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
- 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)
Chemotherapy — magic bullets
- 1944 Streptomycin (Waksman)
- 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
- Treatment same as the old days (sanatoria)
- Need for vigilance and quarantine
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!