OCCASIONAL ESSAY Tuberculosis and High Altitude Worth a Try in Extensively Drug-Resistant Tuberculosis? John F. Murray Professor Emeritus of Medicine, University of California, San Francisco, San Francisco, California
Consumption, or phthisis, later known as tuberculosis, was already the leading killer of Londoners as far back as the early seventeenth century; within the next 100 years, fueled by demographic shifts during the burgeoning Industrial Revolution, tuberculosis grew into—unquestionably— the most important cause of disease and death, first in all of England, and then elsewhere in Western Europe, and later in the eastern United States. During its more than 300-year-long heyday, consumption killed hundreds of millions of people; some estimates put the total as high as 1 billion deaths. Mortality from tuberculosis peaked about at 500 per 100,000 in the years around 1800 in England, much of Europe, and in major cities in the eastern United States. Providentially, the extraordinarily high death rates during the eighteenth century and up to the beginning of the nineteenth began to abate for complex and never fully understood reasons; chief among them were a rising standard of living and, to a lesser extent, primitive medical progress through the identification and isolation of presumed contagious patients. Although the rate of decline varied from one country to another, the trend was relentlessly downward. Although the steady lessening of deaths from consumption had been well underway and growing in scope for over 50 years, a eureka moment was proclaimed on March 24, 1882, when Professor Robert Koch announced his discovery of the cause of tuberculosis, a virulent microscopic bacillus called Mycobacterium tuberculosis. Koch’s momentous scientific breakthrough, which was widely acclaimed
and rapidly disseminated throughout the world, soon laid to rest many of the centuries-long cherished but unfounded beliefs concerning the cause, treatment, and outcome of consumption. The purpose of this essay is to sort out fact from fancy among the abundant, accumulated lore and to take another look at a sometimes discredited theme tucked within the age-old story of tuberculosis: is there a connection between high altitude and the disease?
Part 1: Anecdotes The swath of death carved out by tuberculosis—from one end of Europe to the other, and then the eastern regions of the United States—was a daily part of life and death but remained totally incomprehensible for over 300 years. Both e´minences grises and charlatans alike tackled the problem, and although claims of success were repeatedly made, no remedy stood the test of time very long. The two principal, long-prevailing theories underlying the cause of consumption attracted universal interest and debate but led to divided geographical predilections. On the one hand, Italy and neighboring countries to the south greatly favored the theory of “a contagion,” a malignant miasma that people caught, either through inhaled air or through contact with the body; on the other hand, France and its northerly neighbors adopted the prejudice of “a constitutional hereditary defect,” which was continuously reinforced by the striking number of afflicted families stretching over multiple generations. All
society, whether rich or poor, tried to shelter itself from omnipresent disease and death, but no one really knew what to do and everyone felt threatened: waiting for the scourge to strike. People sick and dying of consumption—the lucky ones who were able to afford it—fled to more agreeable, salubrious climates. Favorite destinations included Nice, Florence, and Rome; less alluring selections were available provided they were warm, dry, and sunny. Later, the search for both pleasant, healthy climates combined with hoped-for cures extended ever wider, always fortified by feelings of euphoria and optimism (1). Not surprisingly, however, no particular climatic condition proved superior to any other. According to Dubos and Dubos (2), it didn’t matter whether doctors referred their patients to “the seashore versus high mountains,” “the hot and dry deserts versus the cool Northern countries,” and “the stimulation afforded by changing climate versus the relaxation that comes from a familiar environment.” During the eighteenth century, Dr. John Lettsom organized treatment facilities for victims of scrofula so they could profit from bathing in the sea and sleeping in the open air in sheltered verandas. Later, Dr. George Bodington advocated “the free use of a pure atmosphere,” supplemented with increasing intervals of, at first, gentle exercise. But the denouement that overturned medical practice for the next 100 years happened without special notice in 1854, when Dr. Hermann Brehmer founded the first high-altitude sanatorium for the treatment of pulmonary tuberculosis
( Received in original form November 20, 2013; accepted in final form December 30, 2013 ) Correspondence and requests for reprints should be addressed to John F. Murray, M.D., International Union against Tuberculosis and Lung Disease, 68 boulevard Saint Michel, 75006 Paris, France. E-mail: [email protected] Am J Respir Crit Care Med Vol 189, Iss 4, pp 390–393, Feb 15, 2014 Copyright © 2014 by the American Thoracic Society Originally Published in Press as DOI: 10.1164/rccm.201311-2043OE on January 2, 2014 Internet address: www.atsjournals.org
390
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 4 | February 15 2014
OCCASIONAL ESSAY at G¨orbersdorf in the mountains of Bavaria (2). At first, Brehmer championed a vigorous life at high altitude, but after realizing his mistake, he switched to rest in bed in the open air, an innovation that quickly caught on. Since 1841, Davos, Switzerland had been used as a treatment center for scrofula, but after Brehmer’s success, it and other highaltitude retreats adopted the Brehmer model and also started treating pulmonary tuberculosis; the good news spread quickly and celebrities soon flocked to Davos. Much later, Nobel Prize winner Thomas Mann’s magnificent novel, The Magic Mountain, featured life and death in a high-end tuberculosis sanatorium at Davos, which attracted worldwide attention and acclaim. Entrepreneurs were quick to acknowledge and exploit assurances that the health benefits of absolute rest and open spaces with pristine air were equally healthful at the seashore and other attractive locations as at high altitude. The sanatorium movement rapidly spread to dozens of countries and places with other special climates, among them the U.S. Territory (and then State) of Colorado, where the denizens of Denver were steadfast about the healing powers of the lightened atmosphere; estimates of the total population of Colorado in 1880 revealed that one-third had relocated for health reasons, chiefly tuberculosis (3). (Denver is located on a high plateau at 1,609 m [5,280 ft] and Davos is at almost the same altitude, 1,560 m [5,118 ft].) It is of considerable interest that among all the hype that accompanied the establishment of high-altitude sanatoriums, virtually nothing was ever said about whether low ambient oxygen pressure— itself—might have therapeutic benefit for pulmonary and other forms of tuberculosis. There was one exception, Denis Jourdanet, an almost forgotten high-altitude physiologist (now newly praised [4]), who strongly believed that patients with pulmonary tuberculosis improved if they lived at altitudes above 2,000 m because of the reduced oxygen tension.
Part 2: Science The death rate from tuberculosis continued its decline because standards of living kept rising and public heath practices kept improving; isolating infectious tuberculars Occasional Essay
in the thousands of sanatoriums that sprang up during the last half of the nineteenth century and first half of the twentieth must have contributed as well. But one crucial factor was missing: finding a cure for the still colossal morbidity and mortality from the disease would take another 63 years after Koch’s identification of M. tuberculosis. (The death rate from tuberculosis in the United States in 1945 was 40 per 100,000.) Effective antituberculosis chemotherapy started in 1945 with the nearly simultaneous discovery of streptomycin and paraaminosalicylic acid, which was then topped off by the miracle drug— isoniazid—in 1952 (5). With all three drugs combined, “triple therapy” proved highly successful and led to the longawaited proclamation: “tuberculosis can regularly be cured.” Mycobacteriology
Much of the early research after Koch’s discovery in 1882 involved improvements in detection, classification, and behavior of M. tuberculosis and a new discipline, mycobacteriology, emerged. Somewhat later, studies examined how environmental conditions, including high and low oxygen pressures, affected the growth and survival characteristics of the organism. In 1925, for example, the experiments of Novy and Soule (6) on the “Respiration of the Tubercle Bacillus” showed that higher than usual ambient oxygen concentrations (e.g., 40 and 60%) enhanced bacillary growth, whereas 80 and 100% retarded it; by contrast, exposure to lower than normal oxygen concentrations showed “for the first time” that growth “decreased progressively as the [oxygen] tension was lowered”; 2 years later, the experiments of Corper, Lurie, and Uyei (7) came to nearly similar conclusions about the effects of low oxygen tensions. Then, in 1939, Kempner (8) determined that the rate of oxygen utilization of cultured tubercle bacilli decreased in curvilinear fashion as the oxygen percentage of exposed bacilli was reduced. By the end of the 1930s, these and other in vitro experiments had shown that M. tuberculosis was an obligate aerobic bacillus and that its growth and oxygen consumption were slowed considerably by worsening exposure to hypoxia. Soon afterward, the classic guinea pig experiments of Rich and Follis (9) demonstrated that the progression of
tuberculosis in animals infected with virulent tubercle bacilli, documented by thorough pathologic examination, was severely inhibited when exposed to a hypoxic environment no higher than 9–10 vol% oxygen (68–76 mm Hg), compared with control animals breathing normal concentrations of atmospheric oxygen. Of note, progression of tuberculosis was nearly the same at oxygen concentrations around 12–14 vol% (91–106 mm Hg) as at room air. Tuberculosis cognoscenti now realized that high altitude–induced hypoxia might have an appreciable effect on M. tuberculosis and the severity of (at least) experimental tuberculosis, but no one knew what to make of it. Adaptation
Pioneering studies over several decades by Peruvian investigators led by A. Hurtado and H. Aste-Salazar (10) and C. Monge Medrano (11) and their associates provided fundamental information about how healthy indigenous highlanders acclimatize to low ambient oxygen pressures at altitudes of, for example, 4,540 m (14,900 ft), barometric pressure of 445 mm Hg; moreover, Peruvians born and raised at high altitudes are able to engage in equally vigorous physical activity, sometimes even greater, than healthy sea-level dwellers of similar age (12). More recent findings demonstrate that indigenous high-altitude Tibetans incorporate an entirely different profile of adaptive mechanisms compared with Peruvian highlanders (13). Thus, it turns out that there are two large but distinct high-altitude populations, one of Tibetan background, whose ancestors settled roughly 25,000 years ago, and the other of Andean ancestry, whose descendants relocated about 11,000 years ago (14). Consistent and sometimes large quantitative findings document how these two populations succeeded in adapting— almost completely differently—to the same low ambient oxygen pressures at identical high altitudes in Tibet and Peru. Resting ventilation, hypoxic ventilatory response, diffusing capacities for both carbon monoxide and nitrogen oxide, exhaled nitrogen oxide, and muscle capillary density are typically higher in indigenous highaltitude residents in Tibet compared with those in Peru; by contrast, oxygen saturation and content, hemoglobin concentration, pulmonary artery pressure, and 391
OCCASIONAL ESSAY erythropoietin concentration are all higher in Andean highlanders compared with those at similar altitude in Tibet (14). Genetic differences appear to explain how these two large and geographically distinct populations used different adaptive mechanisms to achieve the same goal of maintaining oxygen transport at healthful levels. Studies have begun to sort out the contributions of the hypoxia-inducible factor (HIF) pathway to the genetic adaptations of Tibetan and Andean highlanders. (HIFs comprise a complex regulatory network that is sometimes called the “master regulator” of oxygen homeostasis [15].) The results of genomewide association analyses have established that gene variants of the HIF regulator EGLIN1 are found in both Tibetan and Andean highlanders and that other specific adaptive mutations differentiate the two populations (16). But we must ask whether the reshuffling of the genetic deck that accompanied the two millennia-old pathways of adaptation to high altitude affects either the growth-enhancing or growth-inhibiting properties of M. tuberculosis; important information that is not yet available.
Conclusions
reduced atmospheric pressure demonstrates that low oxygen pressures inhibit the ability of M. tuberculosis to survive and multiply. Second, people born and raised at high altitude appear to have a lower prevalence of tuberculosis than those living at sea level, but whether this is strictly a protective effect of low ambient oxygen tension related to a decreased rate of mycobacterial growth, transmission, and development of disease—or other factors—is debatable. Third, whether immunologic defenses against tuberculosis at high altitude have strengthened or weakened the likelihood of disease is unknown, but genetically determined population differences in Tibet and the Andes provide an opportunity to find out. Finally, in the current era of increasing global prevalence of extensively drug-resistant tuberculosis, with upward of 40% mortality, the use of sanatoriums has already been proposed (22). Why not consider sojourns at high altitude: retreats above 2,500 m (8,200 ft), several of which can be found in Colorado, and even higher destinations, such as Cuzco, Peru (3,400 m, 11,150 ft), La Paz, Bolivia (3,780 m, 12,400 ft), Lhasa, Tibet (3,660 m, 12,000 ft), might prove beneficial. This seems like an idea worth testing. n
First, evidence from both in vitro and in vivo studies of oxygen administered at
Author disclosures are available with the text of this article at www.atsjournals.org.
since 1999 in Kenya (.1,000 m) (17), Peru (.3,000 m) (18), Mexico (from 0 to 2,500 m; r = 0.74) (19), and Vietnam (500–900 m) (20) have concluded that death rates, notification rates, detection rates, and tuberculin skin test surveys of tuberculosis are diminished at high altitude compared with people living at sea level. In urban zones in Peru, as distinct from rural areas, the effect of high population density and increased contact with infectious patients “overwhelmed” the beneficial influence of high altitude (21). Several mechanisms probably interact to contribute to the net effect of high altitude on tuberculosis. Most important, surely, must be the particular altitude itself, which determines the magnitude of reduced ambient oxygen pressure. Related variables include the intensity of ultraviolet radiation, temperature, and humidity that influence, in turn, the number of residents per household, ventilation of dwellings, and time spent indoors versus outdoors. Suffice it to say that conclusions from a particular high-altitude location do not guarantee an established reduced risk of tuberculosis; the relationship between these two quantifiable attributes remains a moving target with multiple uncertainties.
Epidemiology
Documenting the effect of high altitudes on tuberculosis had to wait until its prevalence decreased to statistically compliant levels, although confounding influences continue to cloud the issue. Epidemiologic studies
References 1. Knght FI. On the selection of a climate for patients with pulmonary tuberculosis. Boston Med Surg J 1888;118:343–346. 2. Dubos R, Dubos J. The white plague: tuberculosis, man, and society. New Brunswick, NJ: Rutgers University Press; 1952. 3. Rogers FB. The rise and decline of the altitude therapy of tuberculosis. Bull Hist Med 1969;43:1–16. 4. West JB, Richalet JP. Denis Jourdanet (1815–1892) and the early recognition of the role of hypoxia at high altitude. Am J Physiol Lung Cell Mol Physiol 2013;305:L333–L340. 5. Murray JF. A century of tuberculosis. Am J Respir Crit Care Med 2004; 169:1181–1186. 6. Novy FG, Soule MH. Microbic respiration. II. Respiration of the tubercle bacillus. J Infect Dis 1925;36:168–232. 7. Corper HJ, Lurie MB, Uyei N. The variability of localization of tuberculosis in the organs of different animals. III. The importance of the growth of tubercle bacilli as determined by gaseous tension. Am Rev Tuberc 1927;15:65–87. 8. Kempner W. Oxygen tension and the tubercle bacillus. Am Rev Tuberc 1939;40:157–168. 9. Rich AR, Follis RH Jr. The effect of low oxygen tension upon the development of experimental tuberculosis. Bull Johns Hopkins Hosp 1942;71:345–363.
392
10. Hurtado A, Aste-Salazar H. Arterial blood gases and acid–base balance at sea level and at high altitudes. J Appl Physiol 1948;1:304–325. 11. Monge Medrano C. Chronic mountain sickness. Physiol Rev 1943;23: 166–183. 12. Beall CM. Tibetan and Andean patterns of adaptation to high-altitude hypoxia. Hum Biol 2000;72:201–228. 13. Faoro V, Huez S, Vanderpool RR, Groepenhoff H, de Bisschop C, Martinot J-B, Lamotte M, Pavelescu A, Guenard ´ H, Naeije R. Pulmonary circulation and gas exchange at exercise in Sherpas at high altitude. J Appl Physiol (In press) 14. Beall CM. Two routes to functional adaptation: Tibetan and Andean highaltitude natives. Proc Natl Acad Sci USA 2007;104:8655–8660. 15. Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell 2012;148:399–408. 16. Bigham A, Bauchet M, Pinto D, Mao X, Akey JM, Mei R, Scherer SW, Julian CG, Wilson MJ, Lopez ´ Herraez ´ D, et al. Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLoS Genet 2010;6:e1001116. 17. Mansoer JR, Kibuga DK, Borgdorff MW. Altitude: a determinant for tuberculosis in Kenya? Int J Tuberc Lung Dis 1999;3:156–161. 18. Olender S, Saito M, Apgar J, Gillenwater K, Bautista CT, Lescano AG, Moro P, Caviedes L, Hsieh EJ, Gilman RH. Low prevalence and increased household clustering of Mycobacterium tuberculosis infection in high altitude villages in Peru. Am J Trop Med Hyg 2003; 68:721–727.
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 4 | February 15 2014
OCCASIONAL ESSAY 19. Vargas MH, Furuya MEY, Perez-Guzm ´ an ´ C. Effect of altitude on the frequency of pulmonary tuberculosis. Int J Tuberc Lung Dis 2004;8: 1321–1324. 20. Vree M, Hoa NB, Sy DN, Co NV, Cobelens FGJ, Borgdorff MW. Low tuberculosis notification in mountainous Vietnam is not due to low case detection: a cross-sectional survey. BMC Infect Dis 2007; 7:109.
Occasional Essay
21. Saito M, Pan WK, Gilman RH, Bautista CT, Bamrah S, Martı´n CA, Tsiouris SJ, Arguello ¨ DF, Martinez-Carrasco GA. Comparison of altitude effect on Mycobacterium tuberculosis infection between rural and urban communities in Peru. Am J Trop Med Hyg 2006;75:49–54. 22. Dheda K, Migliori GB. The global rise of extensively drug-resistant tuberculosis: is the time to bring back sanatoria now overdue? Lancet 2012;379:773–775.
393
Consumption, or phthisis, later known as tuberculosis, was already the leading killer of Londoners as far back as the early seventeenth century; within the next 100 years, fueled by demographic shifts during the burgeoning Industrial Revolution, tuberculosis grew into—unquestionably— the most important cause of disease and death, first in all of England, and then elsewhere in Western Europe, and later in the eastern United States. During its more than 300-year-long heyday, consumption killed hundreds of millions of people; some estimates put the total as high as 1 billion deaths. Mortality from tuberculosis peaked about at 500 per 100,000 in the years around 1800 in England, much of Europe, and in major cities in the eastern United States. Providentially, the extraordinarily high death rates during the eighteenth century and up to the beginning of the nineteenth began to abate for complex and never fully understood reasons; chief among them were a rising standard of living and, to a lesser extent, primitive medical progress through the identification and isolation of presumed contagious patients. Although the rate of decline varied from one country to another, the trend was relentlessly downward. Although the steady lessening of deaths from consumption had been well underway and growing in scope for over 50 years, a eureka moment was proclaimed on March 24, 1882, when Professor Robert Koch announced his discovery of the cause of tuberculosis, a virulent microscopic bacillus called Mycobacterium tuberculosis. Koch’s momentous scientific breakthrough, which was widely acclaimed
and rapidly disseminated throughout the world, soon laid to rest many of the centuries-long cherished but unfounded beliefs concerning the cause, treatment, and outcome of consumption. The purpose of this essay is to sort out fact from fancy among the abundant, accumulated lore and to take another look at a sometimes discredited theme tucked within the age-old story of tuberculosis: is there a connection between high altitude and the disease?
Part 1: Anecdotes The swath of death carved out by tuberculosis—from one end of Europe to the other, and then the eastern regions of the United States—was a daily part of life and death but remained totally incomprehensible for over 300 years. Both e´minences grises and charlatans alike tackled the problem, and although claims of success were repeatedly made, no remedy stood the test of time very long. The two principal, long-prevailing theories underlying the cause of consumption attracted universal interest and debate but led to divided geographical predilections. On the one hand, Italy and neighboring countries to the south greatly favored the theory of “a contagion,” a malignant miasma that people caught, either through inhaled air or through contact with the body; on the other hand, France and its northerly neighbors adopted the prejudice of “a constitutional hereditary defect,” which was continuously reinforced by the striking number of afflicted families stretching over multiple generations. All
society, whether rich or poor, tried to shelter itself from omnipresent disease and death, but no one really knew what to do and everyone felt threatened: waiting for the scourge to strike. People sick and dying of consumption—the lucky ones who were able to afford it—fled to more agreeable, salubrious climates. Favorite destinations included Nice, Florence, and Rome; less alluring selections were available provided they were warm, dry, and sunny. Later, the search for both pleasant, healthy climates combined with hoped-for cures extended ever wider, always fortified by feelings of euphoria and optimism (1). Not surprisingly, however, no particular climatic condition proved superior to any other. According to Dubos and Dubos (2), it didn’t matter whether doctors referred their patients to “the seashore versus high mountains,” “the hot and dry deserts versus the cool Northern countries,” and “the stimulation afforded by changing climate versus the relaxation that comes from a familiar environment.” During the eighteenth century, Dr. John Lettsom organized treatment facilities for victims of scrofula so they could profit from bathing in the sea and sleeping in the open air in sheltered verandas. Later, Dr. George Bodington advocated “the free use of a pure atmosphere,” supplemented with increasing intervals of, at first, gentle exercise. But the denouement that overturned medical practice for the next 100 years happened without special notice in 1854, when Dr. Hermann Brehmer founded the first high-altitude sanatorium for the treatment of pulmonary tuberculosis
( Received in original form November 20, 2013; accepted in final form December 30, 2013 ) Correspondence and requests for reprints should be addressed to John F. Murray, M.D., International Union against Tuberculosis and Lung Disease, 68 boulevard Saint Michel, 75006 Paris, France. E-mail: [email protected] Am J Respir Crit Care Med Vol 189, Iss 4, pp 390–393, Feb 15, 2014 Copyright © 2014 by the American Thoracic Society Originally Published in Press as DOI: 10.1164/rccm.201311-2043OE on January 2, 2014 Internet address: www.atsjournals.org
390
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 4 | February 15 2014
OCCASIONAL ESSAY at G¨orbersdorf in the mountains of Bavaria (2). At first, Brehmer championed a vigorous life at high altitude, but after realizing his mistake, he switched to rest in bed in the open air, an innovation that quickly caught on. Since 1841, Davos, Switzerland had been used as a treatment center for scrofula, but after Brehmer’s success, it and other highaltitude retreats adopted the Brehmer model and also started treating pulmonary tuberculosis; the good news spread quickly and celebrities soon flocked to Davos. Much later, Nobel Prize winner Thomas Mann’s magnificent novel, The Magic Mountain, featured life and death in a high-end tuberculosis sanatorium at Davos, which attracted worldwide attention and acclaim. Entrepreneurs were quick to acknowledge and exploit assurances that the health benefits of absolute rest and open spaces with pristine air were equally healthful at the seashore and other attractive locations as at high altitude. The sanatorium movement rapidly spread to dozens of countries and places with other special climates, among them the U.S. Territory (and then State) of Colorado, where the denizens of Denver were steadfast about the healing powers of the lightened atmosphere; estimates of the total population of Colorado in 1880 revealed that one-third had relocated for health reasons, chiefly tuberculosis (3). (Denver is located on a high plateau at 1,609 m [5,280 ft] and Davos is at almost the same altitude, 1,560 m [5,118 ft].) It is of considerable interest that among all the hype that accompanied the establishment of high-altitude sanatoriums, virtually nothing was ever said about whether low ambient oxygen pressure— itself—might have therapeutic benefit for pulmonary and other forms of tuberculosis. There was one exception, Denis Jourdanet, an almost forgotten high-altitude physiologist (now newly praised [4]), who strongly believed that patients with pulmonary tuberculosis improved if they lived at altitudes above 2,000 m because of the reduced oxygen tension.
Part 2: Science The death rate from tuberculosis continued its decline because standards of living kept rising and public heath practices kept improving; isolating infectious tuberculars Occasional Essay
in the thousands of sanatoriums that sprang up during the last half of the nineteenth century and first half of the twentieth must have contributed as well. But one crucial factor was missing: finding a cure for the still colossal morbidity and mortality from the disease would take another 63 years after Koch’s identification of M. tuberculosis. (The death rate from tuberculosis in the United States in 1945 was 40 per 100,000.) Effective antituberculosis chemotherapy started in 1945 with the nearly simultaneous discovery of streptomycin and paraaminosalicylic acid, which was then topped off by the miracle drug— isoniazid—in 1952 (5). With all three drugs combined, “triple therapy” proved highly successful and led to the longawaited proclamation: “tuberculosis can regularly be cured.” Mycobacteriology
Much of the early research after Koch’s discovery in 1882 involved improvements in detection, classification, and behavior of M. tuberculosis and a new discipline, mycobacteriology, emerged. Somewhat later, studies examined how environmental conditions, including high and low oxygen pressures, affected the growth and survival characteristics of the organism. In 1925, for example, the experiments of Novy and Soule (6) on the “Respiration of the Tubercle Bacillus” showed that higher than usual ambient oxygen concentrations (e.g., 40 and 60%) enhanced bacillary growth, whereas 80 and 100% retarded it; by contrast, exposure to lower than normal oxygen concentrations showed “for the first time” that growth “decreased progressively as the [oxygen] tension was lowered”; 2 years later, the experiments of Corper, Lurie, and Uyei (7) came to nearly similar conclusions about the effects of low oxygen tensions. Then, in 1939, Kempner (8) determined that the rate of oxygen utilization of cultured tubercle bacilli decreased in curvilinear fashion as the oxygen percentage of exposed bacilli was reduced. By the end of the 1930s, these and other in vitro experiments had shown that M. tuberculosis was an obligate aerobic bacillus and that its growth and oxygen consumption were slowed considerably by worsening exposure to hypoxia. Soon afterward, the classic guinea pig experiments of Rich and Follis (9) demonstrated that the progression of
tuberculosis in animals infected with virulent tubercle bacilli, documented by thorough pathologic examination, was severely inhibited when exposed to a hypoxic environment no higher than 9–10 vol% oxygen (68–76 mm Hg), compared with control animals breathing normal concentrations of atmospheric oxygen. Of note, progression of tuberculosis was nearly the same at oxygen concentrations around 12–14 vol% (91–106 mm Hg) as at room air. Tuberculosis cognoscenti now realized that high altitude–induced hypoxia might have an appreciable effect on M. tuberculosis and the severity of (at least) experimental tuberculosis, but no one knew what to make of it. Adaptation
Pioneering studies over several decades by Peruvian investigators led by A. Hurtado and H. Aste-Salazar (10) and C. Monge Medrano (11) and their associates provided fundamental information about how healthy indigenous highlanders acclimatize to low ambient oxygen pressures at altitudes of, for example, 4,540 m (14,900 ft), barometric pressure of 445 mm Hg; moreover, Peruvians born and raised at high altitudes are able to engage in equally vigorous physical activity, sometimes even greater, than healthy sea-level dwellers of similar age (12). More recent findings demonstrate that indigenous high-altitude Tibetans incorporate an entirely different profile of adaptive mechanisms compared with Peruvian highlanders (13). Thus, it turns out that there are two large but distinct high-altitude populations, one of Tibetan background, whose ancestors settled roughly 25,000 years ago, and the other of Andean ancestry, whose descendants relocated about 11,000 years ago (14). Consistent and sometimes large quantitative findings document how these two populations succeeded in adapting— almost completely differently—to the same low ambient oxygen pressures at identical high altitudes in Tibet and Peru. Resting ventilation, hypoxic ventilatory response, diffusing capacities for both carbon monoxide and nitrogen oxide, exhaled nitrogen oxide, and muscle capillary density are typically higher in indigenous highaltitude residents in Tibet compared with those in Peru; by contrast, oxygen saturation and content, hemoglobin concentration, pulmonary artery pressure, and 391
OCCASIONAL ESSAY erythropoietin concentration are all higher in Andean highlanders compared with those at similar altitude in Tibet (14). Genetic differences appear to explain how these two large and geographically distinct populations used different adaptive mechanisms to achieve the same goal of maintaining oxygen transport at healthful levels. Studies have begun to sort out the contributions of the hypoxia-inducible factor (HIF) pathway to the genetic adaptations of Tibetan and Andean highlanders. (HIFs comprise a complex regulatory network that is sometimes called the “master regulator” of oxygen homeostasis [15].) The results of genomewide association analyses have established that gene variants of the HIF regulator EGLIN1 are found in both Tibetan and Andean highlanders and that other specific adaptive mutations differentiate the two populations (16). But we must ask whether the reshuffling of the genetic deck that accompanied the two millennia-old pathways of adaptation to high altitude affects either the growth-enhancing or growth-inhibiting properties of M. tuberculosis; important information that is not yet available.
Conclusions
reduced atmospheric pressure demonstrates that low oxygen pressures inhibit the ability of M. tuberculosis to survive and multiply. Second, people born and raised at high altitude appear to have a lower prevalence of tuberculosis than those living at sea level, but whether this is strictly a protective effect of low ambient oxygen tension related to a decreased rate of mycobacterial growth, transmission, and development of disease—or other factors—is debatable. Third, whether immunologic defenses against tuberculosis at high altitude have strengthened or weakened the likelihood of disease is unknown, but genetically determined population differences in Tibet and the Andes provide an opportunity to find out. Finally, in the current era of increasing global prevalence of extensively drug-resistant tuberculosis, with upward of 40% mortality, the use of sanatoriums has already been proposed (22). Why not consider sojourns at high altitude: retreats above 2,500 m (8,200 ft), several of which can be found in Colorado, and even higher destinations, such as Cuzco, Peru (3,400 m, 11,150 ft), La Paz, Bolivia (3,780 m, 12,400 ft), Lhasa, Tibet (3,660 m, 12,000 ft), might prove beneficial. This seems like an idea worth testing. n
First, evidence from both in vitro and in vivo studies of oxygen administered at
Author disclosures are available with the text of this article at www.atsjournals.org.
since 1999 in Kenya (.1,000 m) (17), Peru (.3,000 m) (18), Mexico (from 0 to 2,500 m; r = 0.74) (19), and Vietnam (500–900 m) (20) have concluded that death rates, notification rates, detection rates, and tuberculin skin test surveys of tuberculosis are diminished at high altitude compared with people living at sea level. In urban zones in Peru, as distinct from rural areas, the effect of high population density and increased contact with infectious patients “overwhelmed” the beneficial influence of high altitude (21). Several mechanisms probably interact to contribute to the net effect of high altitude on tuberculosis. Most important, surely, must be the particular altitude itself, which determines the magnitude of reduced ambient oxygen pressure. Related variables include the intensity of ultraviolet radiation, temperature, and humidity that influence, in turn, the number of residents per household, ventilation of dwellings, and time spent indoors versus outdoors. Suffice it to say that conclusions from a particular high-altitude location do not guarantee an established reduced risk of tuberculosis; the relationship between these two quantifiable attributes remains a moving target with multiple uncertainties.
Epidemiology
Documenting the effect of high altitudes on tuberculosis had to wait until its prevalence decreased to statistically compliant levels, although confounding influences continue to cloud the issue. Epidemiologic studies
References 1. Knght FI. On the selection of a climate for patients with pulmonary tuberculosis. Boston Med Surg J 1888;118:343–346. 2. Dubos R, Dubos J. The white plague: tuberculosis, man, and society. New Brunswick, NJ: Rutgers University Press; 1952. 3. Rogers FB. The rise and decline of the altitude therapy of tuberculosis. Bull Hist Med 1969;43:1–16. 4. West JB, Richalet JP. Denis Jourdanet (1815–1892) and the early recognition of the role of hypoxia at high altitude. Am J Physiol Lung Cell Mol Physiol 2013;305:L333–L340. 5. Murray JF. A century of tuberculosis. Am J Respir Crit Care Med 2004; 169:1181–1186. 6. Novy FG, Soule MH. Microbic respiration. II. Respiration of the tubercle bacillus. J Infect Dis 1925;36:168–232. 7. Corper HJ, Lurie MB, Uyei N. The variability of localization of tuberculosis in the organs of different animals. III. The importance of the growth of tubercle bacilli as determined by gaseous tension. Am Rev Tuberc 1927;15:65–87. 8. Kempner W. Oxygen tension and the tubercle bacillus. Am Rev Tuberc 1939;40:157–168. 9. Rich AR, Follis RH Jr. The effect of low oxygen tension upon the development of experimental tuberculosis. Bull Johns Hopkins Hosp 1942;71:345–363.
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OCCASIONAL ESSAY 19. Vargas MH, Furuya MEY, Perez-Guzm ´ an ´ C. Effect of altitude on the frequency of pulmonary tuberculosis. Int J Tuberc Lung Dis 2004;8: 1321–1324. 20. Vree M, Hoa NB, Sy DN, Co NV, Cobelens FGJ, Borgdorff MW. Low tuberculosis notification in mountainous Vietnam is not due to low case detection: a cross-sectional survey. BMC Infect Dis 2007; 7:109.
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21. Saito M, Pan WK, Gilman RH, Bautista CT, Bamrah S, Martı´n CA, Tsiouris SJ, Arguello ¨ DF, Martinez-Carrasco GA. Comparison of altitude effect on Mycobacterium tuberculosis infection between rural and urban communities in Peru. Am J Trop Med Hyg 2006;75:49–54. 22. Dheda K, Migliori GB. The global rise of extensively drug-resistant tuberculosis: is the time to bring back sanatoria now overdue? Lancet 2012;379:773–775.
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