Tuberculosis

Updated 2 January 2015

Causative agent: Mycobacterium tuberculosis

  • Related bacterium: M. leprae

TB has many forms (many names)

  • Phthisis (“wasting away”) Hippocrates
  • Scrofula (swollen glands of the neck)
  • “Kings Evil” — cured by the touch of kings
    • Probably a primary lesion that never develops
  • Lupus vulgaris (TB of the skin)
  • Pott’s Disease (vertebral fusion and deformity of the spine)
    • visible in skeletal remains (mummies from 2000 to 4000 BC)
  • Consumption (TB of the lungs)

Epidemiology of TB

Definitions

  • Infection vs. Disease
    • remember Typhoid Mary?
    • tuberculin test measures infection, not disease
    • (no such test for M. leprae)
  • Latent vs. active phase

Cause of disease

  • growth in lung tissue
  • surrounded by white blood cells, walling off the damaged area = tubercle
  • eventual calcification of the lesion (easy to see on X-rays)
  • if not walled off, liquify and then make good aerosols

Problems with treatment

  • can live inside white blood cells
  • can hide without causing symptoms
  • lives in balance with immune response

Transmission

  • Not very infectious, but very serious
  • Main route is breathing
    • controversial as late as 1955 or 1960!
  • 1 sneeze = more than 1,000,000 droplets with 3-10 bacilli per droplet
  • air from a TB ward can infect guinea pigs
    • (uv treated air does not)

Sources of TB disease

  • infection and progression to disease
  • reactivation of latent TB
    • cf shingles and chickenpox
  • reinfection with TB

Overlap with HIV

  • Faster development
    • HIV+: 2-10/100 infected with TB get TB disease
    • HIV-: 10-20/100,000 infected with TB get TB disease
  • about 1/3 of the rise in TB in recent years is associated with HIV in the US
  • about 1/4 of the rise is from communal living conditions such as prisons, shelters, and even hospitals)

Global Burden of TB

  • About 1/3 of all humans are infected
    • Lifetime rist of progressing to illness is about 10%
  • About 9 million fell ill with TB
    • That includes 1.1 million living with HIV
  • Currently, about 1.5 million deaths per year
    • That includes 360,000 with HIV
  • Without aggressive intervention, next 10 years should have
    • 90 million new cases
    • 15 million deaths
  • Even that hard to estimate
    • poverty makes diagnosis, reporting, and cause of death inaccurate.
  • TB kills more people yearly than any other bacterial infection
    • also, leading cause of death for those with HIV
      • about 1/5 of all HIV deaths

Estimating infection rate

  • Tuberculin skin test (more later)
    • if not “vaccinated” with BCG
  • Sputum smears for “acid fast” bacteria
    • waxy walls of Mycobacterium
  • 1% annual risk (tuberculin test) = ca. 50 smear-positive cases per 100,000
  • Active TB only a fraction of infected
    • Perhaps 1/3 of the population of the world is infected
    • That would be about 2 billion people!

“Recent” estimates (2003)

Region TB cases cases per 100,000 TB deaths Deaths per 100,000
S.E.Asia 3,062,000 190 617,000 38
Africa 2,372,000 345 538,000 78
Latin America 370,000 43 54,000 6
US 14,000 5 802 0.3

HIV and TB

  • 33 million persons are HIV+
    • more than 14 million of those are also TB+
    • In Africa, 40% of all TB patients are HIV+
  • AIDS speeds progression from latent to active TB
  • AIDS does not increase transmission rate
    • mostly non-pulmonary (non-infectious)
    • die faster with less time for transmission

Role of Immune System

  • Until AIDS, nobody understood latency and reactivation
  • Now we know it is balance between immune systems and M. tuberculosis
  • Explains why sanitoria worked
    • Good food, rest, exercise, — generally good health led to stronger immune system

Recent trends in US

  • 1953 to 1984, TB declines about 5% per year
  • 1984 to 1992, TB increases about 3% per year (about 20% RISE!)

Increase in US

  • much of the “excess” is ethnic minorities
  • 27% of all cases were foreign born
  • Many AIDS patients are also TB (about 5%)
  • Many TB patients are HIV+
    • 13%, 18% and 21% in 1989, 1990, and 1991, resp.
  • Outbreaks increasing in hospitals, prisons, and shelters

Multiple-drug Resistant TB (MDR)

  • 9 outbreaks in 1990-92
  • mortality high (70%) and fast (4-16 weeks after diagnosis)
  • Treatment by historical methods and isolation

Global Burden: Summary

  • expect about 9 million new cases a year
    • About half a million MDR-TB
  • expect about 1-1.5 million deaths per year
    • About 200,000 MDR-TB
  • the leading cause of death from infectious disease in the world after HIV/AIDS!

History of TB

Pre-history

  • may have had sporadic origins by mutation from animal strains of Mycobacterium
  • not endemic until the rise of agriculture (ca. 8,000 BC)
  • Requires communities of 200-400 persons or it dies out
  • Epidemics require higher densities still, and travel

“Modern” Times

  • In general, Southern Europe thought it was contagious, Northern Europe thought it was not contagious
  • Renaissance led to learning, medicine, and cities — AND an era of extraordinarily high incidence of TB

“Recent” Times

  • 1800-1859 TB (Consumption) accounted for 20-25% of all deaths
  • Not certain it was a single disease and cause was unknown until 1880’s

TB in the Americas

  • Present in Paleolithic times but no epidemics until Europeans
  • pre-Columbian population ca. 60,000,000
    • mostly in South America
    • only a few large population centers

Early evidence in the Americas

  • Some North American skeletons show deformities that look like TB
  • A South American mummy from 700 BC shows acid-fast bacilli
    • deformed skeletons go back to 160 BC
    • most likely endemic in South America
    • agriculture in Peru goes back to ca. 6,000 BC
  • TB was rare in North American natives (reports from a priest in early explorations)

TB in Africa

  • Nile region, common by 3000 BC
    • skeletons, mummies, figurines and drawings
  • Sub-Saharan: Probably unknown until the Europeans brought it
    • some parts, not until 1850 or even 1900!
  • Now very common — a true plague

TB in the Pacific islands

  • Hawaii: rare or absent as late as the 1850’s
  • New Guinea: absent until 1951
    • then symptoms were “typhoidal”
    • as expected for a naive population

TB in Europe

  • Virulent but unimportant until feudalism
  • By early 1600’s, rising in England
  • by 1800’s almost all West Europeans were infected
  • Eastern Europe (Russia) mostly free until 1880 or so

Summary: History of TB

  • Old in Egypt then on to Western Europe with cities
  • Old in South America (North too) but not epidemic until reintroduction in 1700’s
  • Southern Africa, Pacific Islands, Russia, recent infection

People and TB

Chopin

  • Went to Majorca to relieve TB symptoms
    • with George Sand (his mistress) good film
  • Town drove them out
    • Landlord wanted reimbursement for replastering
  • Carriage drivers would carry them or their goods
    • Crossed the island with wheelbarrows
    • Sailed to Barcelona with a load of pigs
  • Innkeeper in Barcelona charged them for the bed (which the authorities burned)
  • Died in 1849, at age 39

Tragic story of the Bronte family

  • 1821: Mother died of TB after birth of 6th child
  • 1825: Maria (eldest) developed symptoms and died at age 12
  • 1825: Elizabeth returned 1 month later and died 1 month after that at age 11
  • 1848: Branwell (opium addicted poet) died of TB at age 31
  • 1848: Emily (Wuthering Heights) came to the funeral, “caught cold” and dies in December of “galloping consumption” at age 30
  • 1849: Anne (Agnes Grey) died of TB (age 29
  • 1855: Charlotte (carried a chronic form of fibrotic TB that occasionally flared up) “caught cold” and developed active TB and died at age 39

Not all stories were so bleak

  • John Keats
    • mother died when Keats was 14, brother too
    • diagnosed in 1820, died in 1821 at age 26
    • he swam the Hellespont! No weakling.
  • Robert Louis Stevenson
    • Traveled widely for his TB (sanatoria)
    • Died in old age of vascular disease unrelated to TB

Alice Marble (1913-1990)

  • Great athlete as a young girl
    • by age 15 warming up with a minor league baseball team!
    • Brother bought her a tennis racket in 1928 (age 15) to get her out of baseball?
    • 1929: won her first tourney
    • 1931 in the Nationals, 1932 ranked 7th!
    • 1933 Whitman Cup team for US
    • 1934 Collapsed with TB. Career Ended!
  • Career Ended?
  • Returned to US in wheelchair
    • improved in California sanatorium
    • doctors strictly forbad all physical activity.
  • Letter from Carol Lombard (actress) said “FIGHT”
    • 8 mo. later, she escaped from sanatorium
    • 1 yr. after that, won the first of 3 consecutive championships
  • died in 1990 at age 77 without any relapse

Conquest of Tuberculosis and Retreat

Robert Koch

  • 1882, identified the tubercle bacillus using fuchsin (German chemical industry and fabric dyes)
    • boil in acid and cells retain fuchsin
    • other stains don’t stain Mycobacterium
    • other bacteria are bleached by the harsh treatment
  • grew it in pure culture on solid medium
  • not so for M. leprae which still requires armadillo footpad culture

Acid Fast stain

  • Erlich (in Koch’s audience) improved the stain
    • later used it to confirm his own TB diagnosis
  • Ziehl and Neelson improved it yet more
  • Ziehl-Neelson is still used to stain sputum smears

Public Health and the Conquest of TB

  • Laws against spitting
  • cultural change
    • end of spittoons
    • proscription of against spitting
  • Sanatoria and confinement
  • Infection leads to immunity

Tuberculin Reaction

  • Inoculate a naive guinea pig with M. tuberculosis, lesion heals quickly but the animal dies later
  • Inoculate a previously exposed animal, the lesion ulcerates, but does not spread
  • Does not require whole cells (culture fluid works) = tuberculin

Tuberculin skin test

  • Koch thought it was a vaccine. Wrong
  • For populations that have not been vaccinated with BCG, it tells exposed or not
    • if you have antibodies, you react, if you’ve never seen M. tuberculosis you don’t
  • Widely used in the US to screen for TB
    • Note: only 3-5% of tuberculin positive get TB disease

BCG (Bacille Calmette and Guerin)

  • late 1890’s, knew of “attenuated” vaccine (rabies)
  • tried one with long-term cultures of M. bovis between 1908 and 1919 (seemed to work then)
  • Clinical success is still in dispute. Widespread use, but not in US
  • Destroys utility of tuberculin skin test

Should BCG be Used?

  • A good example of two different approaches to Public Health

BCG Vaccine

  • most widely used ever
    • about 100 million per year, 3 billion total
  • safe
  • efficacy ranges from a few % to 95%
  • declines in BCG countries (UK, Sweden) no greater than non BCG countries (Netherlands)
    • why the variations?

Chemotherapy — magic bullets

  • 1944 Streptomycin (Waksman)
    • bad protein synthesis
  • 1952 Isoniazid (Robitzek and Selikoff)
    • probably blocks mycolic acid — cell wall unique to Mycobacterium
  • Almost completely effective, but can take a long time after symptoms go away
  • now there are drug resistant forms of TB

Loosing the Battle against TB

  • The glory days
    • Since 1939, isolation, sanatoria, and hygiene led to a steady reduction in cases
    • pre-chemotherapy!
  • Case reporting since 1953 (post drug) showed a steady 5% per year decline till 1984

Since 1985, a steady increase (3%)

  • immigration from places with high TB
  • AIDS
  • Collapse and Abandonment of Public Health measures
  • government budget cuts
    • as many as 90% of patients discharged, stopped taking their antibiotics
    • “civil liberties”

Multiple Drug Resistance

  • Source assumed to be non-compliance
  • Often traced to a single source
    • frequently in hospital
  • Treatment same as the old days (sanatoria)
  • Need for vigilance and quarantine
    • back to Typhoid Mary

TB and the Angelic Death

  • Immigrants, thus dirty and ignoble
  • Nobility too, so maybe OK
  • Slow, lingering, time to philosophize
    • La Boheme and others
    • Need to come to terms with the dying
    • No operas about Cholera!