killed so many? Was it at all possible that tuberculosis was not inherited? The controversy went on for years and became part of a larger international debate over the germ theory itself. Many scientists found it difficult to believe that germs could cause any disease at all. Some dug in heir heels and refused to consider the evidence that Koch had so carefully amassed, stubbornly believing until they went to their graves that TB was hereditary.”⁴

These findings supported the sanatorium movement, which had unwittingly advocated moving TB patients to hospitals in the country where they had access to clean air and sunshine, which also conveniently separated the infected from their families and must have had some impact on its spread.

However, the wait in the sanatoriums would be a long one, because it would be another 62 years before the knowledge of what caused TB could be used to find a drug that could kill it.

Advancements in TB Diagnosis

The intervening years did bring about advances in diagnosis of the disease, however.

Chest X-ray is still used to identify and assess active tuberculosis. The isolation and identification of TB bacille also led to the development of the vaccine, Bacille Calmette-Guérin, or BCG, (prepared from a strain of the weakened live bovine TB; its protective effect appears to vary according to geography) as well as several simple skin tests for the disease.

First was the multiple- puncture Tine test (which left the tell-tale circular dotted scar you can see on the upper arm of many Baby Boomers), which has been replaced by the more accurate Mantoux screening test that is still used today. To conduct the Mantoux test, a small amount of inactive TB bacteria is injected just under the skin, and any reaction is assessed 48-72 hours later.

Unfortunately, the Mantoux test has low specificity, and produces a number of false-positives. Also, prior vaccination with the BCG vaccine (which is standard in many countries outside the U.S.) may result in a false-positive result for many years afterwards, causing unnecessary administration of TB drugs that can contribute to the resistance problem.

A newer TB testing method, interferon-γ (interferon-gamma) release assay (IGRA), provides more accurate diagnosis. In this assay, white blood cells that have been infected by Mycobacterium tuberculosis release interferon-γ in the presence of M. tb specific antigens. Because non-tuberculosis mycobacteria or the BCG vaccine do not express these specific antigens, these tests can distinguish between active and latent tuberculosis infection and produce fewer false positive results.

Current TB diagnostics leave much room for improvement, and the Stop TB Partnership’s Working Group on New Diagnostics and the Foundation for Innovative New Diagnostics are helping researchers pursue new and more effective diagnostic methods as we work with researchers pursuing new treatments.

Sources:

¹“The White Death” by Thomas L. Dormandy, 2000, New York University Press/1999, Hambledon Press; p. 22-25, 9, 8, 8, 27-39, 27-39. This extract is printed by kind permission of the Continuum International Publishing Group.(www.continuumbooks.com)

²“Tuberculosis” by Diane Yancey. Text copyright © 2008 by Diane Yancey. Reprinted with the permission of Twenty-First Century Books, a division of Lerner Publishing Group, Inc.; p. 21. All rights reserved. No part of this text excerpt may be used or reproduced in any manner whatsoever without the prior written permission of Lerner Publishing Group, Inc. (www.lernerbooks.com)

³“The Forgotten Plague” by Frank Ryan, M.D., 1992, Little, Brown and Company, www.littlebrown.co.uk/home; p. 12, 17, 9-11.

⁴ “Timebomb: The Global Epidemic of Multi-Drug-Resistant Tuberculosis” by Lee B. Reichman, MD, MPH, and Janice Hopkins Tanne, 2002, McGraw-Hill, www.mcgraw-hill.com ; p. 24.

⁵NobelPrize.org, http://nobelprize.org/nobel_prizes/physics/laureates/1901/rontgen-bio.html