THERMALLY INDUCED ASTHMA AND AIRWAY DRYING

To the Editor :

McFadden and colleagues (1) describe a study in which they compared FEV₁ before and after hyperventilation with either warm or cold dry air to determine whether mucosal dehydration causes thermally induced asthma. The authors assumed that exhaled air was fully saturated, relied on measurements of airstream temperatures at the mouth to estimate total water loss, and "corrected" this estimate to reflect water loss from intrathoracic airways. The technical difficulties associated with measuring expired air temperature and water loss are well known (2), and the very low expired air temperatures reported in this study likely reflect this problem. The use of similar methods resulted in a mass of inconsistent data and the near abandonment of global measurements of heat and water loss almost a decade ago. The abandonment of this technology was later justified when it was shown, from mathematical modeling, that there were local differences in water flux in different regions along the tracheobronchial tree (3). Direct measurements of airway surface fluid (ASF) osmolality revealed that cool dry air does increase ASF osmolality during and after hyperventilation, and these changes in ASF osmolality correlate with the development of airway obstruction in a canine model of exercise-induced asthma (4).

The authors' principal observation that the greatest expenditures of water were associated with the smallest functional impact is valid only if (at any given level of ventilation) warm and cold dry air penetrated to the same level in the lung, and resulted in identical quantities of water loss. Even if the warm and cold dry air penetrated to the same level of the lung, there would be differences in the loss of heat and water due to local gradients (3). McFadden and coworkers claim that, although the temperature of the warm inspirate at inspiration was almost 100% greater than that of the cold inspirate, there would be only a 30% difference in the total amount of thermal energy spent to bring them to body conditions. They concluded that such events would result in ~ 1° C difference between airstream temperatures at the level of subsegmental bronchi during cold and warm air trials (1). However, on the basis of previously published data (Figure 3) (5), even that estimate translates into nearly a 2-cm difference in location within a sublobar bronchus. Thus, the differences in pulmonary function measured in response to the two treatments evaluated in this study appear to reflect differential water loss from proximal (warm air) and more distal (cold air) locations. If this is correct, comparing water loss-response curves under the two conditions has little relevance, unless you assume the amount of airway surface fluid, water flux, and the sensitivity to water loss at each location are identical. These are unrealistic assumptions. Thus, corrected global estimates of water loss cannot be used to draw any meaningful conclusions about local evaporative water losses in subsegmental airways, nor can they be used to evaluate the potential role of local water flux in the development of exercise-induced asthma.

Department of Environmental Health Sciences, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland

Sandra D. Anderson, and Evangelia Daviskas

Department of Respiratory Medicine, Royal Prince Alfred Hospital, Camperdown, NSW, Australia,

1. McFadden, E. R. Jr., J. A. Nelson, M. E. Skowronski, and K. A. Lenner. 1999. Thermally induced asthma and airway drying. Am. J. Respir. Crit. Care Med. 160: 221-226 [Abstract/Free Full Text].

2. Anderson, S. D., and E. Daviskas. 1997. Pathophysiology of exercise-induced asthma: the role of respiratory water loss. In J. M. Weiler, editor. Allergic and Respiratory Disease in Sports Medicine. Marcell Dekker, New York. 87-114.

3. Daviskas, E., I. Gonda, and S. D. Anderson. 1991. Local airway heat and water vapour losses. Respir. Physiol. 84: 115-132 [Medline].

4. Freed, A. N., and M. S. Davis. 1999. Hyperventilation with dry air increases airway surface fluid osmolality in canine peripheral airways. Am. J. Respir. Crit. Care Med. 159: 1101-1107 [Abstract/Free Full Text].

5. McFadden, E. R. Jr., B. M. Pichurko, H. F. Bowman, E. Ingenito, S. Burns, N. Dowling, and J. Solway. 1985. Thermal mapping of the airways in humans. J. Appl. Physiol. 58: 564-570 [Abstract/Free Full Text].

From the Authors:

The assertions raised by Drs. Freed, Anderson, and Daviskas in response to our article (1) about the purported technical difficulties of measuring temperature and the allegedly conflicting nature of respiratory thermal data are disingenuous. Temperatures are easily accurately and reproducibly measured and the resulting data have been remarkably consistent from laboratory to laboratory. We can only assume that a need to maintain ideological purity for argument's sake has prompted such wildly inaccurate and totally unsupported comments.

In order for bronchial narrowing to develop in EIA, the airways must cool and then rapidly rewarm (2). Amplifying either phase intensifies the response. Every single study, from sites without preconceived notions of pathophysiology, has confirmed our findings. Moreover, temperature measurements have not only provided great insights into the pathogenesis of this condition, but have unraveled how and where heat and water transfer take place in the tracheobronchial tree (3, 4). The largest losses occur in the upper airway where they can be easily replaced by secretion from salivary glands; those in the intrathoracic airways are spread over an enormous surface so that fluctuations/area are trivial. Pretending that such a body of information does not exist, or is inherently flawed, smacks of a fundamentalist preacher arguing that evolution cannot occur because it conflicts with his/her particular interpretation of a given written description of creation.

We submit that the explanation given our findings is inaccurate and derives from a contorted view of intrathoracic thermal events. Every study to date, bar none, has shown that 50% or more of the water loss during hyperpnea occur above the glottis. Arguing that this somehow cannot be true or that the particular site in the intrathoracic airways is critical has no objective data to support it. This is not a new problem. The mathematical model (5, 6) that purportedly delivers a deathblow to our observations, past and present, also lacks objective verification. No experiments were performed to authenticate any of the suppositions made. Instead, Drs. Anderson and Dafiskas used our measurements of intrathoracic temperatures to construct the model, made some unproven assumptions to convert water loss to a cumulative function, and then stated that the original data and conclusions were incorrect. Even Merlin would applaud this feat of legerdemain.

Finally, Dr. Freed's model has unidirectional airflow where water losses are continuous and unreplaced. If ever airway desiccation were to occur, it would be here. Yet, it does not. In the study cited (7), an order of magnitude insufflation of dry air yielded only a 12.5% elevation in osmolality without changing surface fluid volume. The final osmolality was 100 µl/kg less than that found in a "model airway" and several hundred milliosmols less than that required to even begin to initiate histamine release in vitro (8). Moreover, even these minor alterations would not have occurred had the air been allowed to blow back across the airways during expiration. Clearly, the evaporated water was being actively replenished as it was removed to prevent major increases in surface fluid tonicity. Hence, even in the absolute worst case scenario, significant "airway drying" does not occur.

Is it not time that we begin to search elsewhere for the cause of EIA? If we joined together, think of all of the wonderful arguments we could have.

E. R. MCFADDEN, Jr.

J. A. NELSON

M. E. SKOWRONSKI

K. A. LENNER

Division of Pulmonology and Critical Care Medicine University Hospitals of Cleveland Case Western Reserve University

Cleveland, Ohio

1. McFadden, E. R. Jr., J. A. Nelson, M. E. Skowronski, and K. A. Lenner. 1999. Thermally induced asthma and airway drying. Am. J. Respir. Crit. Care Med. 160: 221-226 .

2. Gilbert, I. A., and E. R. McFadden Jr.. 1992. Airway cooling and rewarming: the second reaction sequence in exercise induced asthma. J. Clin. Invest. 90: 699-704 .

3. McFadden, E. R. Jr., B. M. Pichurko, H. F. Bowman, E. Ingenito, S. Burns, N. Dowling, and J. Solway. 1985. Thermal mapping of the airways in humans. J. Appl. Physiol. 58: 564-570 .

4. Gilbert, I. A., J. M. Fouke, and E. R. McFadden Jr.. 1987. Heat and water flux in the intrathoracic airways and exercise-induced asthma. J. Appl. Physiol. 63: 1681-1691 [Abstract/Free Full Text].

5. Daviskas, E., I. Gonda, and S. D. Anderson. 1990. Mathematical modeling of heat and water transport in human respiratory tract. J. Appl. Physiol. 69: 362-372 [Abstract/Free Full Text].

6. Daviskas, E., I. Gonda, and S. D. Anderson. 1991. Local airway heat and water vapour losses. Respir. Physiol. 84: 115-132 .

7. Freed, A. N., and M. S. Davis. 1999. Hyperventilation with dry air increases airway surface fluid osmolality in canine peripheral airways. Am. J. Respir. Crit. Care Med. 159: 1101-1107 .

8. Eggleston, P. A., A. Kagey-Sobotka, R. P. Schleimer, and L. M. Lichtenstein. 1984. Interaction between hyperosmolar and IgE-mediated histamine release from basophils and mast cells. Am. Rev. Respir. Dis. 130: 86-91 [Medline].