Tuberculosis After Lunch

James K. O’Brien MDFor Seattle Prep High School

March 12, 2010

• World TB Day• March 24, 2010• Pavilion at Olympic Sculpture Park• 6-8:30P• RSVP elli.koskella@seattlebiomed.org• Website:

www.seattlebiomed.org/event/world-tb-day

Tuberculosis Outline

• Ancient disease• How do we get it?• History

– Prehistoric– Dark ages– Renaissance– Famous people– Sanitorium movement– Koch and the microbiology revolution– Antibiotics– TB antibiotics

• Public health funding is important• Epidemiology• Principles for the treatment of TB

Everything’s worse with sharks.

…and crocodiles.

…and tuberculosis.

Oldest remnant of tuberculosis DNA discovered in the North American wooly mammoth, 10,000 B.C.

In the 19th and 20th centuries1,000,000,000 dead from TB.

How do we get TB?

• Predominately a respiratory infection. Rare in most areas of US including Seattle.

• Passed by microdroplets emitted by cough, talking and singing. Sneezing less effective.

• If not treated 50% of those infected will die often over years.

• Mode of death: malnutrition, inability to oxygenate blood, bleeding from lungs(hemoptysis).

• 30-40% of close contacts to a TB patient (e.g. spouse or children) will be infected with TB

• Approx 90% of those infected will never develop symptoms of pulmonary TB

• 5% infected will get sick within two years of infection.

• 5% of those infected will develop infection in their lifetime.

• On average, a TB patient infects ten other people before they get treatment.

• It’s the unpredictability of TB that allows it’s survival through history.

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History

• Prehistoric Times• 5,000-1000 B.C.: People began

gathering in “urban” areas. Egytian mummies showed evidence of TB.

• 4,000 B.C.: Indo-europeans of the copper and bronze ages, tracked by the evolution of language, move and settle areas from Northern Europe to India.

• Peak occurrence of TB in Greece 700-500 BC.

• Indo-europeans were cattle herders. The TB bacillus that infects humans is thought to have evolved from a bacillus carried by cows.

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TB in the New World

•We are unclear when tuberculosis arrived in the Western Hemisphere, but believe it accompanied animal and human movement across the Bering land bridge before 8,000 B.C or with ocean-going people after the land bridge was lost.

• Mummy from Peru, dated 1,000 B.C., evidence of TB DNA in the spine.

• Prior to this DNA evidence it was believed that TB was introduced to the New World by Europeans.

Dark Ages

Renaissance (15th century-18thcentury)

• 1450, migration of Greek scholars to Northern Italy

• 1540, Girolamo Fracastoro, Padua, Italy, enunciates a theory of contagion.

• 1500-1700, Southern Europe initiates public health measures, Northern Europe laughs at Southern Europe. More TB in Northern Europe and its colonies.

• By 1800, 1 in 3 people who died in Europe died of TB.

1821 Keats wrote, “ ’Bring me the candle,’he called to Brown, with whom he was staying,‘and let me see this blood.’ He looked at the bright red spoton his pillow and then, his excitement and intoxication gone, he said calmly,‘I know the colour of that blood. It’s arterial blood…that is my death warrant.’ ” Keatsdied at age 26 of TB.

• Some famous people with tuberculosis

– King Tut, Samuel Johnson, Moliere, Maupassant, Voltaire, John Calvin, Rousseau, Goethe, Sir Walter Scott, Chopin, Immanuel Kant, Louis XIII and Louis XVII, Napoleon II, Bartholdi(Statue of Liberty), Stephen Crane, Washington Irving, Anton Chekov, Tad and Edward Lincoln (children of A. Lincoln), Edvard Munch, Paganini, Laennec (stethoscope), Shelley, John Keats, Elizabeth Barrett Browning, Charlotte/Emily/Anne Bronte, Dostoyevsky, Grieg, Robert Louis Stevenson, Alexis de Tocqueville, Henry David Thoreau, Paul Gauguin, Cecil Rhodes, “Doc” Holliday, W. Somerset Maugam, Eleanor Roosevelt, DH Lawrence, Franz Kafka, Albert Camus, George Orwell, Eugene O’Neil, W.C. Fields, Vivien Leigh(Scarlet O’Hara), Nelson Mandela, Carlos Guillien (former Mariners shortstop).

Sanatorium

• Rest, fresh air, altitude and nutrition.

• Davos, Switzerland. est. 1880. Robert Louis Stevenson finished Treasure Island here. Thomas Mann’s Magic Mountain.

• Saranac Lake, NY. First US sanatorium, 1885. Edward Trudeau.

• Firland’s Sanatorium, est. 1911. • Betty McDonald, wrote The Plague

and I about experience at Firland’s.

Robert Koch: Microbiology

• Late 19th Century: Anthrax and cholera• Popular others: Louis Pasteur, Paul Ehrlich, Rene Dubos,

Alexander Fleming, Selman Waxman.• Koch’s Postulates– Bacteria is found all disease examined– Prepared in pure culture– Reintroduced to animal, causes disease– Retrievable in inoculated animal with disease

• In 1908 gave a lecture contradicting the hypothesis that cow TB, Mycobacterium bovis, was related to human TB. Wrong, it was. Marred Koch’s reputation.

• Failed vaccine for TB.

Antibiotics• Bayer (of aspirin fame) was a manufacturer of dyes for the textile industry,

with a small pharmaceutical division.• In 1920s Bayer hired Dr. Gerhardt Domagk. Tested dyes with chemist Josef

Klarer. Many not only killed the bugs, by ‘staining’ and destroying cell walls, but killed the inoculated animals as well.

• Red dye KL-730 given to mice, inoculated with bacteria, and allowed mice to live while control mice died of infection.

• Sulphonamide, or sulpha, drugs were discovered.• In 1933, a young woman namd Heidi, was nearly dead from complications

of strep throat. At Wuppertal-Elberfeld Hospital in Germany she was given Prontosil, first marketed sulpha drug, and was better in twenty four hours.

• These findings were repeated in larger trials. • Fleming’s Penicillium notatum extract, penicillin, was given to a sick friend

in 1936.• Neither compound worked against TB.

Tb Antibiotics

• Selma Waxman PhD and Albert Schatz, a PhD student in soil microbiology, discover Streptomycin. Rutgers University.

• Hypothesis: soil is a battleground for microbes. They must emit chemicals to keep others ‘off their turf’.

• Streptomyces discovered over years of research with manure and soil. – Other antibiotics discovered from the Streptomyces genus include: erythromycin,

neomycin, tetracycline, vancomycin, rifamycin, and chloramphenicol.• First patient got Streptomycin at the Mayo Clinic, an elderly farmer from

with TB meningitis. Hinshaw and Feldman at Mayo Clinic conducted clinical trials.

• Jorgen Lehmann discovers PAS in Sweden, derivative of aspirin, and similar in structure to first sulpha drugs.

• Later drugs developed, multiple drugs at a time, for many months, needed to treat TB.

Reported TB CasesUnited States, 1981-2001

10000120001400016000180002000022000240002600028000

80 82 84 86 88 91 92 94 96 98 2000

Year

1981 1985 1989 1993 1997 2001

No

. of

Ca

ses

Public Health Funding is Important

New York as an example

Decimation of the TB Control Budget

• In 1979 the New York State budget crisis led to state TB funding to NYC of $0.

• In 1978 NYC spent $23 million on TB control and between 1985 and 1993 it spent $2-4 million/yr.

• As the TB budget dropped in NYC the cases of TB rose: 1980=1514 TB cases, 1990=3520 TB cases, 1994=greater than 4000 TB cases.

• More than $40 million in 1994 to NYC alone from federal government to curb the epidemic

• Between 1980 and 1993, estimated 20,000 extra cases of TB in NYC with each case costing $20,000 per case to treat.

Epidemiology

Incidence Number of cases of TB

US 4.2/100,000 12,898

Washington State 3.5/100,000 228

King County 6.5/100,000 121

2008

In US 2% of cases resistant to the two best drugs, isoniazid and rifampin, and this isMultidrug resistant (MDR) TB.

Prevalence Number of cases of TB

Europe 60/100,000 525,000

Africa 511/100,000 3,773,000

SE Asia 290/100,000 4,809,000

India 283/100,000 962,000

2007

Worldwide: 2 billion infected with TB (evidence by TB skin test), 2 million die each year.

Previous attempts to cure TB

• Hippocrates, honey-barley gruel-wine resin in water, and herbs grown in the gardens of temples dedicated to Aesculapius, the god of healing.

• In China, pith balls soaked in the blood of executed criminals.• In Europe, a live trout was attached to the sufferer’s chest, a

fresh catskin was wound around the body, and a piece of meat moistened with the sufferer’s urine was fed to a dog.

• Important principles of tuberculosis treatment– Find and treat people with positive TB skin test.– Most common antibiotic regimen for those with

tuberculosis• 4 months of isoniazid, rifampin, pyrazinamide, and

ethambutol each day, then 2 more months of isoniazid and rifampin each day. Total of 6 months of therapy.• Use directly observed therapy (DOTS)

– Develop vaccine. At least 15 years away.

Tuberculosis Outline

• Ancient disease• How do we get it?• History

– Prehistoric– Dark ages– Renaissance– Famous people– Sanitorium movement– Koch and the microbiology revolution– Antibiotics– TB antibiotics

• Public health funding is important• Epidemiology

– Including MDR and XDR TB• Principles for the treatment of TB

• World TB Day• March 24, 2010• Pavilion at Olympic Sculpture Park• 6-8:30P• RSVP elli.koskella@seattlebiomed.org• Website:

www.seattlebiomed.org/event/world-tb-day