Grantville Gazette 38

The White Plague

Run! Yes, run, do not walk . . . to the nearest doctor's office and demand that they write a prescription for a twelve-month supply of isoniazid for every member of your family.

Unfortunately, even if the pharmacy has any of the drug, he is going to tell you "Hell, no." He knows just as well as you do that in 1631 you have been dropped in the middle of an epidemic that will last another 250 years. No, it's not the black plague. It's not smallpox, and it's not any of the sexy, fast-burning epidemics.

It is the white plague-tuberculosis.

Every person in Grantville is very likely to be infected with tuberculosis mycobacterium within the first year. One-third of them will get sick. Without modern medical treatment, probably half of those who get sick will die in the next five years. About one-fifth will be chronically sick and eventually die from the disease, and one-third will recover.

How do "they" prevent that from happening? I'm sorry, but "they" includes you and you have an important role to play. How? First you have to learn everything you can about tuberculosis.

Mycobacterium tuberculosis and Mycobacterium bovis, the main two causative agents of tuberculosis(TB), have preyed on their human and animal hosts for thousands of years. Tuberculi and tubercular lesions were found in mummies from Egypt that are thousands of years old. They were found in pre-Columbian mummies and skeletons in Peru. On most continents, there is evidence of TB as soon as people gathered in agricultural communities. M. tuberculosis causes most human TB. M. bovis, which also infects cattle, sheep and goats, is responsible for 5-25% of human infections depending on time period, geographic area, and control measures.

The common names for tuberculosis disease include TB, consumption, scrofula, phthisis, Pott's disease, and white plague. Phthisis is the ancient Greek and Roman name for TB and was the name used by doctors until the 1800s. Consumption, the common name for TB for centuries, was so ubiquitous in the 1800s that the pale skin and wasted appearance of its upper-class victims became fashionable. That fashion has persisted to this day. Think of the heroin addict appearance of many top models or the pale-skinned, razor-thin vampires of contemporary fiction. Consumption was associated with vampirism in some superstitious cultures of the Early Modern Era.

The fashionable consumptive appearance of TB is not the only aspect of the disease that has persisted into the present. Up to one-third of the world's population today is or has been infected with TB. One-tenth of those infected with TB develop disease. Of those that develop disease, over half die within five years if not treated. Between one and two million people die each year from tuberculosis. It is the most common infectious disease on Earth . . . just as it has been since antiquity. Most of today's TB infections and disease occur in Asia and Africa, where the same poor living conditions that were common in 1600-1900 Europe predominate. The sub-optimal living conditions include overcrowding (even in rural villages), poor workplace and home ventilation, malnutrition, poor hygiene, other common diseases, and lack of basic healthcare.

TB can affect nearly all of the body's organs. The most common and well known symptoms are related to the respiratory system. Small and large pulmonary granulomatous (cheesy) abscesses, known as tubercles, form and destroy normal lung tissue and rupture blood vessels in the lung. The disease can spread to other organs from the lungs.

The bovine strain of TB is usually acquired by ingesting infected milk (especially) and meat. It most commonly attacks the digestive system forming tubercles in the lining of the intestines. Tubercular meningitis is common in infants exposed to the bacteria. Scrofula refers to the form of the disease in which the lymph nodes of the throat are visibly swollen. In Pott's disease, the bacteria attacks the bones and connective tissue. The skin form of TB is known as lupus vulgaris. It causes terrible ulcerous disfigurations of the face that resemble leprosy.

Most forms of TB are chronic diseases. They take years to kill their victim. The forms that act quickly usually affect the very young or the very old. Infants and young children are very likely to develop TB disease if exposed to the bacteria. School-age children seem to be more resistant to the disease, but, the age group that TB disease affects the most is people in the prime of their life-the 15-50 year-olds.

Not all TB infections lead to disease. The TB organism invades the body, where it attempts to reproduce. In most instances, the body's immune system succeeds in walling off the TB bacteria and killing it. Sometimes the bacteria remains alive, but is not causing disease and cannot be passed to another person. That state is called a latent infection which can become active disease if the host's immune system is compromised. The part of the immune system that is active against TB is called cell-mediated immunity and is moderated and controlled by T-cell lymphocytes. Anything that weakens the controller T-cells weakens the body's resistance to TB. Some of the things that compromise T-cells are: injuries to the lungs (such as silicosis and black lung disease), infectious agents (such as HIV today and measles in the past), malnutrition and low body weight, certain genetic factors, and stress (which cause the body to release corticosteroids, which negatively affects the immune system). Research has shown that those who are 10% underweight are three times as likely to get TB. In overcrowded, unventilated conditions. the body-particularly the lungs-is exposed to many more aerosolized TB bacteria, so there are more infections and more chances for infections to turn into disease. There are some genetic factors that make some people more susceptible to TB disease than others. Cell-mediated immunity is impaired in those more likely to develop disease.

TB epidemics differ from epidemics of other diseases. Other diseases cause epidemics that last months, years, or even decades. TB epidemics last centuries. The number of TB-diseased people steadily rose from the late 1500s to a peak in the late 1800s. The people in Grantville are dropped into the earlier stages of what was called the Great White Plague of Europe. The number of cases gradually dropped off in most of Europe in the late 1800s and early 1900s. This was beforeany effective treatment or vaccination was discovered.

Why did the epidemic wane? To this day, no one knows for sure. Despite the white plague epidemic's centuries old existence, that is still too short a time for natural selection to have any effect. Most experts think that better living conditions and nutrition played a big part. People have a stronger immune system with better nutrition and less crowded living conditions. Also, when people have more breathing room, there is less exposure to the TB bacteria in the air. Some speculate that there was a "helper infection" to TB that adversely affected their T-cells, much like HIV virus does today. The population became resistant to the helper infection to the point it became much less common. Today we know that there are many mycobacteria that do not cause disease. Some speculate that there was a rise in the exposure to another mycobateria that partially immunized a significant part of the population against TB.

Another characteristic of TB epidemics is that they can wax and wane in geographic areas. One village or country may be in the midst of a terrible outbreak where nearly everyone is TB infected and diseased, while their neighbors have much less or even no disease. The neighbors will have infection, but less disease. Then the pattern will reverse in the next year or century. Environmental factors and living conditions alone cannot account for the huge difference in the number of cases. It is another one of the unknowns about TB.

Physicians and scientists have studied TB for millennia trying to understand the disease in order find effective cures, preventatives, or treatments. Ancient Indian and Chinese texts refer to TB. Hippocrates and Galen, famous physicians of antiquity, were familiar with the disease. Hippocrates did not think that TB was passed from person to person. Galen did think TB was a communicable disease. In 1680, Franciscus Sylvius, a Frenchman living in Germany, described pulmonary tubercles and thought the disease might be hereditary. The specific cause of TB remained unknown until Robert Koch, the Prussian doctor, revealed in 1882 that he had isolated and identified the TB mycobacterium from diseased patients and produced TB in laboratory animals with the organism. Koch also produced tuberculin by killing the TB mycobacteria and filtering the solution of dead organisms. He touted tuberculin as a cure for TB-in which role it failed miserably. However, tuberculin is still used today to test for TB in the host.

Before the advent of modern vaccines and antimicrobials, treatment for TB was very hit and miss. Mostly miss. Galen advocated bleeding, among other things. Bleeding TB patients not only doesn't work, it will make them worse.

In Europe, until the early modern era, it was believed that the touch of a ruling monarch could cure scrofula. Any of the old treatments that decrease further exposure to TB bacilli or that strengthens the body's immune system will have some positive effects. Fresh air and sunshine actually work to some degree. Modern research has shown that a person with vitamin D deficiency is more likely to develop TB disease. Exposure to UV light in sunshine increases the body's stores of vitamin D. Proper rest was also prescribed for TB patients. Rest enhances the immune system, as does the absence of stress factors. Various changes of diet were also advocated. Those changes usually eliminated malnutrition.

In our world, it has proven much easier to significantly decrease the incidence of bovine TB affecting people than the human strain. Once it was discovered in the late 1800s that most bovine TB was caused by ingesting infected milk and meat, control measures were quickly implemented in most American and European countries. Boiling or pasteurizing all milk kills TB bacilli. Sale of meat from TB infected livestock was forbidden. Skin-testing livestock using tuberculin was implemented. TB infected herds were quarantined or destroyed with compensation paid by the government to the owners. Extensive education programs aimed at healthcare workers, farmers, and consumers were initiated. In the UK, there was widespread opposition to control measures by farmer's groups and the MP's that they controlled. So the UK fell decades behind in controlling bovine TB. Once bovine TB control measures were put in place, the rate of TB meningitis in infants and small children was cut in half.

Albert Calmette, a bacteriologist, and Camille Guerin, a veterinarian, developed the first effective and safe vaccine for human TB. Working out of the Pasteur Institute in Lille, France, they attenuated (weakened) a strain of TB using multiple subcultures in a glycerin-bile-potato culture medium. Each subsequent culture in the medium was less virulent than the last. They named the attenuated TB strain Bacillus Calmette-Guerin (BCG). Human tests of the BCG live vaccine began in 1921. BCG is still the only vaccine used to combat TB. It is variably effective. It will prevent some forms of TB more effectively than others. It also works better in northern Europe than it does near the equator. A tuberculin skin test should be done on everyone, except newborns, before they get BCG vaccine. A positive tuberculin test indicates prior exposure to TB or another mycobacterium. BCG should not be given to those who have a positive reaction to a tuberculin skin test. In tuberculin reactors there can be a severe local reaction to vaccine with scarring. BCG vaccine will cause a positive reaction on a tuberculin test given later. So it is important to test before the vaccination to differentiate between natural infection and vaccination positives. People should not take antimicrobials for a few weeks after BCG vaccination. The antimicrobial will very likely kill the live vaccine in the body before it can produce immunity.

Detection of TB uses several methods. Chest x-rays can detect typical pulmonary TB lesions in the lungs. Sputum and other body fluids from those suspected to be infected is stained to find the very typical TB bacilli. The tuberculin skin test, made from killed, filtered, and diluted T. bovis bacilli has been the most common test for TB for many years. A tiny amount of tuberculin is injected intradermally. Three days later the skin reaction, if any, is measured. The size of the reaction is used to determine whether the person is positive or negative for TB infection. Tuberculin testing can detect those with active disease, those with latent (currently inactive) infection, and those that were infected in the past but don't have TB bacilli in their systems now.

The first antimicrobials that were effective against TB were developed in the 1940s in the US, Sweden, and Germany. Streptomycin was developed in the US, PAS in Sweden, and thioacetazone was developed in Germany. At first they were considered miracle drugs because they were so effective in treating all forms of TB. Within a couple of years many patients treated with the drugs were relapsing with TB. Even worse, the TB bacteria in the relapses were now resistant to the drug first used to treat the TB.

In their race to find better drugs, three competing drug companies nearly simultaneously discovered that isoniazid had very strong ant-TB effects. Isoniazid is a coal tar derivative that was discovered by Czech chemists in 1912. It has remained one of the first-line treatments of TB to this day. Treatment is more effective and less drug resistance develops when two or more anti-TB drugs are used together. Ethambutol, thioacetazone, rifamycins, pyrazinamide, and PAS, are other drugs that are used to treat TB.

Chloramphenicol kills mycobacteria in test tubes. I have not found any references to testing the drug in humans for control of TB. Strains of TB that are resistant to multiple drugs are emerging. Most multi-drug resistance stems from improper drug use. Some patients don't comply with the often months-long therapy. When they don't, resistant bacteria are more likely to occur.

What measures can Grantville take to protect their citizens and their neighbors from White Plague? First, start a new fashion trend. Surgical masks for everyone in indoor gathering and work places. It is the single most important step that can be taken for immediate protection from airborne TB bugs. Never ingest a milk product unless you know the milk was boiled or pasteurized. Segregate all people who show obvious signs of TB disease. None of the measures are going to be very popular. Public health education about the danger that TB and other diseases pose is essential. Establish good exhaust ventilation in indoor meeting and work places. Re-circulating air in those places is a very bad idea unless the air is treated with strong UV light.

It is going to take some time to develop tuberculin for testing, BCG for vaccination, and isoniazid for treatment and prevention. The technology is there to begin right away and all can be achieved in a reasonable amount of time.

"Immediately" is the time to spread the word throughout Europe that much about TB is known in Grantville. That many cases of TB can be prevented and treatments are on the way in the near future.

The short-term goal is to protect Grantville and its neighbors with public health measures and education. The medium-term goal is develop tests, vaccine, and treatment. The long-term goals include shortening and eventually eliminating the European TB epidemic. It cannot be allowed to rage unchecked until the twentieth century. Up-timers must find effective ways to disseminate their knowledge of TB to all corners of Europe. The up-timers have centuries of discoveries to build on and share. They can stand on the shoulders of the OTL heroes of the fight against TB. They have a wealth of information from the current TB epidemic in the third world about which programs work and which have failed.

Prevention

Good ventilation in workplaces, public meeting places, and habitations is essential. TB bacilli can stay aerosolized for several hours in a room after they are coughed into the atmosphere. Evacuating the air to the outside clears the room. The TB germ will be quickly killed by UV light once it is outside. If a recirculating air system is used, the bacilli can be moved to the air in other rooms as well as the first room. Recirculating systems must have a micro filter or UV light filter to prevent the spread of TB. The type of filters needed will probably not be developed right away because of technology and manufacturing limitations. Surgical masks worn by the infected and the uninfected are a cheap, easy way to cut the number of exposures to aerosolized TB mycobacteria.

Preventing and alleviating overcrowded living conditions is essential in controlling TB over the long haul. In all ages, overcrowded people are much more susceptible to TB.

Eliminating malnutrition is absolutely necessary if TB is to be effectively controlled. Low body weight from malnutrition makes a person many times more likely to develop TB disease. Malnourished people's immune system(especially the T-cells) are much less robust than those with a good plane of nutrition. Supplementing with vitamin D helps bolster the immune system.

Minimize war. TB always flourishes during or right after wars. Overcrowding, infected refugees moving from place to place, malnutrition, exposure to other diseases, and stress are just some of the wartime conditions that greatly increase the incidence of TB.

Good general sanitation and the mindset that accompanies it will help. Infection with other diseases makes it more likely that a person will develop TB disease. In the 1800s those who contracted measles or whooping cough were very likely to develop TB disease afterward.

Eradicate the bovine form of TB. Milk, meat and herd inspection are essential. Pasteurizing or boiling milk products is a must. Boiling milk is a very easy practice to implement. Culling TB infected animals is needed to insure the long-term safety of the food supply. The same tuberculin that is used in human skin tests can be used in intradermal tests of livestock. If livestock show signs of TB or react on a tuberculin test, then don't sleep in the same enclosed building with them.

Tuberculin skin testing to detect latent (inactive) infection and early TB disease are very important. Find people before they spread the TB bacilli.

Separating those with active TB disease and those who react to tuberculin skin testing is another method of protecting the uninfected. It may have to be done, but there are many social and medical problems with this.

•For one, how do you sequester the infected and sick when in some areas the rate of infection is nearly 100%?

•Do you want to create a new class of medical and social "lepers"?

•How do you enforce quarantine?

•Those with latent (inactive) infection are not contagious. If you sequester them with those with active infection they are very likely to get re-infected with TB and develop active disease.

•Overcrowding in quarantine facilities will make those with TB disease worse.

•People will hide their infections rather than be singled out.

Developing BCG vaccine as quickly as possible is essential. All should be tuberculin skin tested and vaccinated if negative to the test. Policies will need to be developed concerning the vaccination of tuberculin-positive people. There are too many variables to have a "one size fits all" policy on vaccinating tuberculin reactors. Along with vaccinating, there must be an education program that informs all about the limitations of the vaccine. BCG does not protect against all forms of TB. It is generally much more effective in the young than in adults. Today in India, BCG does not prevent pulmonary TB in adults. Once a person is vaccinated with BCG, they will test positive for TB on a tuberculin skin test. More effective vaccines are in the final testing stages today. Most of them rely on technology, such as recombinant DNA, that is not going to possible for a long time in the 1630s.

TB can be prevented by a daily dose of isoniazid. The dose is less than that used for treatment. The drawbacks are lack of patient compliance and the tendency to forget other forms of control when you have a magic bullet. Treating TB infected people with isoniazid or other drugs will eventually eliminate the bacilli from their sputum and other body fluids.

Treatment

Until the discovery of antimicrobial drugs, there was no effective treatment for TB. Most of the drugs used to treat TB today are chemical antimicrobials rather than antibiotics. Antibiotics are gathered from micro-organisms, while chemical antimicrobials are produced in the chemistry lab. The two antibiotics are streptomycin and the rifamycins. The rest are chemical antimicrobials. Isoniazid is the most effective and seems to be the easiest to make. Pyridine is necessary to produce isoniazid. Today pyridine is produced with petrochemicals, while in the past it was produced from coal tar, which is available in the 1630s. There may not be enough pyridine produced for industrial users, but there should be enough for medical chemical production. While I was unable to find any references to whether chloramphenicol is effective in treating TB in people, the antibiotic can be tested on those with TB disease. Most anti-TB antimicrobials eventually produce resistant strains of bacilli when used alone in the treatment of diseased individuals. They don't cause resistance when used as a preventative or as a treatment for latent (inactive) infection. Luckily, isoniazid treatment takes much longer to produce resistant TB bacilli, so it can be used alone for a time. If chloramphenicol is effective against TB, it can be used in combination with isoniazid as the first line treatment of the disease. That will take some pressure off those trying to develop a second drug to use with isoniazid. Thioacetazone seems to me to be the most likely candidate as a second drug. It was produced by Bayer in post WWII Germany with limited production facilities. Other chemical antimicrobials are PAS, ethambutol, and pyrazinamide.

Discussion

Mitigation of the Great White Plague of Europe is not going to be easy. It is going to take decades, rather than months or years. The elimination of TB is going to take centuries if what has happened up-time is any consideration. I certainly don't presume to have all the answers. Smarter, more knowledgeable people than me are still trying to control TB in this century. Today up to one-third of the world's population has been infected with TB. The good news is the leaders in the fight against TB know what needs to be done. The bad news is that gaining compliance with control measures has been-and still is-an uphill battle. Our down-timers have an advantage over those left up-time: they have a huge head start in the fight against TB. They can see how others triumphed and how they failed, building on the past successes. They can build programs that are more likely to get local compliance which is absolutely essential for the programs to succeed. There are forward looking universities in Jena and Padua to work with them.

I am an optimist. I see control and prevention of TB moving outward in concentric rings from Grantville and places that accept help and knowledge from Grantville until the epidemic is finally controlled in a future decade or century. I see breakthroughs coming from downtime scientists in the coming decades and centuries. What will you do to help blunt the effects of the Great White Plague?

Bibliography and References

Daniel, Thomas M. Captain of Death: The Story of Tuberculosis.University of Rochester Press. 1997. ISBN 1-58046-070-4. Print.

Ryan, Frank, MD. The Forgotten Plague: How the Battle Against Tuberculosis Was Won – and Lost. Little, Brown and Company. First published in the UK as Tuberculosis: The Greatest Story Never Told. 1992. ISBN 03-316-76381-0. Print.

Dormandy, Thomas. The White Death: A History of Tubewrculosis. New YorkUniversity Press. 2000. ISBN 0-8147-1927-9. Print.

Kleeburg, H.H., DMV. "Tuberculosis and other Mycobacterioses." Diseases Transmitted from Animals to Man.Eds. William T. Hubbert, DVM, MPH, Ph.D. William F. McCulloch, DVM, MPH. Paul R. Schnurrenberger, DVM, MPH. Charles C. Thomas – Publisher. 1975. ISBN 0-398-03056-1. Print.

http://www.bikupan.se/tuberculosis/tuberc.html

Puranen, Bi. Tuberculosis: The Occurrence and Causes in Sweden 1750-2000. 2003. Web article.

http://hektoeninternational.org/Schwartz_TB.htm

Schwartz, Mindy A. "Tuberculosis – A Journey Across Time". Hektoen International: A Journal of Medical Humanities. Volume 1, Issue 4. August 2009. Web article.

http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowAbstract amp;ProduktNr=224278 amp;Ausgabe=226544 amp;ArtikelNr=29220

Herzog, H. "History of Tuberculosis". Respiration: International Journal of Thoracic Medicine. Volume 65, No.1, 1998. Web article.

http://onlinelibrary.wiley.com/doi/10.1111/j.1863-2378.2009.01265.x/pdf

Fetene, T., Kebede, N., Alem, G. "Tuberculosis Infection in Animal and Human Populations in Three Districts of Western Gojam, Ethiopia". Zoonoses Public Health. 58. 2011. Web article.

http://www.oie.int/fileadmin/Home/eng/Health_standards/tahm/2.04.07_BOVINE_TB.pdf

"Bovine Tuberculosis". OIE Terrestrial Manual 2009. Web publication.

http://www.cdc.gov/tb/

Centers for Disease Control: Tuberculosis. Web.

http://www.who.int/topics/tuberculosis/en/

WHO: Tuberculosis. Web.

http://www.nlm.nih.gov/medlineplus/tuberculosis.html

MedLine Plus: Tuberculosis. Web.

http://en.wikipedia.org/wiki/Tuberculosis

Wikipedia: Tuberculosis. Web.

http://en.wikipedia.org/wiki/History_of_tuberculosis

Wikipedia: History of Tuberculosis. Web.

http://en.wikipedia.org/wiki/Tuberculosis_treatment

Wikipedia: Tuberculosis Treatment. Web.

http://en.wikipedia.org/wiki/Isoniazid

Wikipedia: Isoniazid .Web.

http://en.wikipedia.org/wiki/Bacillus_Calmette-Gu%C3%A9rin

Wikipedia: Bacillus Calmette-Guerin. Web.

http://tuberculosis.emedtv.com/tuberculosis/tuberculosis.html

EmedTV: Tuberculosis. Web.

http://www.emedicinehealth.com/tuberculosis/article_em.htm

Emedicinehealth: Tuberculosis. Web.