historical statistics support a hypothesis linking tuberculosis and air pollution caused by coal

INT J TUBERC LUNG DIS 11(7):722–732© 2007 The Union

Historical statistics support a hypothesis linking tuberculosis and air pollution caused by coal

G. A. Tremblay

S U M M A R Y

Phoresia Biotechnology Inc., Laval, Québec, Canada

Tuberculosis (TB) is generally considered to be linked toindustrialisation and urbanisation. Peaking in the 1800sand receding slowly after, the disease declined sharply inthe West after World War II. TB has made a comeback inthe last 20 years in developing countries such as Chinaand India. Because socio-economic conditions alone can-not explain the connection between industrialisation andTB, factors remain to be determined in the aetiology ofthe disease. Historical statistics on coal consumption and

TB disease in Canada, USA and China are correlated.A hypothesis linking TB and air pollution is developedin the context of industrialisation. A model is proposedwhereby triggering of the interleukin-10 (IL-10) cascadeby carbon monoxide in lung macrophages promotes thereactivation of Mycobacterium tuberculosis.KEY WORDS: tuberculosis; coal; air pollution; carbonmonoxide; IL-10

THE INVENTION of the blast furnace and the steamengine were key developments that led to industriali-sation. From that point on, fossil fuel has driven theevolution of the world as we know it today; withprogress and technical innovations, changes in life-style ensued promptly. However, as humans unlockedtheir creative potential in mechanics, they may alsohave unleashed the avatar of progress.

A century-old belief blamed foul air or miasmasfor diseases such as tuberculosis (TB), malaria, rheu-matism and cholera. A number of scientists, includingFlorence Nightingale and William Farr, supported thetheory. Nevertheless, miasmas fell into disgrace whenLouis Pasteur discarded spontaneous generation andit became clear that micro-organisms were largely re-sponsible for mankind’s ills.

Mycobacterium tuberculosis, the agent responsiblefor TB—also called phthisis or consumption—wasidentified in 1882 by the German physician RobertKoch. At the time, TB claimed about one death in sixin Europe.

TB has made a comeback in the last 20 years, mostlyin parts of the developing world. In 2004, 9 millionnew TB cases were diagnosed and approximately 2million persons died of TB around the world. Morethan 80% of all TB patients live in sub-Saharan Africaand Asia. People infected with the human immunode-ficiency virus (HIV) are more susceptible to TB.1 In Af-rica, for example, HIV is said to drive the TB epidemic.2

TB has been termed a ‘social disease’ because it islinked to poverty, overcrowding and unsanitary con-

ditions. Improvements in living conditions are there-fore likely to affect TB incidence.

There is general agreement that the TB epidemicincreased dramatically in Europe in the eighteenthand nineteenth centuries and began to decline there-after.3 TB is intrinsically linked to industrialisation.For example, both industrialisation and TB occurredlater in Japan.4 As there is no obvious reason to be-lieve that there was less poverty before industrialisa-tion, and considering that overcrowding is relevant toall communicable diseases, one is forced to questionwhy industrialisation and TB go together.

Another unresolved issue concerns the decline ofTB in the West. For example, between 1850 and 1910,TB death rates declined in England and Wales muchfaster than indicators of social deprivation.5 It seemstherefore that social factors alone cannot explain thedecline in TB incidence.

There may in fact have been some degree of confu-sion between social and environmental factors. Forexample, in a 1911 study,6 Marie-Davy compared TBmortality and the average number of windows perhousehold (Figure 1) in Paris arrondissements (urbandistricts) between 1858 and 1902. Scientists of thetime were aware that inadequate aeration of houseswas related to the development of TB in residents;Figure 1 may also indicate high levels of indoor airpollution in urban households.

In recent years, air pollution has been identified asa risk factor for TB. Mishra et al. linked biomasscooking fuels and TB:7 based on a 1992–1993 survey

Correspondence to: Guy A Tremblay, 3126, 5ième Rue, Laval, Québec H7V 1M1, Canada. Tel: (�1) 514 436 9272. e-mail:[email protected] submitted 24 September 2006. Final version accepted 26 January 2007.

REVIEW ARTICLE

Air pollution caused by coal impacts on tuberculosis 723

on 90 000 households, the study provides evidencethat women in biomass-using households are threetimes more likely to report TB than those in householdsusing cleaner fuels. Another Indian study found thathouseholds using wood or dung cakes as fuel had 2.5times more clinically confirmed TB.8 Cigarette smokingis now recognised as a risk factor for TB infection.9Miners in coal and gold mines are also prone to TB, al-though it is considered an effect of silicosis.10,11

Based on the observation that industrialisation andTB coincide, and on the assumption that a determi-nant factor remains to be identified in the TB epi-demic, historical statistics of disease and energy werecompared to assess the impact of environmental fac-tors on TB.

The present hypothesis suggests that pollutioncaused by combustion of coal and possibly town gasduring industrialisation aggravated the historical TBepidemic in the West and the present epidemic in de-veloping parts of the world. The possibility that car-bon monoxide (CO) and particulate matter (PM) ac-tivate the interleukin-10 (IL-10) anti-inflammatory

cascade is discussed. The observations shed new lighton TB biology and epidemiology and emphasise theimportance of environmental health.

METHODS

Historical statistics of disease in Canada, as incidenceper 100000 population, are gathered from StatisticsCanada Historical Statistics on ‘Annual rates of notifi-able diseases, Canada, 1926 to 1975’ (series B517–525).12 For electricity production, ‘Electric utilities—number of customers by class, 1920 to 1975’ (seriesQ97–101) is used.12 Electricity production is ex-pressed as percentage of maximum customers over theperiod interval. ‘Principal statistics of the Canadian coalmining industry, 1918 to 1976’ (series Q137–142) isused for the numbers of employees in the coal indus-try.12 Number of coal employees is expressed as per-centage of maximum over the period. Bacille Calmette-Guérin (BCG) vaccination in Canada, expressed as totalnumber of vaccine shots, was compiled by Malissard.13

US Department of Energy Official Energy Statisticsprovides historical statistics on coal consumption bysector in million short tons from 1949 to 2005,14 andthe Centers for Disease Control and Prevention (CDC)Division on Tuberculosis Elimination Statistics dataon historical TB in the US (incidence/100 000 between1953 and 2005).15

Data on coal consumption (exajoules) in China aretaken from the China Statistical Yearbook 2003,16

and TB notification rate (/100 000) from the WHO TBreport 2005.17 The poverty headcount index repre-sents the percentage of the population living in house-holds with income per person below the poverty line.The headcount index is provided by the World BankPolicy Research Working Paper Series.18

Pearson correlation coefficients, R2 and P numberwere calculated using Microsoft Excel mathematicalfunctions. Pearson correlation is carried out with datafrom the corresponding figure for the given time period

Figure 1 TB mortality rate as related to the average number ofwindows per household in Paris urban districts or arrondisse-ments between 1858 and 1902. pop � population.

Table Pearson partial correlation coefficients relating disease incidence or notification rate (China), electrification and indicators of coal consumption in Canada, USA and China

Disease incidenceper 100 000 population

Canada USA China

Employees inthe coalindustry

(1940–1975)

Electricity,total numberof customers(1940–1975)

Residential coalconsumption,

million short tons(1953–1990)

Total coalconsumptionin exajoules

(1982–2002)

TB 0.97 �0.95 0.99* 0.95†

Typhoid fever 0.87 �0.86Whooping cough 0.85 �0.87Diphtheria 0.77 �0.76Scarlet fever 0.55 �0.55Poliomyelitis‡ 0.31 �0.21

* Correlation in the US for residential coal is done with TB incidence/100 000 population. When using TB death rate/100 000 in the US, the correlation was also 0.99.† In China, TB notification rate/100 000 is used.‡ Correlations for the period 1940–1964.TB � tuberculosis.

724 The International Journal of Tuberculosis and Lung Disease

in the Table. Steel industry numbers, population dataand electric drive figures for Norway are from Statis-tike Centralbyrå,19,20 whereas TB mortality figures(/100 000) are taken from Wood.21 The progress ofurban gas lighting (total number of gas lights installed)in Paris is from Bouteville,22 whereas TB mortalityfigures (/1000) in Paris are derived from Barnes.23

Waldron provides the number of notified workplaceaccidents during World War II,24 and TB historicalstatistics (total number of cases) for England andWales are from the United Kingdom’s Statutory Noti-fications of Infectious Diseases (NOID).25

RESULTS

TB decline in twentieth century North AmericaFigure 2 shows the incidence of notified diseases andBCG vaccination in Canada between 1926 and 1975.There was a global downward trend of all diseases overthe period. TB incidence rose after 1930 (Figure 2A),increased further with the advent of WWII to peak in1944, and declined steadily after the war. In contrast,whooping cough increased around 1935, but not atthe onset of the war (Figure 2C). Scarlet fever showscyclic behaviour every 8 years or so (Figure 2D). An

Figure 2 Incidence of notified disease (A, C–F) in Canada during the twentieth century. Vertical dottedlines highlight WW II. In B, BCG vaccination in the province of Quebec (solid line), in the province of New-foundland (dotted line) and in the rest of Canada (dashed line) are shown. pop � population.


outbreak of typhoid fever occurred in 1927; it de-clined sharply then steadily afterwards, to almost dis-appear (Figure 2E). Diphtheria also decreased after1930, came back to some extent before WWII andvirtually disappeared after the war, presumably as aconsequence of vaccination (Figure 2F).

Of all the diseases shown in Figure 2, TB is perhapsthe disease most closely associated with WWII. Thiscan be explained by the arrival of the mass workforcein manufactures involved in the war effort, consideringthat factory and construction labourers were the primetargets of TB in the 1930s.26 The cyclic behaviour ofscarlet fever was somewhat altered by the war, andthe increase in diphtheria may also have something todo with living and working conditions during the war.

The number of BCG vaccine shots administered inthe province of Quebec, Newfoundland and the rest ofCanada are shown in Figure 2B. It is likely that BCGvaccination had only a limited impact on the decline ofpulmonary TB in Canada and elsewhere after WWII.First, TB decreased in countries where BCG was not ad-ministered, such as the USA and the Netherlands. Sec-ond, in Canada, the vaccine was mostly administered inQuebec and Newfoundland (Figure 2B), and only ex-ceptionally in the rest of Canada, whereas no bound-aries were observed in TB incidence. Finally, BCG is acontroversial vaccine, with an efficacy that has been re-ported to vary between 0 and 80%.27 In addition, threemeta-analyses carried out in the mid-1990s have showna protective overall effect of 50%,28–30 with greater ef-ficacy for disseminated forms and meningitis but lesserefficacy in the case of pulmonary TB.

As regards anti-tuberculosis drugs, streptomycin(SM) did not become available before 1948, and resis-tance soon developed. Introduced in 1952, isoniazidreduced resistance when used in combination withSM.31 However, the decline in TB incidence in 1952 isnot sharper than before, as could have been expectedif the anti-tuberculosis drugs had had 100% effect(Figure 2A), and if it was administered systematically.

Figure 3A shows the number of coal workers, thenumber of customers of electric utilities and TB ratesin Canada after WWII, based on data obtained fromStatistics Canada.32 One important advance of the post-war era was the electrification of homes. In Canada,gasoline and electricity replaced coal as the principlemeans of heating households. The relative number ofcoal workers during that period is used to illustratethe decline of the coal industry in Canada, mainly dueto the loss of the residential market. In Canada, TBdeclined to levels below 20/100 000. This drop pre-cedes that of coal employees, which may reflect a de-lay in the lay off of the workforce relative to the evo-lution of the coal market. Nonetheless, the timelinesof TB decline and the indicators of residential coalconsumption do coincide.

A similar pattern of TB decline is observed be-tween 1953 and 1975 in the United States, where BCG

was not administered (Figure 3B). Data for residentialcoal consumption in the USA are available. TB de-clines in the US again coincide with a reduction in res-idential coal consumption. A peak in TB incidence in1977 is visible and the increase in TB due to the HIVepidemic between 1990 and 1997 can be seen. As forresidential coal, its use has almost completely disap-peared by 1980.

Modern-day TB epidemic in ChinaOverall coal consumption in China,16 when com-pared to TB notification rates,17 shows an apparentclose relationship between global increases in coal con-sumption and TB disease notification rates (Figure 4A).TB incidence and coal use have increased in a similarfashion in the last 20 years, with simultaneous peaksaround 1986, 1990 and 1996, and a correspondingdrop around 2000. In sharp contrast to trends in TBnotifications and coal consumption in China, Figure4B shows that overall poverty for rural and urbanareas decreased during the same period in China.18

Social deprivation cannot, therefore, explain the in-crease in TB notifications (Figure 4A).

China is the largest consumer and producer of coal inthe world. Today, coal is widely used in China as asource of energy for both electricity production andhousehold use.33 Coal largely dominates the energy

Figure 3 A. TB incidence (solid line), total number of coalemployees in the coal industry (dashed line) and electric utilitycustomers (dotted line) in Canada between 1940 and 1975.B. Historical US domestic coal consumption (dashed line) and TBincidence (solid line) between 1953 and 2003. pop � population.


landscape of the country;16 estimates suggest that 330million people use coal for domestic purposes.34 Ac-cording to Finkelman et al., coal stoves and small coalboilers provide more than 50% of the energy for urbanhouseholds, and 22% of rural households rely on coal.33

Low-grade coal is often burned in cheap, poorly ventedor even unvented stoves, resulting in various illnesses.33

Correlation between energy and diseaseThe Table correlates notified disease, coal employeesand electrification in Canada between 1940 and 1975,and coal consumption and TB disease indicators inChina and the USA. The Pearson correlations are de-rived from the data used in Figures 2 and 3.

In Canada, although the onset of TB precedes indi-cators of residential coal consumption, the Pearsonpartial correlation coefficient of 0.97 is strongest com-pared to other notified diseases for the same period. Itis interesting to note that the negative correlation forelectricity of �0.95 is strongest for TB compared toother diseases, as is the case for coal. Also, the corre-lations for electric utility customers are similar in ab-solute value to those of coal employees for notified dis-ease in Canada, indirectly indicating that the electricitymarket develops at the expense of the coal market.

In the US, again, a very strong correlation of 0.99is found linking residential coal consumption and TB

incidence between 1953 and 1990. The correlation of0.95 between total coal consumption and TB notifi-cation rate in China is also high.

The strong correlations in Canada, USA and Chinabetween coal consumption and TB disease thereforehighlight the possibility that coal consumption directlyimpacts on TB disease.

Coal and industrialisationBefore industrialisation in Europe, wood became scarceand expensive, while coal became affordable. Char-coal and coal combustion yield more energy thanwood; inventions and innovations led to the blast fur-nace and the steam engine.

One key feature of industrialisation is the develop-ment of the steel industry. The advent of this industrymay be considered a consequence of innovations inthe process of iron smelting. The blast furnace is ametallurgical furnace used for smelting, notably ironore. Charcoal or coke, limestone and iron ore are fedinto the blast furnace while air is blasted at the bot-tom. Iron is reduced to metal by charcoal, whichyields oxides of carbon as products of combustion.

Beginning in the UK in 1709, the use of coke (bakedbituminous coal) instead of charcoal (baked wood) inblast furnaces was of paramount importance in theadvent of the industrial revolution, as it enabled the pro-duction of iron that was cheaper and less brittle. In turn,the availability of coal on the market spurred the use ofand technological innovations on the steam engine, aswell as the development of heavy industry. This serves toillustrate how industrialisation boils down to coal.

TB and industrialisationThere is some agreement that TB incidence peakedaround 1800 in Western Europe.35 TB accounted for25% of deaths in New York city between 1810 and1815.36 However, according to Barnes,23 TB in Parispeaked around 1865, whereas in Norway it peakedaround 1900.21 Therefore, based on the present hy-pothesis, the peak in TB disease depends on the extentof air pollution and industrialisation in an area; inChina, for example, industrialisation may be consid-ered to be occurring now.

TB numbers before the 1900s are difficult to find.In Norway21 and Japan,4 for example, industrialisa-tion occurred later than in the rest of Europe, as didthe rise in TB incidence.

Figure 5 shows TB incidence between 1855 and 1945in Norway. Beginning slowly around 1840, Norway in-dustrialised its pulp and paper industry and introducedsteel works. The number of steel workers jumped from1608 to 7161 employees and from 9.3% to 22.8% ofthe total workforce between 1860 and 1870.19 Thelate onset of industrialisation, exemplified by the emer-gence of the steel industry in Norway (Figure 5), co-incides with a delayed increase in TB incidence.

Figure 4 A. Tuberculosis notification rates (solid line) and totalcoal consumption (dashed line) in China between 1980 and 2002.B. Poverty in China as a whole, in urban and rural areas: percent-age of the population living in households with income per personbelow the poverty line between 1981 and 2001. pop � population.


Another idiosyncrasy of Norway in regard to in-dustrialisation is the early electrification of the country,early in the twentieth century, due to the abundanceof large water basins; the capacity of water plantsjumped from 10 MW in 1907 to 1250 MW in 1920and to 2250 MW in 1939.37

The TB epidemic receded earlier in Norway thanin other industrialised countries such as the UK, Can-ada or the US. As illustrated in Figure 5, early electri-fication, as exemplified by the use of electric motordrive in the manufacturing industry between 1900and 1938, may explain the early decline in TB preva-lence in Norway, although the decline seemed to startslightly before the onset of electrification. Neverthe-less, electrification proceeded very rapidly in Norway.Again, as was the case in Canada and the US, theswitch to a cleaner energy coincides with a dramaticdecrease in the prevalence of TB.

In the late nineteenth century, Japan opened to theworld following the Meiji restoration, and reformsensued. The silk industry financed the Meiji restora-tion to some extent. During the late nineteenth and earlytwentieth centuries, the industrial production of silkin Japan was revolutionised by the use of steam boilersfor continuous, even heating of the reeling basins usedto soften cocoons to be reeled into raw silk;38 coal wasused to heat the steam boilers.39 TB incidence was highin the silk and spinning industry, and the young girlsemployed for spinning were the first victims. Later, asecond phase of heavy industrialisation in the 1930sshifted the trend, and young men became the primetargets of TB (T Shimao, personal communication).

Back in Europe, in the early nineteenth century,technical advances by the Scottish engineer WilliamMurdoch and others introduced town gas, also calledsynthetic gas or syngas. Town gas was produced bygasification, a process whereby coal is heated in thepresence of water vapour. Syngas produced with coalin processes with water-coal slurry systems is typically

and mainly composed of (vol%) H2 27–30%, CO 35–45%, carbon dioxide (CO2) 10–15%, H2O 15–25%,hydrogen sulphide (H2S) 0.2–1.2% and hydrogenchloride (HCl) 50–500 ppm.40

A passage in the book by Flora Tristan describes ascene at the coal gasification factory, the Gas Lightand Coke Company’s Horseferry Road Works, inLondon in the 1830s:

Two rows of furnaces on each side were fired up [. . .]The foreman told me that stokers were selected fromamong the strongest, but that nevertheless they allbecame consumptive after seven or eight years of toiland died of pulmonary consumption.41

Town gas was first used for lighting streets and homesusing the gaslight or ‘bec de gaz’. The first gaslightshad a notoriously bad reputation: they were very in-efficient and leaked large amounts of unburned gasthat added to the coal fumes in urban areas. An ac-count by Lecouturier depicts industrialised Paris aroundthe 1850s:

If you contemplate from the summit of Montmartrethe congestion of houses piled up at every point of avast horizon, what do you observe? . . . One is temptedto wonder whether this is Paris; and, seized with asudden fear, one is reluctant to venture into this vastmaze, in which a million beings jostle one another,where the air, vitiated by unhealthy effluvia, rising ina poisonous cloud, almost obscures the sun.23

Figure 6A depicts the progress of urban gas lightingin Paris—la ville lumière (the city of light)—duringthe nineteenth century.22 Between 1831 and 1852, all13 000 urban lighting oil lamps of Paris were replacedby gaslights as gas pipelines were installed for urban,industrial and domestic usage.

In Paris, the TB epidemic peaked in the middle ofthe century, around 1865 (Figure 6B), and recededslowly thereafter.23 It may be considered that a criticalfactor for the acute crisis in Paris is the introductionof gaslight. As town gas allowed night shifts in manu-factures, it is likely that TB incidence increased amongfactory labourers during the course of the nineteenthcentury. In defence of the thesis is the shift in sex ratiofor TB during that period: in 1830, two thirds ofwomen suffered from TB, while in 1860 the trend re-versed and two thirds of men suffered from TB;23 menthen constituted the majority of the labour force inmanufactures. The peak of the TB epidemic in Parisaround 1865 can therefore be explained by the wide-spread use of town gas during that period. Thus, indi-rectly because of the advent of night shifts in the indus-try and directly due to town gas fumes, the utilisationof combustible town gas is likely to have had an im-pact on TB incidence during the nineteenth century.

The decline in TB mortality towards the end ofthat century may be explained by improved combus-tion and lighting technologies, such as the Auer lampinvented by Dr Carl Auer von Welsbach in 1885,

Figure 5 Mortality due to TB in Norway between 1855 and1945 (solid line) with indicators of industrial developmentshown on the timeline (diamonds). Electric motor drive in themanufacturing industry between 1900 and 1938 in Norway(dashed line). pop � population.


whose use spread around 1890. It may be noteworthyto mention that town gas is still used in industrialisingparts of the world today where natural gas is rare orexpensive, such as in China or South Africa.42

TB, industry and ventilationIn a 1930 occupational hazards study, constructionand factory labourers were found to be the prime tar-get of TB, with a death rate of 227.3/100 000 com-pared to 180.0 for waiters, 173.3 for servant classes,165.6 for teamsters and carriage drivers, 106.0 forcoal mine operatives and 23.7 for physicians and sur-geons,26 trends that are in sharp contrast with today’soccupational statistics.

The prevalence of TB in industry and manufac-tures is a recurrent theme during the nineteenth andtwentieth centuries. A 1914 paper by Hastings directlylinks TB and air pollution:

Among garment workers many cases of tuberculosisdevelop. This is due largely to long hours, dusty, badlyventilated, overcrowded rooms, in which they fre-quently use gas stoves, or gas flat irons and charcoalstoves. Cases of chronic gas poisoning are not unusualamong these people from leaky gas stoves.43

TB made a comeback in the West during WWII. Thewar effort brought masses of workers into manufac-tures. Figure 7A shows carbon monoxide, nitrousfumes and lead intoxications in UK manufactures,while Figures 7A and 7B compare intoxication acci-

dents and the number of TB notifications in the UKduring WWII, showing a concomitant increase inworkplace accidents and TB in the UK during thistime. Generally speaking, there was an increase in alltypes of workplace accidents. How can this be ex-plained? According to Waldron, work was arduous inUK factories during the war:

. . . a large and often inexperienced workforce spentlong hours in factories that were often poorly lit,badly heated and badly maintained. The requirementfor complete blackout meant that ventilation systemswere often inadequate, and this resulted in greaterexposure than normal to some toxic substances. [. . .]there is no question that the number of cases of spe-cific industrial diseases increased substantially [. . .].24

It is possible that the increase in TB in the West duringWWII is due to working conditions in manufacturesinvolved in the war effort. In this regard, TB thereforetranslates into an industrial disease, considering thehigh rates of TB in construction and factory labourersin the 1930s. It also highlights the possibility that aspecific workplace pollutant is involved in reactiva-tion of the disease. Generally speaking, if poverty wassuch an important factor in the incidence of TB, thedisease would have increased mostly in the 1930s, aspoverty was rampant during the Great Depression.

Considering that ventilation in the workplace wasless than satisfactory in the first half of the twentieth

Figure 6 A. Total numbers of urban lighting oil lamps (grey)and town gas lamps (black) installed in Paris in 1831, 1848 and1852. B. TB mortality rates in Paris during the nineteenth cen-tury. pop � population.

Figure 7 Reported workplace accidents in factories and tuber-culosis notifications between 1937 and 1946 in the UK, show-ing A) number of carbon monoxide (solid line), nitrous fumes(dashed line) and lead (dotted line) poisoning notifications; andB) total number of pulmonary TB notifications.


century, it is conceivable that the high incidence of TBin manufactures is explained by workplace air pollut-ants. Electricity gradually replaced internal combus-tion engines as the source of mechanical drive, andproper ventilation systems were installed in the indus-try. These changes occurred in parallel to the shift inhousehold energy sources, thereby reducing the totalburden of air pollution.

Pertaining to the issue of ventilation, ‘open-air treat-ment’ or ‘sanatorium treatment’ was introduced inGermany by Hermann Brehmer in Görbersdorf, Sile-sia, in 1854.44 Although some variations existed be-tween sanatoria (e.g., rest vs. exercise, altitude vs. sealevel), open-air treatment was essentially based on ex-posing the patient to fresh air, night and day, in a re-mote area. In studies of sanatoria in England, it hasbeen said that patients increased in weight within thefirst week (2–6 pounds), cough was seldom heard, andnight sweats tended to cease within days.45,46 Sanatoriawere generally considered beneficial. Strangely enough,no comparative study on the efficacy of sanatoria wasever carried out. Bardswell made a careful follow-upstudy of patients admitted to the King Edward VIIsanatorium in Sussex between 1907 and 1914.47 Hefound that by 1916, 751 of 1707 (44%) patients haddied, making sanatoria less than a panacea. In retro-spect, and in the light of the present hypothesis, thesanatorium treatment may be regarded as a way tokeep patients away from polluted urban, industrialand domestic environments.

DISCUSSION

The present analysis suggests that air pollution result-ing from coal combustion directly affects TB incidence.Although the decrease in TB observed in the West canbe explained by socio-economic factors, the use ofanti-tuberculosis drugs and/or the BCG vaccine, thecoincidence with coal consumption is nothing shortof troubling.

In China, HIV prevalence is low48 and thereforecannot explain the increase in TB in the last 20 years.The correlation may, however, reflect a direct associ-ation between coal consumption and TB incidence. Inthe case of China, notification rate instead of TB inci-dence was used (Figure 4). It should be added that abetter health system in a wealthier state can result inincreased TB notifications.

Generally speaking, the evidence presented in thepresent paper should be regarded with caution giventhe inherent limitations of the ecological approach.The correlations are prone to the ecological fallacy,because no confounders can be tested. For example,in Canada, the overall improvement of the health sys-tem after WWII, concomitant with the electrificationof cities, could explain a global decrease in TB. Nev-ertheless, it is an hypothesis to be investigated, as bio-mass cooking fuel7 and cigarettes9 have been identi-

fied as risk factors for TB, and social factors may notconvincingly explain the aetiology of the disease.5

The US Environmental Protection Agency esti-mated US coal emissions in 2000 by fuel combustionelectric utilities for the principal pollutants: sulphurdioxide (SO2) 10 723 thousand short tons (tst), nitro-gen oxides (NOx) 4573 tst, CO 234 tst, PM �10 �m(PM10) 242 tst, PM �2.5 �m (PM2.5) 116 tst, volatileorganic compounds (VOC) 30 tst, and lead (Pb) 56short tons.49

The prime pollutant in coal is SO2, followed byNOx. CO is substantially less, but partial combustionof coal is known to produce large amounts of CO,and it has been suggested that US tabulated data forCO emissions may be underestimated.50 Ash from coalcombustion, or PM, is composed primarily of oxidesof silicon, aluminium and iron. On the whole, coal isconsidered to be a very polluting fuel.

Bygone coal furnace technologies are likely to havehad an impact on indoor air pollutants and CO levels.They were not nearly as efficient as they are today, andtherefore resulted in partial combustion of coal, indoorbuild-up of CO and heavy PM emissions. Today inChina, low-grade coal is often burned in cheap, poorlyvented or even unvented stoves, resulting in various ill-nesses.33 In addition, keeping stockpiles of moist lignitecoal near a source of heat will result in CO leakage, aprocess reminiscent of industrial coal gasification.

Considering the present hypothesis, the impact ofcoal on TB disease should transpose into a specificmechanism in vivo. A closer look at the physiologicaleffects of CO and the biology of TB suggests a plau-sible mechanism whereby coal fumes shut down theimmune response of the host.

Termed the silent killer, CO is an odourless, taste-less and colourless gas with a well-known tendency tobuild up indoors. Identified in recent years as an intra-cellular signalling molecule, CO is generated endoge-nously by haeme oxygenase enzymes (HOs). The IL-10anti-inflammatory pathway requires the activation ofhaeme oxygenase-1 (HO-1), which degrades the haemeof haemoglobin, yielding CO, biliverdin and iron asby-products.51 Anti-inflammatory action was foundto be mediated by CO, as its removal blocks the effectsof IL-10 and HO-1.52 A major effect of CO is the down-regulation of tumour necrosis factor-alpha (TNF-�).

TNF-� plays a central role in the formation ofgranulomata and containment of TB.53,54 Inhibitionof TNF-� by drugs on trial has been linked to reacti-vation of TB.55,56 In addition, macrophages are of par-amount importance in the defence against M. tuber-culosis. Growth inhibition is mostly mediated bynitrogen oxide NO species57–60 promoted by TNF-�.Interferon-gamma (IFN-�) and TNF-� are centralto the process, as they induce macrophage activation,inducible nitric oxide synthase (iNOS) expression andNO generation.60,61

On the other hand, M. tuberculosis encodes trun-


cated haemoglobins (trHbs) whose function remainsunclear. TrHbs have been associated with protectionagainst nitrosative damage by virtue of their NO di-oxygenase activity, utilisation of CO as a carbonsource, O2/NO sensing, redox reactions, O2 deliveryin hypoxic conditions and long term ligand/substratestorage.62–66 M. tuberculosis trHb has, along its haemegroup, an a-polar tunnel system through the proteinmatrix endowed with more than one entry/exit pointsand is able to store diatomic molecules in its cavity.67

The model shown in Figure 8 details a mechanismwhereby M. tuberculosis responds to macrophage ni-trosative attack with the release of CO stored in trHbmolecules, followed by suppression of immunity, amodel termed ‘CO-doping’. In addition to activelyprotecting the bacilli through NO oxidation by trHbnitric dioxygenase activity, CO-doping functions toinduce an IL-10-like response. As a result, a decline inTNF-� production, macrophage activation and cell-mediated immunity ensues. In either case, irrespectiveof the capacity of M. tuberculosis to actively triggerthe IL-10 pathway, elevated ambient levels of CO re-sult in lower levels of TNF-� through activation ofthe IL-10 pathway.

It is noteworthy to add that polymorphism in theslc11a1 (formerly Nramp1) gene has been identifiedas a factor of resistance to TB in mice.68 slc11a1 isthought to be an iron transporter localised to mem-branes of phagocytes in macrophages. Polymorphismsin IL-10 and TNF-� have also been linked to pulmo-nary TB.69 The precise role of Slc11a1 in TB resis-tance remains to be elucidated: however, it has been

suggested that Slc11a1 influences susceptibility to TBby regulation of IL-10 because a polymorphism inSlc11a1 was associated not only with TB, but also witha higher endotoxin-induced production of IL-10.70 Inthe scope of the CO-doping model, modification ofthe iron pool by Slc11a1 serves to desensitise the IL-10pathway in lung macrophages or to capture availableiron used in trHb haeme, thereby impacting on theanti-inflammatory activity of CO and/or the ability ofM. tuberculosis to feed macrophages with CO.

Another issue yet to be considered is the link be-tween PM from coal combustion and the activationof the IL-10 pathway in fibrotic lungs. It is knownthat miners in coal and gold mines are more prone toTB as a result of silicosis.10,11 It has been shown that,in mice, the IL-10 pathway is activated in the courseof fibrosis of the lung,71,72 but not in rats.

Coal ash differs from wood ash, which could ex-plain an enhanced activation of TB by coal as opposedto wood; TB existed before industrialisation, but pre-sumably to a lesser extent. Logically, the amount ofCO produced by the combustion of coal should begreater than that produced by the combustion of wood.In combustion experiments for different fuels in a lab-oratory system designed to mimic the fire pit used inXuan Wei County in China, emissions of anthracite,bituminous coal and pine wood were compared.73

These results show that the total PM emissions for bi-tuminous coal were 5.6-fold those of pine wood,whereas there were only 1.6-fold more CO emissionsfor bituminous coal than for pine wood. However, inChina, the use of cheap grades of coal such as moistlignite may result in worse figures for CO.33

In conclusion, coal, the workhorse of progress,seems an inevitable step in the emergence of an indus-trialised country. Thus, in the light of the present hy-pothesis, the white plague will rise and vanish alongthe path of entry into modernity; the disease will fluc-tuate in the population in a complex interplay of fac-tors: domestic and industrial use of various types ofcoal, combustion technologies, the number and genderof workers in manufactures, and the source of mechan-ical drive. Finally, as electrification progresses and pov-erty plummets, TB regresses to a bad memory—untilAIDS brings it back on topic. Jean and René Dubos,in their book The White Plague, called TB a disease of‘incomplete civilization’.74 It could also be said thatTB is a disease of incomplete industrialisation.

Although micro-organisms are causative agents ofmany illnesses, environmental health factors are notto be underestimated in the aetiology of the disease.The present evidence should prompt investigators tostudy the effects of air pollution, notably coal, in re-gard to TB. An epidemiological approach that cantake into account confounders could substantiate thehypothesis. Furthermore, the impact of various airpollutants on the outcome of TB should be investi-gated in animal models.

Figure 8 CO-doping model in the reactivation of latent tuber-culosis. Release to macrophages of CO stored in trHb of M.tuberculosis, mimicking the IL-10 anti-inflammatory pathway,results in inhibition of gene transcription, TNF-� production andleads to reduced macrophage activation, nitric oxide produc-tion and cell-mediated immunity. CO � carbon monoxide; LPS �lipopolysaccharide; TLR � toll-like receptor; trHb � truncatedhaemoglobins; TNF � tumour necrosis factor; NO � nitric ox-ide; HO � haeme oxygenase; IL-10 � interleukin-10; iNOS �inducible nitric oxide synthase.


AcknowledgementsI would like to thank Dr D Menzies for critical review of the manu-script. I am also grateful to Dr T Shimao for information on histor-ical facts pertaining to TB in Japan.

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R É S U M É

On considère généralement que la tuberculose (TB) vade pair avec l’industrialisation et l’urbanisation. Avec unpic dans les années 1800 et une lente régression ultérieure,la maladie a décliné fortement en Occident après la deu-xième guerre mondiale. La TB fait un retour dans les 20dernières années dans les pays en développement commela Chine et l’Inde. Comme les seules conditions socio-économiques ne peuvent pas expliquer la connexion entrel’industrialisation et la TB, des facteurs étiologiques de

la maladie doivent encore être déterminés. On met encorrélation les statistiques historiques de consommationde charbon et de maladie TB au Canada, aux USA et enChine. On élabore une hypothèse liant la TB et la pollu-tion de l’air dans le contexte de l’industrialisation. Unmodèle est proposé dans lequel la stimulation de la cascadeIL-10 par le monoxyde de carbone dans les macrophagespulmonaires favorise la réactivation de Mycobacteriumtuberculosis.

R E S U M E N

La tuberculosis (TB) se considera generalmente vincu-lada con la industrialización y la urbanización. La enfer-medad presentó el pico de frecuencia más alto en el sigloXIX, declinó luego lentamente y mostró una dismi-nución drástica después de la segunda guerra mundial,en Occidente. Durante los últimos 20 años, la TB ha sur-gido de nuevo en países en desarrollo como China eIndia. Puesto que las condiciones socio-económicas porsí solas no explican la correlación entre industrializacióny TB, deben determinarse los demás factores que con-

tribuyen a la etiología de la enfermedad. Las estadísticashistóricas de consumo de carbón presentan una correla-ción con la incidencia de tuberculosis en Canadá, losEstados Unidos y China. Se plantea una hipótesis queasocia la TB con la contaminación atmosférica en elcontexto de la industrialización. Se propone un modelosegún el cual la activación de la cascada de la inter-leucina 10 por el monóxido de carbono en los macrófa-gos del pulmón promueve la reactivación de Mycobacte-rium tuberculosis.

historical statistics support a hypothesis linking tuberculosis and air pollution caused by coal

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