High-altitude treatment: A therapeutic option for patients with severe, refractory asthma?

Clinical and Experimental Allergy

Volumn 41, Issue 6, 2011, Pages 775-782

  Rijssenbeek Nouwens, L H ^a   Bel, E H ^b  

^a Dutch Asthma Centre Davos   (Switzerland)

^b UNIVERSITY OF AMSTERDAM   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

BETA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; CORTICOSTEROID;

AIR POLLUTION; ALTITUDE ACCLIMATIZATION; ANTIINFLAMMATORY ACTIVITY; ASTHMA; ATOPY; DISEASE SEVERITY; ENVIRONMENTAL FACTOR; FUNGUS SPORE; HOUSE DUST ALLERGY; HUMAN; IMMUNOMODULATION; LUNG DISEASE; LUNG FUNCTION; POLLEN; PRIORITY JOURNAL; REVIEW; ULTRAVIOLET RADIATION;

ALLERGENS; ALTITUDE; ANIMALS; ASTHMA; ENVIRONMENT; HUMANS; PYROGLYPHIDAE;

EID: 79955750094     PISSN: 09547894     EISSN: 13652222     Source Type: Journal    
DOI: 10.1111/j.1365-2222.2011.03733.x     Document Type: Review

References (99)

1. Spieksma FT, Zuidema P, Leupen MJ. High altitude and house-dust mites. Br Med J 1971; 1:82-4.
2. European Environment Agency. Air quality maps of Europe. 2010. Available at
3. Leuschner RM, Boehm W. Pollen and inorganic particles in the air of climatically very different places in Switzerland. Grana 1981; 20:161-7.
4. Platts-Mills TA, Chapman MD. Dust mites: immunology, allergic disease, and environmental control. J Allergy Clin Immunol 1987; 80:755-75.
5. Karagiannidis C, Hense G, Rueckert B et al. High-altitude climate therapy reduces local airway inflammation and modulates lymphocyte activation. Scand J Immunol 2006; 63:304-10.
6. Anonymous. Davos and the Enghadine. Lancet 1876; 101:482-3.
7. Allbutt C. The past winter in Davos. Lancet 1879; 114:76-8 and 118-9.
8. Turban K, Spengler L. Resultate der Asthmabehandlung im Hochgebirge. Jahresb schweiz balneol Gesellsch 1906; 2:72.
9. Stäubli K. Ueber die Indikat und Kontra-Indikat des Hohenklimas. Deutsche med Wschr 1912; 4.
10. Storm van Leeuwen W, Varekamp H, Bien Z. Asthma bronchiale und Klima. Klin Wschr 1924; 3:520.
11. Storm van Leeuwen W. Asthma and Tuberculosis in relation to "Climate Allergens". Br Med J 1927; 2:344-7.
12. Voorhorst R, Spieksma F.Th.M, Varekamp H. House-dust atopy and the house-dust mite Dermatophagoides pteronyssinus (Trouessart 1897). Leiden: Stafleu's Scientific Publishing Company, 1969.
13. Vervloet D, Penaud A, Razzouk H et al. Altitude and house dust mites. J Allergy Clin Immunol 1982; 69:290-6.
14. Kerrebijn KF, de Kroon JP, Roosenburg JG, Zuidema P. Corticosteroid therapy of children with chronic aspecific respiratory disease. Discontinuation of the treatment in the mountains. Ned Tijdschr Geneeskd 1967; 111:2353-9.
15. Kerrebijn KF. Endogenous factors in childhood chronic nonspecific lung disease; methodological aspects in population studies. In: Orie N.G.M, van der Lende R, eds. Bronchitis III. Assen, the Netherlands: Royal Van Gorkum, 1970; 38-48.
16. Platts-Mills TA, Mitchell EB, Nock P, Tovey ER, Moszoro H, Wilkins SR. Reduction of bronchial hyperreactivity during prolonged allergen avoidance. Lancet 1982; 3:675-8.
17. Boner A, Niero E, Antolini I, Warner JO. Biphasic (early and late) asthmatic responses to exercise in children with severe asthma, resident at high altitude. Eur J Pediatr 1985; 144:164-6.
18. Boner AL, Niero E, Antolini I, Valletta EA, Gaburro D. Pulmonary function and bronchial hyperreactivity in asthmatic children with house dust mite allergy during prolonged stay in the Italian Alps (Misurina, 1756m). Ann Allergy 1985; 54:42-5.
19. Piacentini GL, Martinati L, Fornari A et al. Antigen avoidance in a mountain environment: influence on basophil releasability in children with allergic asthma. J Allergy Clin Immunol 1993; 92:644-50.
20. Boner AL, Peroni DG, Piacentini GL, Venge P. Influence of allergen avoidance at high altitude on serum markers of eosinophil activation in children with allergic asthma. Clin Exp Allergy 1993; 23:1021-6.
21. Peroni DG, Boner AL, Vallone G, Antolini I, Warner JO. Effective allergen avoidance at high altitude reduces allergen-induced bronchial hyperresponsiveness. Am J Respir Crit Care Med 1994; 149:1442-6.
22. Valletta EA, Comis A, Del CG, Spezia E, Boner AL. Peak expiratory flow variation and bronchial hyperresponsiveness in asthmatic children during periods of antigen avoidance and reexposure. Allergy 1995; 50:366-9.
23. Valletta EA, Piacentini GL, Del CG, Boner AL. FEF25-75 as a marker of airway obstruction in asthmatic children during reduced mite exposure at high altitude. J Asthma 1997; 34:127-31.
24. Piacentini GL, Vicentini L, Mazzi P, Chilosi M, Martinati L, Boner AL. Mite-antigen avoidance can reduce bronchial epithelial shedding in allergic asthmatic children. Clin Exp Allergy 1998; 28:561-7.
25. Piacentini GL, Peterson C, Peroni DG, Bodini A, Boner AL. Allergen avoidance at high altitude and urinary eosinophil protein X. J Allergy Clin Immunol 1999; 104:243-4.
26. Peroni DG, Piacentini GL, Costella S et al. Mite avoidance can reduce air trapping and airway inflammation in allergic asthmatic children. Clin Exp Allergy 2002; 32:850-5.
27. Bodini A, Peroni D, Vicentini L et al. Exhaled breath condensate eicosanoids and sputum eosinophils in asthmatic children: a pilot study. Pediatr Allergy Immunol 2004; 15:26-31.
28. Piacentini GL, Peroni DG, Bodini A, Boner AL. Exhaled nitric oxide in children with asthma at high altitude. J Allergy Clin Immunol 2007; 120:1226-7.
29. Peroni DG, Piacentini GL, Vicentini L, Costella S, Pietrobelli A, Boner AL. Effective allergen avoidance reduces residual volume and sputum eosinophils in children with asthma. J Allergy Clin Immunol 2001; 108:308.
30. Piacentini GL, Del Giudice MJ, Bodini A et al. Exhaled NO reduced on allergen avoidance. Allergy 2001; 56:251-2.
31. Piacentini GL, Bodini A, Costella S et al. Exhaled nitric oxide in asthmatic children exposed to relevant allergens: effect of flunisolide. Eur Respir J 2000; 15:730-4.
32. Piacentini GL, Bodini A, Costella S et al. Allergen avoidance is associated with a fall in exhaled nitric oxide in asthmatic children. J Allergy Clin Immunol 1999; 104:1323-4.
33. Piacentini GL, Martinati L, Mingoni S, Boner AL. Influence of allergen avoidance on the eosinophil phase of airway inflammation in children with allergic asthma. J Allergy Clin Immunol 1996; 97:1079-84.
34. Sensi LG, Piacentini GL, Nobile E et al. Changes in nasal specific IgE to mites after periods of allergen exposure-avoidance: a comparison with serum levels. Clin Exp Allergy 1994; 24:377-82.
35. Milanese M, Peroni D, Costella S et al. Improved bronchodilator effect of deep inhalation after allergen avoidance in asthmatic children. J Allergy Clin Immunol 2004; 114:505-11.
36. Boner AL, Comis A, Schiassi M, Venge P, Piacentini GL. Bronchial reactivity in asthmatic children at high and low altitude. Effect of budesonide.. Am J Respir Crit Care Med 1995; 151:1194-200.
37. Simon HU, Grotzer M, Nikolaizik WH, Blaser K, Schoni MH. High altitude climate therapy reduces peripheral blood T lymphocyte activation, eosinophilia, and bronchial obstruction in children with house-dust mite allergic asthma. Pediatr Pulmonol 1994; 17:304-11.
38. 4 excretion and airway responsiveness to histamine in children with atopic asthma. Eur Respir J 1995; 8:357-63.
39. van Velzen E, Van Den Bos JW, Benckhuijsen JA, van ET, de BR, Aalbers R. Effect of allergen avoidance at high altitude on direct and indirect bronchial hyperresponsiveness and markers of inflammation in children with allergic asthma. Thorax 1996; 51:582-4.
40. Benckhuijsen J, van den BJW, van Velzen E, de Bruijn R, Aalbers R. Differences in the effect of allergen avoidance on bronchial hyperresponsiveness as measured by methacholine, adenosine-5'-monophosphate, and exercise in asthmatic children. Pediatr Pulmonol 1996; 22:147-53.
41. Grootendorst DC, Dahlen SE, Van Den Bos JW et al. Benefits of high altitude allergen avoidance in atopic adolescents with moderate to severe asthma, over and above treatment with high dose inhaled steroids. Clin Exp Allergy 2001; 31:400-8.
42. Huss-Marp J, Kramer U, Eberlein B et al. Reduced exhaled nitric oxide values in children with asthma after inpatient rehabilitation at high altitude. J Allergy Clin Immunol 2007; 120:471-2.
43. Hedlin G, Bush A, Lodrup CK et al. Problematic severe asthma in children, not one problem but many: a GA2LEN initiative. Eur Respir J 2010; 36:196-201.
44. Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults. Lancet 2006; 368:780-93.
45. Barnes PJ. New therapies for asthma: is there any progress? Trends Pharmacol Sci 2010; 31:335-43.
46. Walsh LJ, Wong CA, Oborne J et al. Adverse effects of oral corticosteroids in relation to dose in patients with lung disease. Thorax 2001; 56:279-84.
47. Brightling C, Berry M, Amrani Y. Targeting TNF-alpha: a novel therapeutic approach for asthma. J Allergy Clin Immunol 2008; 121:5-10.
48. Busse WW, Corren J, Lanier BQ et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 2001; 108:184-90.
49. Haldar P, Brightling CE, Hargadon B et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009; 360:973-84.
50. Nair P, Pizzichini MM, kjarsgaard M et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009; 360:985-93.
51. Berry MA, Hargadon B, Shelley M et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 2006; 354:697-708.
52. Call RS, Ward G, Jackson S, Platts-Mills TA. Investigating severe and fatal asthma. J Allergy Clin Immunol 1994; 94:1065-72.
53. Peden D, Reed CE. Environmental and occupational allergies. J Allergy Clin Immunol 2010; 125:S150-60.
54. Ho SM. Environmental epigenetics of asthma: an update. J Allergy Clin Immunol 2010; 126:453-65.
55. Bernstein JA, Alexis N, Bacchus H et al. The health effects of non-industrial indoor air pollution. J Allergy Clin Immunol 2008; 121:585-91.
56. Wang J, Visness CM, Calatroni A, Gergen PJ, Mitchell HE, Sampson HA. Effect of environmental allergen sensitization on asthma morbidity in inner-city asthmatic children. Clin Exp Allergy 2009; 39:1381-9.
57. Denning DW, O'Driscoll BR, Hogaboam CM, Bowyer P, Niven RM. The link between fungi and severe asthma: a summary of the evidence. Eur Respir J 2006; 27:615-26.
58. Sandhu MS, Casale TB. The role of vitamin D in asthma. Ann Allergy Asthma Immunol 2010; 105:191-9.
59. Custovic A, Taggart SC, Francis HC, Chapman MD, Woodcock A. Exposure to house dust mite allergens and the clinical activity of asthma. J Allergy Clin Immunol 1996; 98:64-72.
60. National Institutes of Health, National Heart, Lung, and Blood Institute., Global initiative for asthma. Global strategy for asthma management and prevention. NHLBI/WHO workshop report, 2008. Available at (accessed April 2010).
61. Custovic A, Simpson A, Chapman MD, Woodcock A. Allergen avoidance in the treatment of asthma and atopic disorders. Thorax 1998; 53:63-72.
62. Gotzsche PC, Johansen HK, Schmidt LM, Burr ML. House dust mite control measures for asthma. Cochrane Database Syst Rev, 18 October 2004, 18;(4):CD001187 2004;CD001187.
63. Platts-Mills TA. Allergen avoidance in the treatment of asthma: problems with the meta-analyses. J Allergy Clin Immunol 2008; 122:694-6.
64. Morgan WJ, Crain EF, Gruchalla RS et al. Results of a home-based environmental intervention among urban children with asthma. N Engl J Med 2004; 351:1068-80.
65. Delfino RJ, Coate BD, Zeiger RS, Seltzer JM, Street DH, Koutrakis P. Daily asthma severity in relation to personal ozone exposure and outdoor fungal spores. Am J Respir Crit Care Med 1996; 154:633-41.
66. Zureik M, Neukirch C, Leynaert B, Liard R, Bousquet J, Neukirch F. Sensitisation to airborne moulds and severity of asthma: cross sectional study from European Community respiratory health survey. BMJ 2002; 325:411-4.
67. Fairs A, Agbetile J, Hargadon B, Bourne M et al. IgE sensitisation to Aspergillus fumigatus is associated with reduced lung function in asthma. Am J Respir Crit Care Med 2010; 182:1362-8.
68. Denning DW, O'Driscoll BR, Powell G et al. Randomized controlled trial of oral antifungal treatment for severe asthma with fungal sensitization: the Fungal Asthma Sensitization Trial (FAST) study. Am J Respir Crit Care Med 2009; 179:11-8.
69. Burr ML, Matthews IP, Arthur RA et al. Effects on patients with asthma of eradicating visible indoor mould: a randomised controlled trial. Thorax 2007; 62:767-72.
70. Howden-Chapman P, Matheson A, Crane J et al. Effect of insulating existing houses on health inequality: cluster randomised study in the community. BMJ 2007; 334:460-9.
71. Burge HA. An update on pollen and fungal spore aerobiology. J Allergy Clin Immunol 2002; 110:544-52.
72. Brehm JM, Schuemann B, Fuhlbrigge AL et al. Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. J Allergy Clin Immunol 2010; 126:52-8.
73. Black PN, Scragg R. Relationship between serum 25-hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey. Chest 2005; 128:3792-8.
74. Brehm JM, Celedon JC, Soto-Quiros ME et al. Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica. Am J Respir Crit Care Med 2009; 179:765-71.
75. Sutherland ER, Goleva E, Jackson LP, Stevens AD, Leung DY. Vitamin D levels, lung function, and steroid response in adult asthma. Am J Respir Crit Care Med 2010; 181:699-704.
76. Searing DA, Zhang Y, Murphy JR, Hauk PJ, Goleva E, Leung DY. Decreased serum vitamin D levels in children with asthma are associated with increased corticosteroid use. J Allergy Clin Immunol 2010; 125:995-1000.
77. Banerjee A, Damera G, Bhandare R et al. Vitamin D and glucocorticoids differentially modulate chemokine expression in human airway smooth muscle cells. Br J Pharmacol 2008; 155:84-92.
78. Clifford RL, Knox AJ. Vitamin D - a new treatment for airway remodelling in asthma? Br J Pharmacol 2009; 158:1426-8.
79. Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One 2010; 5:e11088.
80. Ginde AA, Mansbach JM, Camargo CA Jr Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med 2009; 169:384-90.
81. O'Connor GT, Neas L, Vaughn B et al. Acute respiratory health effects of air pollution on children with asthma in US inner cities. J Allergy Clin Immunol 2008; 121:1133-9.
82. Silverman RA, Ito K. Age-related association of fine particles and ozone with severe acute asthma in New York City. J Allergy Clin Immunol 2010; 125:367-73.
83. Gilliland FD. Outdoor air pollution, genetic susceptibility, and asthma management: opportunities for intervention to reduce the burden of asthma. Pediatrics 2009; 123 (Suppl. 3):S168-73.
84. Zemp E, Elsasser S, Schindler C et al. Long-term ambient air pollution and respiratory symptoms in adults (SAPALDIA study). The SAPALDIA Team. Am J Respir Crit Care Med 1999; 159:1257-66.
85. Ackermann-Liebrich U, Leuenberger P, Schwartz J et al. Lung function and long term exposure to air pollutants in Switzerland. Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) Team. Am J Respir Crit Care Med 1997; 155:122-9.
86. Nordenhall C, Pourazar J, Ledin MC, Levin JO, Sandstrom T, Adelroth E. Diesel exhaust enhances airway responsiveness in asthmatic subjects. Eur Respir J 2001; 17:909-15.
87. McCreanor J, Cullinan P, Nieuwenhuijsen MJ et al. Respiratory effects of exposure to diesel traffic in persons with asthma. N Engl J Med 2007; 357:2348-58.
88. Sunyer J, Basagana X, Belmonte J, Anto JM. Effect of nitrogen dioxide and ozone on the risk of dying in patients with severe asthma. Thorax 2002; 57:687-93.
89. Avol EL, Gauderman WJ, Tan SM, London SJ, Peters JM. Respiratory effects of relocating to areas of differing air pollution levels. Am J Respir Crit Care Med 2001; 164:2067-72.
90. Downs SH, Schindler C, Liu LJ et al. Reduced exposure to PM10 and attenuated age-related decline in lung function. N Engl J Med 2007; 357:2338-47.
91. Renzetti G, Silvestre G, D'Amario C et al. Less air pollution leads to rapid reduction of airway inflammation and improved airway function in asthmatic children. Pediatrics 2009; 123:1051-8.
92. Skloot G, Permutt S, Togias A. Airway hyperresponsiveness in asthma: a problem of limited smooth muscle relaxation with inspiration. J Clin Invest 1995; 96:2393-403.
93. Chen E, Miller GE. Stress and inflammation in exacerbations of asthma. Brain Behav Immun 2007; 21:993-9.
94. Haczku A, Panettieri RA Jr Social stress and asthma: the role of corticosteroid insensitivity. J Allergy Clin Immunol 2010; 125:550-8.
95. Sandberg S, Paton JY, Ahola S et al. The role of acute and chronic stress in asthma attacks in children. Lancet 2000; 356:982-7.
96. Bosley CM, Corden ZM, Cochrane GM. Psychosocial factors and asthma. Respir Med 1996; 90:453-7.
97. Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357:266-81.
98. Rijssenbeek-Nouwens LH, Bron AO, Naves C, Weller F, Weersink EJ, Bel EH. How persistent is "persistent airflow limitation" in severe asthma. Eur Respir J 2006; 28 (Suppl. 50).
99. Rijssenbeek-Nouwens LH, Fieten KB, Bron AO, Weersink EJ, Sterk PJ, Bel EH. Clinical improvement in patients with severe asthma at high altitude occurs irrespective of allergy to house dust mite. Am J Respir Crit Care Med 2010; 181, A5416.