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Acetazolamide for Monge’s Disease: Efficiency and Tolerance of 6- Month Treatment

June 17, 2008

By Richalet, Jean-Paul Rivera-Ch, Maria; Maignan, Maxime; Privat, Catherine; Pham, Isabelle; Macarlupu, Jose-Luis; Petitjean, Olivier; Leon-Velarde, Fabiola

Rationale: Monge’s disease is characterized by an excessive erythrocytosis, frequently associated with pulmonary hypertension, in high-altitude dwellers. It has a considerable impact on public health in high-altitude regions. A preliminary study demonstrated the efficiency of acetazolamide (Acz) (250 mg/d for 3 wk) in reducing serum erythropoietin and hematocrit. Objectives: Evaluate the efficacy and tolerance of a 6-month treatment with 250mgAcz that could be chronically implemented and its effects on pulmonary artery pressure and cardiac function.

Methods: A two-phase study was performed in patients (hematocrit >/= 63%) from Cerro de Pasco, Peru (4,300 m). First phase: a doubleblind, placebo-controlled study in 55 patients who received a single dose of either 250 mg Acz (n = 40) or placebo (n = 15) by daily oral administration for 12 weeks. Second phase (open label): after a 4-week washout period, all patients received 250mgAcz for 12 weeks. Hematocrit, blood gases, clinical outcome, and pulmonary artery circulation were evaluated.

Measurements and Main Results: First phase: Acz decreased by 44% the number of polycythemic subjects (P = 0.02), decreased hematocrit from 69 to 64% (P

Conclusions: Acz reduces erythrocytosis and improves pulmonary circulation in Monge’s disease without adverse effects. Its implementation as a chronic treatment for this disease appears efficient and safe.

Clinical trial registered with www.clinicaltrials.gov (NCT 00424970).

Keywords: hypoxia; altitude; pulmonary hypertension; chronic mountain sickness

Monge’s disease or chronic mountain sickness (CMS) is characterized by an excessive erythrocytosis (hemoglobin concentration > 21 g/dl or hematocrit > 63%) associated with chronic hypoxemia (1, 2). Severe pulmonary hypertension is frequently associated (3, 4). CMS leads to right cardiac failure and/or neurologic disorders (1). Clinical signs include headache, fatigue, sleep disturbances, dyspnea, and digestive complaints. The clinical status becomes progressively incapacitating, leading to social exclusion and psychological degradation. It is a severe public health problem for Andean countries where it affects 5 to 15% of the population residing at and above 3,200 m (i.e., ~2 million people) (1, 2).

Acetazolamide (Acz), an inhibitor of carbonic anhydrase, was recently shown to reduce erythropoiesis in patients suffering from CMS (5). Two doses of Acz were evaluated (250 and 500 mg daily) for a 3-week treatment: 250 mg of Acz reduced hematocrit, serum erythropoietin (EPO), and plasma-soluble transferrin receptors as markers of excessive erythropoiesis. No greater effect was observed with 500 mg. Mechanisms of action were mainly attributed to metabolic acidosis and secondary increased ventilation and reduced hypoxemia. No adverse effects were recorded. However, a prolonged treatment would certainly be needed to obtain a long-lasting hematocrit reduction in those patients, and the prolonged effects of Acz on acid-base balance and plasma potassium are not known in patients with excessive erythrocytosis.

Moreover, Acz was recently shown to reduce acute hypoxic pulmonary vasoconstriction in conscious dogs (6), rats (7), isolated rabbit lungs (8), and humans (9), through a mechanism that seems to be unrelated to carbonic anhydrase inhibition (10-12). However, its effects on chronic hypoxia-induced pulmonary hypertension, as present in CMS, is not known.

The objective of this study was to evaluate the beneficial and potentially adverse effects of a prolonged (12-24 wk) treatment using Acz in patients with CMS, with an additional interest in pulmonary hypertension and cardiac function. The primary endpoints were hematocrit and blood oxygen pressure. Secondary endpoints were acid-base status and echocardiographic variables. Measurements were also performed during two washout periods of 4 weeks to assess the speed of resetting hematologic and blood gas variables. Some of the results of this study have been previously reported in the form of an abstract (13).

METHODS

Patients and Procedure

Fifty-five male patients suffering from CMS, with a hematocrit of 63% or greater, and 15 normal male subjects living at Cerro de Pasco (4,300 m) gave their written, informed consent to participate in this two-phase study (randomized, double-blind, placebo-controlled trial, followed by an open-label trial), which was approved by the ethics committee of Universidad Cayetano Heredia (Lima, Peru). All subjects were natives of high altitude region (>4,000 m) and were residing permanently at Cerro de Pasco, except for occasional travels to low altitude (56 ml/min). Arterial blood gases (Pa^sub O^sub 2^^, Pa^sub CO^sub 2^^, pHa [arterial pH], Sa^sub O^sub 2^^), as well as plasma bicarbonate, sodium, and potassium concentrations, were measured from 150 [mu]l arterialized blood samples taken from an ear lobe prewarmed with capsaicin cream (OPTI CCA blood gas analyzer; AVL, Roswell, GA). Hematocrit was measured by a microcentrifuge from a 70-[mu]l sample from a finger tip (Microcentrifuge IEC; Thermo Electron, Waltham, MA).

Echocardiography was performed in supine position to evaluate the tricuspid pressure gradient, the pulmonary acceleration time, and an index of pulmonary vascular resistance (PVR), all parameters evaluating the presence of pulmonary hypertension (Acuson Cypress portable ultrasound; Siemens, Mountain View, CA). These echographic parameters have been correlated to invasive measurements with right heart catheterization in high-altitude conditions (15, 16). Briefly, the maximal velocity of the tricuspid regurgitation (Vmax^sub TR^) was measured by continuous wave Doppler, and the tricuspid pressure gradient (TR^sub max^), calculated with the simplified Bernoulli formula 4 * Vmax^sub TR^^sup 2^, was used as a surrogate of systolic pulmonary arterial pressure (17). The pulmonary flow was recorded by pulsed-wave Doppler 2 mm below the valve and acceleration time was measured from the onset of the flow to the maximal velocity. Pulmonary acceleration time less than 100 ms is predictable for a mean pulmonary arterial pressure greater than 20 mm Hg and is negatively correlated with PVR (18). PVR was evaluated by the ratio of peak tricuspid regurgitant velocity to the right ventricular (RV) outflow tract time-velocity integral. A value greater than 0.175 indicates PVR over 2 Wood units, which is clinically relevant for pulmonary hypertension (19). Cardiac output was calculated as the product of the left ventricle outflow tract area with the left ventricle outflow tract time-velocity integral and heart rate. End- diastolic left ventricular (LV) and RV diameters (ED-RV/LV) and RV area shortening fraction (RVSF) and LV ejection fraction (LVEF) were measured and then calculated from two-dimensional and time motion (TM) images.

The study was organized in two phases: (1) a randomized double- blind placebo-controlled phase, in which 40 patients were treated by Acz and 15 patients by placebo and (2) an open-label phase in which all patients received Acz. The two phases were separated by a 4- week wash out period (Figure 1). Baseline characteristics of the subjects are given in Table 1.

First phase (double blind). Allocation to treatment was done randomly through computer-generated random numbers balanced between the two treatment groups (n, age in yr, weight in kg, and height in m): (1) Patients with CMS treated by placebo (Pla) (n = 15, 48 +- 11 yr, 67 +- 8 kg, 1.63 +- 0.06 m); (2) Patients with CMS treated by 250 mg Acz daily (Acz) (n = 40, 44 +- 10 yr, 67 +- 8 kg, 1.65 +- 0.06 m). A group of normal subjects (n = 15, age = 44 +- 9 yr, 66 +- 8 kg, 1.64 +- 0.06 m) living at the same altitude, with no apparent disease at examination and with a hematocrit at or below 55%, served as control subjects. Measurements were made at the Laboratory of Cerro de Pasco (Instituto de Investigaciones de Altura) before and after 4, 8, and 12 weeks of treatment, and after 2 and 4 weeks of a washout period without treatment. Subjects were asked to come to the laboratory every week to take a flask of seven capsules and to take their capsule daily, in the morning. Active and placebo capsules were identical in appearance. Treatment was double blind. Second phase (open label). All subjects remaining within the study after the first phase (n = 42) received 250 mg Acz daily for 12 weeks, in an open-label procedure. Measurements were made before and after 4, 8, and 12 weeks of treatment, and after 4 weeks of a washout period without treatment. A six-minute-walk test was performed by 26 patients before and during the second phase to evaluate the clinical significance of the changes in the biological parameters.

Results are presented in Tables 2 and 3 for the two groups: the group that received placebo during the first phase and Acz in the second one (Pla-Acz), and the group that received Acz during the first and the second phase (Acz-Acz).

Statistical Analysis

On the basis of data from the previous study (5), we estimated that 46 men were required to detect a reduction of 5% of hematocrit, with an estimated variance of 2.8 and a power of 90%, with a 5% type I error. Our calculation allowed for a 20% loss to follow-up, and a ratio of 2.5:1 was applied between Acz and Pla groups, to raise the power of detection for adverse effects, namely hypokalemia (K^sup +^

The details of the follow-up procedure are given in Figure 1. A perprotocol analysis was undertaken for the present study. Normal distribution was tested by a Kolmogorov test. Data were summarized in frequencies (percentage) for categorical variables and as mean +- SD for continuous variables. The chi^sup 2^ (or Fisher’s exact) test, the Wilcoxon rank-sum test, and a two-way analysis of variance (ANOVA) with a post hoc Tukey test were used to compare differences between groups for dichotomous, discontinuous, and continuous variables, respectively. Changes between the baseline and post- treatment measures in each group were evaluated by a Wilcoxon signed- rank test for discontinuous variables, and by a paired t test for continuous ones. A P value less than 0.05 was considered as significant for ANOVA, whereas a two-sided P value less than 0.0182 was chosen for the t test because of repeated analyses. Statistica software for Windows 7.0 (StatSoft, Inc., Tulsa, OK) was used.

RESULTS

Characteristics of Patients with CMS

When compared with the control group, patients with CMS (n = 47, pooled placebo- and Acz-treated groups before treatment) showed a higher hematocrit and CMS score, a lower Sa^sub O^sub 2^^, Pa^sub O^sub 2^^, pHa, and plasma sodium, and a higher Pa^sub CO^sub 2^^, plasma bicarbonate, and potassium (Table 1). Quality-of-life score was lower in the CMS group. Among the 47 patients with CMS, a tricuspid regurgitation was found at echocardiography in only 37 ones. Tricuspid pressure gradient was higher and pulmonary acceleration time shorter in the CMS versus control group, revealing the presence of pulmonary hypertension in 21 of 37 patients (57%), following the definition of normal tricuspid gradient depending on age and body weight (17), whereas 1 of 15 subjects in the control group showed pulmonary hypertension (P = 0.006 CMS vs. control). However, PVR was not different between the two groups. Indexes of right (RVSF) and left (LVEF) ventricular systolic function were normal in both groups. Patients with CMS showed a dilatation of the right ventricle (ED-RV/LV).

Efficacy of Treatment with Acz on Clinical and Hematologic Outcomes

Phase 1 (double blind, placebo controlled). No difference was found for any variable between the Acz and Pla groups before initiating the treatment. The number of polycythemic patients (hematocrit >/= 63%) decreased from 34 to 19 in the Acz and from 13 to 12 in the Pla group (P = 0.02 Acz vs. Pla) (Table 2). When compared with Pla, the 12-week treatment with Acz decreased hematocrit by 5%, increased Pa^sub O^sub 2^^ by 3 mm Hg and Sa^sub O^sub 2^^ by 2%, decreased Pa^sub CO^sub 2^^ by 3 mm Hg, pHa by 0.03 units, and plasma bicarbonate by 2.8 mmol/L. These changes clearly show that Acz induced a metabolic acidosis that increased ventilation and arterial oxygen pressure and saturation, blunting erythropoiesis and reducing hematocrit. A significant change in all variables of interest was obtained after 4 weeks of treatment (Figure 2 for hematocrit, Pa^sub O^sub 2^^, and pHa; results not shown for Sa^sub O^sub 2^^, Pa^sub CO^sub 2^^, and bicarbonate). No further significant change was observed during the following 8 weeks except for hematocrit, which decreased by 2% between Weeks 4 and 8.

CMS clinical score decreased by 8 units in Pla and Acz groups. Quality-of-life score showed an increase in both groups. Systolic and diastolic systemic arterial pressure did not change with Acz or placebo treatment.

Washout phase 1 (double blind, placebo controlled). Four weeks after the cessation of treatment, hematocrit had returned to baseline values (Figure 2), whereas 2 weeks were sufficient for blood gas variables to return to normal. Clinical scores remained different from baseline after 4 weeks of washout (Table 2).

Phase 2 (open label). Variations of parameters observed in the Acz group during the first phase were found to be similar for the two Acz-treated groups during the second phase, with a decrease in hematocrit, pH, Pa^sub CO^sub 2^^, and bicarbonate and an increase in Pa^sub O^sub 2^^ and Sa^sub O^sub 2^^ (Figure 2 and Table 2). There was no additive effect on biological and clinical parameters between the first and the second phase.

Washout phase 2 (open label). Similarly to what happened during the washout period after phase 1, all biological variables had returned to baseline 4 weeks after cessation of treatment. Clinical scores were still ameliorated, when compared with baseline.

Efficacy of Treatment with Acz on Echocardiographic Outcome

During phase 1, echocardiographic measurements showed that mean cardiac output, tricuspid pressure gradient, and PVR did not change significantly with treatment, although a tendency for ameliorating pulmonary acceleration time was seen in the Acz group (P = 0.09) (Table 3). Morphologic (ED-RV/LV) and functional measures (LVEF and RVSF) were also not modified by 12 weeks of treatment.

During phase 2, cardiac output increased and PVRs decreased in both groups, whereas pulmonary acceleration time increased only in the group treated by Acz for 24 weeks (Acz-Acz; Table 3). Tricuspid pressure gradient was not modified in either group. At the end of phase 2, the right ventricle was significantly enlarged in the group treated by placebo then Acz (Pla-Acz) when compared with inclusion levels. Therefore, RV diameter was higher in the Pla-Acz group than in the Acz-Acz group. There was no difference in RV and LV systolic function indexes (LVEF and RVSF).

When considering only the group who received Acz during the two phases (24 wk), 8 out of 27 patients (30%) were considered as having an elevated PVR (>2 Wood units) at inclusion, whereas 0 out of 22 patients had an elevated PVR at the end of phase 2 (P = 0.005).

The results of the six-minute-walk test showed a transient but significant increase (+6.2%) in the distance walked, as well as an increase in Sa^sub O^sub 2^^ at the end of the walk (Table 4).

Tolerance of Treatment with Acz

The tolerance to the medication was good. In the double-blind, placebo-controlled phase, the only mentioned adverse effects were increased diuresis (44 and 76% of events in the Pla and Acz groups, respectively; P

Observance of Treatment

Because capsules were given to the patients once a week, no control was available to ensure that the medication was properly taken daily. Because no medication is available for Monge’s disease, the motivation of the recruited population was high. However, the values of plasma bicarbonate in four patients that were under Acz treatment appeared particularly high, which suggests that these patients did not fully conform to the instructions, because a major effect of Acz is to increase bicarbonate excretion. Therefore, unchanged values of plasma bicarbonate under Acz treatment are unlikely. However, with no formal proof of bad observance being available, they were maintained in the general analysis.

DISCUSSION

The present study confirms our preliminary results on the efficacy of Acz to reduce excessive erythrocytosis in patients with CMS (5). Moreover, it shows that a prolonged 24-week treatment is well tolerated, and that no tachyphylaxis to the treatment is observed. Acz treatment did not significantly reduce systolic pulmonary arterial pressure, but reduced PVR and increased cardiac output. In Cerro de Pasco, Peru (4,300 m, 80,000 inhabitants), the mean prevalence of excessive erythrocytosis has been estimated to be up to 15% (1), suggesting that treatment with Acz may be relevant for 12,000 inhabitants of this town. In the present study, the patients with CMS showed, by definition, a high CMS score and a high hematocrit. They presented a lower arterial O2 pressure and saturation and a higher CO2 pressure than normal control subjects, compatible with the known mechanisms of the disease. The physiopathology of CMS has been attributed to hypoventilation inducing an exaggerated hypoxemia and an excessive erythropoiesis (1, 20).

Although the beneficial effects of a short-duration treatment with Acz on ventilation and Sa^sub O^sub 2^^ had already been shown in subjects with CMS (5), the present study is the first to show a decrease in hematocrit, an increase in Pa^sub O^sub 2^^ and Sa^sub O^sub 2^^, and a decrease in Pa^sub CO^sub 2^^ that persisted for two periods of 12 weeks. Following the definition of excessive erythrocytosis (hematocrit >/= 63%) (2), Acz treatment reduced by almost half the proportion of polycythemic patients in the studied population. The 5% decrease in hematocrit corresponds to a 16% decrease in blood viscosity (21) and in overall vascular resistance, therefore potentially reducing the risk of stroke or heart failure, two major long-term consequences of CMS (1, 2). The decrease in hematocrit may have been hindered by the diuretic effect of Acz, leading to a slight hemoconcentration. Unfortunately, neither direct measure of hemoglobin mass nor indirect evaluation of plasma shrinkage via plasma protein concentration was available. A significant effect of Acz was obtained after only 4 weeks, with a slight further improvement for hematocrit with 8 weeks of treatment, suggesting that the inhibition of erythropoiesis plateaued slightly after the reduction of hypoxemia. No tachyphylaxis was observed, showing that the rapid initial effect is maintained for 3 months. At the cessation of treatment, the initial values of blood gases are reached after only 2 weeks and the initial level of polycythemia is recovered after 4 weeks, suggesting that no more than 2 weeks of interruption of treatment can be recommended in order to maintain a permanent effect of Acz.

The most common treatment of CMS is phlebotomy, a technique that has very transient effects (22, 23). In fact, a number of patients must move their residency to sea level, although this has a considerable negative impact on their family organization and socioeconomic status. Pharmacologic treatments have been evaluated, such as medroxyprogesterone (24) or enalapril (25, 26). However, either adverse effects (female hormones given to male subjects in the case of medroxyprogesterone, potential risk of systemic hypotension with enalapril) or elevated monthly cost are substantial obstacles for the large diffusion of these treatments in developing countries.

The ventilatory stimulant effect of Acz is the most probable mechanism explaining the beneficial effect of this drug on the hematologic status of patients with CMS, via the metabolic acidosis induced by carbonic anhydrase inhibition. The acid-base status of the treated patients in the present study confirms the relative acidosis with lower pH and bicarbonate concentration (Table 2). The rapid recovery of blood gases after cessation of treatment (=2 wk) is in agreement with the short half-life of Acz (3 to 6 h). Acz is known to facilitate the renal excretion of potassium, which may lead to harmful hypokalemia. Although potassium slightly decreased in the group that received 24 weeks of treatment, no significant hypokalemia was observed, probably because patients with CMS showed high baseline values of plasma bicarbonate and potassium when compared with the control healthy subjects (Table 1).

No significant effect of a 12-week treatment with Acz was found on pulmonary hypertension, although mean pulmonary acceleration time tended to increase. After 24 weeks of treatment, a significant effect was found on pulmonary circulation. A 17% reduction in pulmonary resistance was associated with a 28% increase in cardiac output, without change in pulmonary pressure. If we consider the 6% parallel decrease in hematocrit, we can estimate, from experimental curves relating blood overall viscosity and hematocrit (21), that the blood viscosity decreased by 15% at the same time, similarly to the change in vascular resistance. Therefore, by reducing blood viscosity, Acz reduced the vascular resistance and allowed cardiac output to increase, probably without any significant effect on the vascular motor tone. Interestingly, the decrease in hematocrit offset the increase in arterial PO2 so that the arterial O2 content (Table 2) was not modified by the treatment. Therefore, Acz induced an increase in O2 transport to the tissues only by increasing cardiac output. Because hemoglobin is a potent nitric oxide (NO) scavenger, reducing hematocrit with Acz may have increased the NO availability, promoted pulmonary vasodilation, and improved ventilation/perfusion matching (27). However, the reduction in EPO secretion induced by Acz (5) might impair the NO production by endothelial cells, which has been suggested by NO synthase inhibition in mice overexpressing EPO (28).

Up to now, very few studies had looked at the effect of Acz on hypoxic pulmonary vasoconstriction in humans during an acute hypoxic challenge (9) or after a 10-day exposure of sealevel natives to an altitude of 3,700-4,700 m (29). Although the former study evidenced a clear reduction of pulmonary artery pressure with Acz, the latter study failed to find any effect. In Monge’s disease, pulmonary hypertension is mainly due to a remodeling of pulmonary arteries with chronic exposure to hypoxia (3, 30). If any, the effect of Acz on the regression of smooth muscle cells might necessitate a longer time to be appreciable. Although a higher dose (500 mg/d) than the one used in the present study (250 mg/d) was already shown to have no further effect on SaO2 or hematocrit (5), no dose-response study was performed on pulmonary artery pressure.

The placebo effect observed in the present study on the clinical score of CMS and on the quality-of-life score is not surprising. A similar effect had been shown in our previous study (5). It is interesting to note that the “headache” item was present in both CMS and tolerance questionnaires. In the CMS score, this item decreased in both groups (placebo effect), whereas in the tolerance score, it was much less mentioned in the Acz than in the Pla group. The CMS score is probably a too simple score to clearly evidence the efficiency of a treatment but is rather an epidemiologic tool to evaluate the prevalence of CMS in a given population. It is well known that any subjective symptom scoring system is potentially vulnerable to a placebo effect. However, no such effect was found in biological parameters (hematocrit, blood gases, etc.). The absence of any available treatment for this incapacitating disease has created a great frustration among high-altitude residents. Any new clinical trial develops a huge hope that may explain the desire to contribute to the proof of its efficiency and the desire to please the physician promoting the study (5). A new CMS clinical scoring system should be sought for use in interventional studies. The improvement observed with the six-minute-walk test, although transient, gives a good evidence that the changes in the biological and hemodynamic parameters had a clinical significance. Long-term morbidity and mortality studies will be necessary to ascertain the potential benefit of this treatment on the quality of life and functional capacity of these patients.

In conclusion, this study shows that Acz is an efficient and safe treatment of CMS, by increasing arterial O2 pressure and decreasing hematocrit. A 6-month treatment was sufficient to reduce PVR and increase cardiac output, with no change in pulmonary artery pressure. We propose Acz (250 mg daily for renewable periods of 3 mo, with no more than 2-wk periods of interruption) as an inexpensive treatment that could be implemented at a large scale in high-altitude regions of the world.

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Acknowledgment: The authors thank Rosario Tapia Ramirez, Juan Carlos Ordonez, Flor Raymundo, Justinio Panez, Ronald Rivera, David Ramos, and Hugo Ju for their help in Cerro de Pasco. We thank Sanofi Aventis S.A. for providing acetazolamide and Siemens S.A. for the Cypress ultrasound device.

AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject

Chronic mountain sickness, affecting 10% of the population residing at high altitude, is characterized by an excessive number of red cells and pulmonary hypertension. A preliminary study showed that acetazolamide could be an efficient treatment.

What This Study Adds to the Field

This study showed that prolonged treatment with 250 mg acetazolamide (6 mo) is well tolerated and efficient in reducing hematocrit, increasing the arterial oxygen pressure, and increasing cardiac output.

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Jean-Paul Richalet1,2, Maria Rivera-Ch3, Maxime Maignan1,4, Catherine Privat3, Isabelle Pham1,5, Jose-Luis Macarlupu3, Olivier Petitjean2, and Fabiola Leo n-Velarde3

1Universite Paris 13, Laboratoire “Reponses cellulaires et fonctionnelles a l’hypoxie”, EA 2363, ARPE, UFR SMBH, Bobigny, France; 2AP-HP, Hopital Avicenne, Service de Physiologie et Explorations Fonctionnelles, Service de Pharmacie, Bobigny, France; 3Universidad Peruana Cayetano Heredia, Facultad de Ciencias y Filosofia, Dpto. de Ciencias Biologicas y Fisiologicas, Laboratorio de Fisiologia Comparada, Lima, Peru; 4CHU Grenoble, Pole Urgences, La Tronche, France; and 5AP-HP, Hopital Jean Verdier, Service de Physiologie et Explorations Fonctionnelles, Bondy, France

(Received in original form February 1, 2008; accepted in final form March 31, 2008)

Supported by Legs Poix.

Correspondence and requests for reprints should be addressed to Pr. Jean-Paul Richalet, M.D., Dr.Sc., Laboratoire EA 2363, UFR SMBH, 74 rue Marcel Cachin, 93017 Bobigny Cedex, France. E-mail: richalet@smbh.univ-paris13.fr

Am J Respir Crit Care Med Vol 177. pp 1370-1376, 2008

Originally Published in Press as DOI: 10.1164/rccm.200802-196OC on April 3, 2008

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Copyright American Thoracic Society Jun 15, 2008

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