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(Chest. 2005;128:3336-3344.)
© 2005 American College of Chest Physicians

Factors Associated With Dyspnea in Adult Patients With Sickle Cell Disease*

Christophe Delclaux, MD, PhD; Françoise Zerah-Lancner, MD; Dora Bachir, MD; Anoosha Habibi, MD; Jean-Luc Monin, MD; Bertrand Godeau, MD and Frédéric Galacteros, MD, PhD

* From the Service de Physiologie (Drs. Delclaux and Zerah-Lancner), Explorations Fonctionnelles, the Centre de la Drépanocytose (Drs. Bachir, Habibi, and Galacteros), the Service de Cardiologie (Dr. Monin), and the Service de Médecine Interne (Dr. Godeau), Hôpital Henri Mondor, Assistance Publique–Hôpitaux de Paris, Créteil, France.

Correspondence to: Christophe Delclaux, MD, PhD, Service de Physiologie-Radio-Isotopes, Hôpital Européen Georges Pompidou, 20-40, rue Leblanc, 75908 Paris cedex 15, France; e-mail: christophe.delclaux{at}egp.aphp.fr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objective: The aim of this prospective study was to determine the cardiorespiratory factors associated with dyspnea in patients with sickle cell SS-hemoglobin disease, with a specific interest in lung vascular involvement.

Measurements: Forty-nine patients (29 women and 20 men; mean [± SD] age: women, 29 ± 6 years; men, 31 ± 11 years) underwent direct evaluations (Borg scale evaluation during a 6-min walk test) and indirect evaluations (modified Medical Research Council [MRC]score) of their dyspnea, pulmonary function tests (PFTs) [spirometry, volumes, diffusing capacity of the lung for carbon monoxide (DLCO), diffusing capacity of the alveolar-capillary membrane, and pulmonary capillary blood volume measurements], echocardiography, and biological evaluation.

Results: Thirty-four patients complained of significant breathlessness (MRC score, > 1). Indirect and direct evaluations of dyspnea were correlated. PFT results depicted a very mild restrictive pattern (mean total pulmonary capacity, 86 ± 11% predicted) and an impairment of DLCO (mean DLCO corrected for the degree of anemia, 69 ± 13% predicted). The statistical analysis demonstrated that dyspnea and exercise performance were closely linked to indexes of DLCO but not with any echocardiographic or biological measure including anemia. Nevertheless, only approximately 25% of the variability was explained by these associations. Despite having a similar history of vasoocclusive crisis events, women had more severe anemia, dyspnea, decreases in DLCO (corrected for the degree of anemia), and a higher capillary blood volume (corrected for alveolar volume) than men.

Conclusion: Lung vascular disease contributes to dyspnea and the exercise limitation of patients with sickle cell disease. A sequential assessment of DLCO would therefore constitute one of the objective functional end points for follow-up studies of these patients.

Key Words: dyspnea • lung diffusion of carbon monoxide • 6-min walk test • pulmonary capillary blood volume • sickle cell disease


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Patients with sickle cell disease (SCD) often complain of breathlessness, a symptom that has gained little attention, perhaps because it could seem trivial in these anemic patients. SCD is characterized by mild abnormalities in pulmonary function test (PFT) results such as mild airflow limitation, mild lung restrictive defect, and alteration of the diffusing capacity of the lung for carbon monoxide (DLCO),12345 but the incapacitating symptoms could seem to be out of proportion with the objective functional abnormalities. Consequently, the aim of this study was to assess whether parameters obtained from routine pulmonary and cardiologic evaluations are related to dyspnea in adult patients with moderate SCD. Inasmuch as we hypothesized that clinical or silent pulmonary vascular disease may contribute to pulmonary injury during SCD, the diffusing capacity of the alveolar-capillary membrane (DM) and the pulmonary capillary blood volume available for gas exchange (VC) were also determined. For a similar reason, multiple-flow analysis of exhaled nitric oxide (NO), which allowed us to calculate the alveolar NO concentration, was measured in a subgroup of patients because we hypothesized that this concentration may reflect endothelial function.6 Furthermore, exhaled NO measurements were justified owing to the results of a study7 suggesting a relationship between decreased exhaled NO fraction and dyspnea.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
Biological evaluation, PFTs, and echocardiography are part of the regular follow-up at the Sickle Cell Disease Center at our institution. Inclusion criteria were as follows: sickle cell SS-hemoglobin disease (documented by high-pressure liquid chromatography), age > 18 years, the absence of the recent (ie, < 3 months) occurrence of a vasoocclusive crisis (VOC), acute chest syndrome (ACS), or blood transfusion, the ability to perform a 6-min walk test (6MWT), the absence of any associated cardiac or respiratory disease (other than that due to SCD) including the absence of smoking history and the absence of treatment by hydroxyurea or nocturnal oxygen administration or exchange-transfusion program. All patients were French-speaking natives (either from western Africa or France). The protocol was approved by the local ethics committee, and informed consent was obtained from each patient.

PFTs
PFTs included spirometry, lung volume assessment (measured using body plethysmography), single-breath measurements of DLCO (MSR; Rungis, France), and arterial blood gas analysis (ABL 520; Radiometer; Copenhagen, Denmark), which were all performed according to American Thoracic Society standards.89

The PO2 at which hemoglobin is 50% saturated with oxygen was calculated according to the Hill equation in arterial blood samples (corrected value for pH 7.40, PaCO2 40 mm Hg). Results were expressed in absolute values and as percentage of normal predicted values. Since all of the patients in this study were from Africa, the reference values determined by Miller and coauthors10 were used.

Determination of the DM and VC
DLCO was determined twice with washout intervals of at least 4 min (the average was taken as the final result) using a standard single-breath technique. The maneuver was performed using a test gas with 0.28% carbon monoxide, 0.3% acetylene, 0.3% methane, and 21% O2, with the balance made up of nitrogen, and was then repeated using test gases with an 80% O2 concentration. The DM and VC were determined using the classic method described by Roughton and Forster.11

The standardized value of DLCO is that which would obtain at an arbitrary hemoglobin concentration is given by:

(1)
When correcting for the effects of anemia, an assumed value for the DM/VC ratio of 0.7 may not be justified. Consequently, the standardized value of DLCO for the arbitrary hemoglobin concentration (14.6 g/dL) was calculated using the measured values of DM and VC.

Due to chronic hemolysis, the carboxyhemoglobin (HbCO) percentage was increased despite the absence of smoking history; consequently, the standardized value of DLCO was calculated using the following formula:

(2)

Exhaled NO Measurement
Technical aspects have been reported previously.6 Briefly, four to six fractions of exhaled NO (FENO) values were obtained at expiratory flow (V’) rates between 50 and 250 mL/s. The FENO was measured using a chemiluminescent NO analyzer (EVA4000; Seres; Aix en Provence, France). NO measurements were made as recommended by American Thoracic Society guidelines.13 At each V’, NO output was calculated as

(3)
where Q’NO was expressed in nanoliters per minute, FENO was expressed in parts per billion, and V’ in mL/s; 0.06 was a unit-correcting factor.

As shown by Tsoukias and George,14 the slope of this regression line is the concentration of NO from the expansible compartment of the lung (CANO), and the intercept to zero flow is the total maximum flux of NO from airways.

Alveolar NO concentration is described by the equation 1

(4)
where V’NO,ALV is the NO diffusing rate from tissue to alveolar air and DLNO is the alveolar NO diffusing capacity in pulmonary vessels. Thus, CANO can be decreased because of decreased NO production in lung parenchyma, causing decreased V’NO,ALV, or because of increased diffusion of NO from alveolar air to pulmonary blood caused by increased DLNO. Because the DLNO is approximately four times the DLCO, equation 1 can be rearranged to give

Indirect Method of Measurement of Breathlessness and Fatigue
Dyspnea was measured according to American Thoracic Society guidelines.15 Breathlessness was assessed using the modified Medical Research Council (MRC) dyspnea scale. The major limitation is that the intervals between categories are quite wide. Due to this limitation, dyspnea was also rated by asking the patient how many flights of stairs he can climb without experiencing breathlessness.

Fatigue evaluation was based on both direct and indirect measures (see below) similar to dyspnea assessment. The indirect assessment of fatigue was recorded using the fatigue impact scale (FIS),16 which has previously been translated into French.17

6MWT With Direct Assessment of Breathlessness and Fatigue
The 6MWT was conducted according to the 2002 recommendations of the American Thoracic Society guidelines.18 The 6MWT was performed indoors, in a 50-m corridor. Since the PFT and 6MWT were performed on the same day, the two procedures could have influenced dyspnea and fatigue. Consequently, before the PFT, after the PFT (which was the same as before the 6MWT), and after 6MWT the following variables were recorded: heart rate; oxygen saturation (using pulse oximetry); respiratory frequency and dyspnea; and overall fatigue (rated using the Borg CR-10 scale). Consequently, patients were rated on three occasions in order to assess both the effect of PFTs and 6MWT on fatigue and dyspnea. At the end of the test, the 6-min walking distance was recorded.

Echocardiography
Cardiac measurements were performed according to the guidelines of the American Society of Echocardiography.19 Tricuspid regurgitation was assessed in the parasternal right ventricular inflow view, parasternal short-axis view, and the apical four-chamber views, and a minimum of five sequential complexes were recorded. Continuous-wave Doppler sampling of the peak regurgitant jet velocity was used to estimate the right ventricular-to-right atrial systolic pressure gradient with the use of the modified Bernoulli equation. Pulmonary artery systolic pressure was quantitated by adding the Bernoulli-derived pressure gradient to the estimated mean right atrial pressure. The mean right atrial pressure was calculated according to the degree of collapse of the inferior vena cava with inspiration.

Statistical Analysis
The first step of our analysis was to evaluate whether the different indexes of dyspnea obtained from both direct assessment (6MWT) and indirect assessments were correlated since some of these evaluations could appear to be subjective. The number of flights of stairs that the patient can climb without experiencing breathlessness is an index of both dyspnea and exercise performance that was compared to other indexes of dyspnea and to the 6-min walk distance.

Owing to the fact that age, anthropometric parameters (ie, height and weight), and sex are known to influence performance, the indexes of exercise limitation (ie, the number of flights of stairs and the distance walked) were compared to predicted values obtained from PFTs. For instance, the 6-min walk distance was logically correlated with all raw values obtained from PFTs (eg, total lung capacity, FEV1, VC, and DLCO), and with age and height. By contrast, the MRC score and the Borg scores were compared to raw values since they are independent of the effect of age, anthropometric parameters (height and weight), and sex. Log values of NO parameters are normally distributed and were used in the statistical analysis.

The problem of functional relevance depends on the context. Inasmuch as dyspnea, exercise limitation, and hypoxemia are known to be of multifactorial origin, all significant associations were reported when background knowledge is justified, even if causation cannot be directly inferred.

All analyses were performed using a statistical software package (Statview 4; SAS Institute; Grenoble, France). The data were expressed as the mean ± SD. Unpaired t tests were used for the comparison of parameters measured in the female and male groups or in patients with and without pulmonary hypertension. Comparisons of categoric data were made using the {chi}2 test. For small samples, the Yates correction was used. A paired t test was performed to compare the responses obtained with two techniques. The least-squares regression method described the relationship between continuous variables, and multiple regression analysis was also performed. Backward stepwise multiple regression allowed the determination of the factors that were independently associated with a dependent variable. For all comparisons, p values < 0.05 were considered to be significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Fifty consecutive patients who were referred for PFTs were prospectively included during a 10-month period; one patient was excluded a posteriori since she had sickle-hemoglobin C anemia. The characteristics of the 49 patients are described in Table 1 . The results of their functional evaluation are described in Table 2 .


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  		Table 1. Clinical Characteristics and Relevant Blood Variables*

 

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  		Table 2. Cardiorespiratory Evaluation*

 
The MRC scores of the 49 patients are described in Figure 1 . Despite a similar previous history of SCD, women, who were more anemic than men, complained of more dyspnea and fatigue than men and were more tachypneic at rest, resulting in a mild hypocapnia. The performance of 6MWT induced a significant increase in Borg dyspnea score, in Borg fatigue score, in respiratory rate (RR), and in heart rate, but induced no significant impairment of pulse oximetry (data not shown).



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  		Figure 1. Figure 1. MRC scores of the 49 patients.

 
Validation of Indexes of Dyspnea and Fatigue
The comparison of dyspnea and fatigue scores (direct and indirect) are described in Table 3 .


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  		Table 3. Correlations Between the Different Indexes of Dyspnea and Fatigue

 
Patients Complaining From Respiratory Limitation During 6MWT
Ten patients thought that their performance during the 6MWT was limited by respiratory symptoms. These patients had a higher mean Borg dyspnea score (after the 6MWT) than the 39 patients who thought they were not limited by dyspnea (3.5 vs 1.8, respectively; p = 0.016), and they also had a lower mean DM/alveolar volume (VA) ratio (7.0 vs 9.1, respectively; p = 0.015).

Patients Thinking That Their Performance During 6MWT Was Not Limited
Twenty-seven patients who thought that their performance was not limited by either dyspnea or leg fatigue had lower mean MRC scores (1.7 vs 2.3, respectively; p = 0.038), mean Borg dyspnea scores before 6MWT (0.4 vs 1.2, respectively; p = 0.018) and after 6MWT (1.2 vs 3.4, respectively; p < 0.0001), and higher mean values of the CO transfer coefficient (87% vs 75%, respectively; p = 0.009) and DM/VA ratio (9.4 vs 7.9, respectively; p = 0.030) than the 22 patients who thought that they had experienced a limitation (respiratory and/or muscular) in their performance during the 6MWT.

Factors Associated With Dyspnea, Exercise Performance, and Oxygenation
The main result is to demonstrate that dyspnea is clearly linked to a decrease in DLCO whether or not DLCO was corrected for the degree of anemia. The main determinant of DLCO associated with dyspnea parameters is DM. Similarly, DLCO parameters were also linked to exercise performance. Dyspnea was not correlated with any index of airflow limitation or lung restriction (Table 4 ).


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  		Table 4. Factors Associated With Dyspnea, Exercise Performance, and Oxygenation*

 
When using a reference equation for 6MWT results that have been obtained in a white population (age range, 40 to 80 years), an impairment of exercise ability is clearly suggested, with a mean distance of 66 ± 9% predicted for women and 75 ± 12% predicted for men; the impairment in exercise performance seems to be higher in women than in men (p = 0.003). In a multiple regression analysis (p < 0.0001; R2 = 0.49), variables that influenced the alveolar-arterial oxygen difference were hemoglobin level (p = 0.0003) and body mass index (p = 0.004).

Echocardiography Results
The echocardiography results were similar in women and men. Among the 49 patients, 13 (27%; 9 men) exhibited a mild pulmonary hypertension that was defined by a systolic pulmonary arterial pressure of > 30 mm Hg (mean, 34 ± 3 mm Hg; maximum, 38 mm Hg). The echocardiography results were not significantly correlated with any parameter obtained from PFTs or from both dyspnea and fatigue assessments. When comparing patients with or without pulmonary hypertension, no significant difference was shown in term of dyspnea test and PFT results, and exhaled NO parameters.

Exhaled NO Measurement in a Subset of Patients
In 25 patients, multiple-flow analysis of exhaled NO was performed; the results are shown in Table 5 . Women tended to exhibit a lower concentration of alveolar NO than men. The logarithmic value of the alveolar NO concentration was negatively correlated with VC/VA ratio (R2 = 0.20; p = 0.028). Exhaled NO results were not correlated with any parameter of dyspnea. The mean value of V’NO,ALV was significantly lower in women than in men (183 ± 132 vs 347 ± 175 nL/min, respectively; p = 0.017).


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  		Table 5. Results of Exhaled NO Measurements*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study confirmed that adult patients with SCD during a mild phase of their disease can experience mild-to-severe dyspnea. This functional complaint was illustrated by a rapid breathing frequency. The exact prevalence of dyspnea in SCD patients is, to our knowledge, unknown but could be elevated; for instance, in the study by Miller and Serjeant,1 17 of 25 patients experienced mild-to-severe dyspnea. Furthermore, Lonsdorfer and colleagues2 noticed empirically that the degree of anemia encountered in a group of patients with SCD exhibiting a mild course of the disease leads frequently to a more severe impairment of common life habits than does a similar degree of anemia in patients with other diseases.

Lung Vascular Origin of Dyspnea
The main finding of this study was the demonstration that dyspnea is linked to an impairment of indexes of DLCO, whether or not they were corrected for the degree of anemia. The pathophysiology of dyspnea is complex and can be related to an increased sense of effort, hypoxia, hypercapnia, or dynamic airway compression.15 The stimulation of pressure receptors in the pulmonary vasculature has been suspected as a cause of dyspnea in vascular diseases without any formal demonstration.15 Our results clearly demonstrate that dyspnea is statistically associated with the parameters of DLCO but not with restrictive or obstructive defects, suggesting a role for its vascular origin. The mild restrictive disease observed in our study (12% in women and 17% in men) is in agreement with the results of Miller and Serjeant1 (11% in women and 12% in men).

During SCD, microvascular occlusion and infarction ensue, causing alveolar wall necrosis and scarring; the end result is a loss of lung units. Consequently and logically, the impairment of DM was the main pathophysiologic factor associated with dyspnea. Miller and Serjeant1 have previously suggested that the cause of the reduction in DM above that due to small lungs was probably located in the pulmonary circulation. DM includes the entire diffusion path from the alveolar gas to the surface of the RBC (ie, not only across the pulmonary membrane but also within the plasma). A reduction of DM has constantly been found in SCD patients, mainly in those who have a history of pulmonary complications and do not smoke (in the study by Femi-Pearse and coauthors,3 48 mL/min per mm Hg; in the study by Miller and Serjeant1: men, 45.7 mL/min/mm Hg; women, 29.0 mL/min/mm Hg [similar to our results]) [Table 2]. By contrast, we were not able to demonstrate a relationship between a history of ACS and the degree of vascular impairment. We previously demonstrated that there was no evidence that recurrent ACS may be associated with more severe lung damage as assessed by lung function tests.4

Previous investigators demonstrated a compensatory increase in the values of VC in patients with SCD, which seems paradoxical in a disease that is characterized by tissue infarction (in the study by Miller and Serjeant1: women, 78.0 mL; men, 89.6 mL; in the study by Femi-Pearse and coauthors, 82 mL).3 Our observed values of VC are in close agreement (Table 2). The explanations for the increase in VC in patients with SCD are lacking but are consistent with autopsy findings demonstrating dilated pulmonary vessels.20 Finally, the higher increase in capillary blood volume corrected for lung volume in women than in men and their higher degree of dyspnea constitute a strong argument for vasculature-induced dyspnea. We may hypothesize that the common mechanism leading to the augmentation of VC in anemia is an increase in cardiac output resulting in pulmonary vascular recruitment, as has been suggested elsewhere.21

Echocardiography and the Measurement of Exhaled NO Do Not Provide Useful Contributions to the Explanation of Dyspnea
The high frequency of mild pulmonary hypertension that was observed is in keeping with the results of Gladwin and coauthors22 (32%; estimated pulmonary-artery systolic pressure, at least 30 mm Hg), who demonstrated the prognostic value of such a complication. Unexpectedly, this mild degree of pulmonary hypertension does not seem to contribute to functional complaints and is not associated with a greater diffusion defect. Similarly, we were unable to establish a relationship between dyspnea and parameters of exhaled NO.

Dyspnea and Fatigue Are Linked
This study also shows that fatigue is a common complaint in patients with SCD. The fact that dyspnea and fatigue were linked may suggest common pathophysiologic mechanisms. Along this line, an increase in transforming growth factor-ß levels has been demonstrated in patients with either SCD or chronic fatigue syndrome.2324

Women Exhibit More Severe Lung Impairment Than Men
Another main finding of this study was the demonstration that women were more prone to exhibit lung involvement and its functional consequences in SCD despite a clinical history similar to men. The DLCO was lower in women than in men despite a higher increase in capillary blood volume (VC) corrected for VA. The women also tended to exhibit lower concentrations of alveolar NO. The lower values of NO diffusing rate from tissue to alveolar gas in women could be related to local consumption associated with the increased capillary blood volume. These findings are unexplained inasmuch as sex difference in clinical outcomes that have previously been described in patients with SCD favored women. For instance, Baum and colleagues25 observed a striking increase in VOC in men with SCD after age 15 years, resulting in a greater rate of pain attacks in men than in women. More recently, Gladwin and colleagues26 have demonstrated that NO bioavailability and NO responsiveness are greater in women than in men with SCD using forearm blood flow analysis. Estrogen increases endothelial NO synthase expression and basal endothelial NO production, and appears to prevent endothelial dysfunction in the setting of classic risk factors for atherosclerosis.2728

Impairment of Performance
Due to the lack of appropriate reference equations for predicted distance during 6MWT in African subjects, we cannot ensure that the observed values were abnormally reduced. However, when using the reference equation for 6MWT published in 199829 for older white subjects, a clear impairment of exercise capacity is suggested, which is greater for women than for men. Along this line, Callahan and colleagues30 evidenced low peak values of oxygen consumption in 17 women during exercise testing, with 11 subjects having a pattern that was consistent with exercise limitation due to pulmonary vascular disease. Similarly, Pianosi and coauthors31 found that exercise was accompanied by abnormally increased ventilation in children with SCD, due mainly to an increased dead space that may be related to the effects of intrapulmonary sickling. In our study, exercise performance, like dyspnea, was associated with abnormal DLCO, suggesting their common pathophysiology. One unexpected finding was the demonstration that the degree of anemia is not correlated with dyspnea, fatigue, or exercise performance.

Limitations of the Study
One limitation of this study is that healthy African subjects were not enrolled, and appropriate reference values are unavailable for some of the parameters that have been studied. Nevertheless, numerous previous studies allow comparison with our results. The second limitation of this study is that respiratory muscle weakness was not assessed. The measurement of respiratory muscle function was beyond the scope of this study, but this could partly justify why only approximately 25% of the variability of the observed associations was explained.

In summary, both dyspnea and exercise performance were closely linked to DLCO parameters. By contrast, the degree of anemia was not correlated with dyspnea, fatigue, or exercise performance, a fact that should be taken into consideration for the need of therapeutic transfusion. The sequential assessment of DLCO would therefore constitute one of the functional end points for the follow-up of patients with SCD. It constitutes an objective assessment of silent pulmonary vascular disease, and its progressive impairment could constitute an indication for more aggressive therapy (eg, with hydroxyurea with or without arginine32).


   Acknowledgements
 
This study is dedicated to the memory of Alain Harf.


   Footnotes
 
Abbreviations: ACS = acute chest syndrome; CANO = concentration of nitric oxide from the expansible compartment of the lung; DLCO = diffusing capacity of the lung for carbon monoxide; DLNO = alveolar nitric oxide diffusing capacity; DM = diffusing capacity of the alveolar-capillary membrane; FENO = fraction of exhaled nitric oxide; FIS = fatigue impact scale; HbCO = carboxyhemoglobin; MRC = modified Medical Research Council; 6MWT = 6-min walk test; NO = nitric oxide; PFT = pulmonary function test; RR = respiratory rate; SCD = sickle cell disease; V’ = expiratory flow; VA = alveolar volume; VC = pulmonary capillary blood volume available for gas exchange; V’NO,ALV = nitric oxide diffusing rate from tissue to alveolar air; VOC = vasoocclusive crisis

This study was supported by l’Association Soutiens aux Actions contre les Maladies du Globule rouge.

Received for publication January 28, 2005. Accepted for publication May 8, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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