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Published ahead of print on September 11, 2003, doi:10.1164/rccm.200302-174OC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 1373-1377, (2003)
© 2003 American Thoracic Society

Induced Sputum versus Bronchoalveolar Lavage during Acute Chest Syndrome in Sickle Cell Disease

Emmanuelle Lechapt, Anoosha Habibi, Dora Bachir, Frederic Galacteros, Annette Schaeffer, Dominique Desvaux, Laurent Brochard, Bruno Housset, Bertrand Godeau and Bernard Maitre

Departments of Pathology, Pulmonary Disease, and Critical Care Medicine, Sickle Cell Disease Center, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Inserm U492, Université Paris XII, Créteil, France

Correspondence and requests for reprints should be addressed to Bernard Maitre, M.D., Ph.D., Unité de Pneumologie, Hôpital H. Mondor, Assistance Publique-Hôpitaux de Paris & Université Paris XII 151, Avenue du Mal de Lattre de Tassigny, 94010 Créteil Cedex, France. E-mail: bernard.maitre{at}hmn.ap-hop-paris.fr


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Previous reports have shown that in more than 40% of adults with acute chest syndrome (ACS), fat droplets suggestive of pulmonary fat embolism were present in alveolar macrophages. To determine whether induced sputum (IS) is a reliable test for detecting this embolism, we compared bronchoalveolar lavage and IS results in 20 patients with ACS. We found a correlation between the number of Oil Red O–stained macrophages in sputum and lavage fluid (Spearman's coefficient: {rho} = 0.657, p < 0.018). Sputum cytology was then studied in another 60 patients who had sickle cell disease with ACS. An elevated percentage of Oil Red O–stained macrophages was found in the sputum of 37/47 patients, but they did not include any of the patients with sickle cell disease but no clinical symptoms. Patients suffering from ACS with Oil Red O–stained macrophages had more extrathoracic concomitant pain than those without (76 vs. 50%, p < 10-8), had more neurologic symptoms (7 vs. 0%, p < 10-8), a lower differential platelet count (-49 ± 121 vs. +85 ± 229, p < 0.04), and higher abnormal transaminase values (28 vs. 17%, p < 0.01). We conclude that IS analysis is a safe, noninvasive, and useful test for fat embolism detection in ACS.

Key Words: fat embolism • fiberoptic bronchoscopy • acute lung injury

Acute chest syndrome (ACS) is a frequent and potentially life-threatening pulmonary illness. It is a complication of sickle cell disease and is the leading cause of death from this disease in adults (1, 2). Several pathologic processes are recognized causes of ACS, including infectious diseases, in situ thrombosis, hypoventilation secondary to chest pain, and pulmonary fat embolism (3–12). During episodes of ACS, bacterial pathogens and pulmonary fat embolism can be detected by bronchoalveolar lavage (BAL), and a recent review recommended bronchoscopy for patients who fail to respond to initial treatment (13). Our group has shown that, in patients with sickle cell disease, the presence of more than 5% of lipid-laden alveolar macrophages in BAL fluid permits the diagnosis of pulmonary fat embolism (14). However, the BAL is too invasive for its use to be recommended for all episodes of ACS. Analysis of induced sputum (IS) has been proposed as a less invasive method of measuring airway inflammation. It was also recently shown to be useful for the diagnosis of various diseases, including Pneumocystis carinii pneumonia and left ventricular dysfunction (15, 16). Although IS or tracheal aspiration has occasionally been described as a tool for detecting lipid-laden macrophages in ACS (13, 17), IS and BAL have never been compared as methods of diagnosing pulmonary fat embolism. The present clinical investigation was therefore designed to establish whether IS is a useful tool for this purpose.

To validate IS as a clinical test for lipid-laden alveolar macrophage detection, we prospectively compared findings in IS and BAL samples. In addition, in a larger cohort of patients, we prospectively assessed the feasibility and usefulness of IS in everyday practice.

Some of the results of these studies were previously reported in the form of an abstract at the American Thoracic Society international conference in San Francisco in May 2001 (18).


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Patients in whom ACS was diagnosed were recruited from the Sickle Cell Disease Center in the Henri Mondor university hospital in Créteil, France between April 1997 and June 2000. All Patients gave oral informed consent to participate in the study, which was approved by our hospital's ethics committee. Diagnosis of ACS was based on the presence of fever or chest pain, combined with new pulmonary infiltrates on chest X-ray (19, 20). Patients with life-threatening respiratory failure or bilateral wheezing after bronchodilator treatment were excluded from the study. Clinical data were recorded and blood samples collected for measurement of several hematologic parameters. Baseline individual values corresponded to those measured more than 1 month before any clinical event and at least 3 months after the last transfusion. Blood and urine cultures were performed for each patient on admission. Room air arterial blood gases were generally measured once, and chest X rays were recorded on the day of ACS diagnosis.

A uniform standard treatment was prescribed for each patient, including oxygen therapy, antibiotics (for febrile patients), and fluid management (30 ml/kg). The pain management protocol always included the use of proparacetamol and when necessary morphinomimetics. Clinical monitoring according to guidelines was performed to avoid morphine overdose. Transfusion therapy was standardized and given only to (1) pregnant patients or those with postoperative conditions, (2) patients with respiratory distress at admission (respiratory rate > 30 and/or PaO2 < 50 mm Hg), and (3) patients with worsening of symptoms despite supportive treatment after a follow-up of 3 days.

To compare the cytologic results of BAL and IS (Study 1), 20 patients whose physician decided to perform fiberoptic bronchoscopy with BAL for diagnostic purposes underwent IS in the hour before bronchoscopy. We also report in Study 2 our subsequent experience with IS in a larger cohort of 60 patients and compare the results of IS analysis with the clinical characteristics and outcome of ACS.

Fiberoptic Bronchoscopy
Bronchoscopy was performed 1 hour after sputum induction using an Olympus BFP30 fiberoptic bronchoscope, as described previously, (14). The plugged telescoping catheterization was performed to obtain samples for quantitative bacterial cultures (21). Standard BAL was performed, and the second and third 50-ml aliquots of BAL fluid were pooled and immediately processed for cytologic examination. BAL fluid was also transported to the microbiology laboratory for gram staining and quantitative bacterial cultures (22).

Sputum Induction
IS was performed between 24 and 48 hours after hospitalization. All subjects were premedicated with 2 mg nebulized terbutaline. Analgesia was optimized with 1 g intravenously administered proparacetamol and then completed if necessary with opioids before the induction. Sputum was induced according to Pizzichini and coworkers (23) by inhalation of 3% saline for 15 minutes through a mouthpiece without a nose clip (Systam LS260; System Assistance Medical, Villeneuve sur Lot, France). The procedure was stopped if the patient experienced worsening chest pain or bronchial hyperresponsiveness, indicated by a fall of 20% in peak flow measurement.

Cytologic Preparation and Examination
Whole sputum samples were pretreated with 0.1% dithiothreitol in PBS. The resulting IS suspension and BAL fluid were filtered, and the total number of nonsquamous cells was counted in a hemocytometer. Centrifuged smears were prepared and stained by the May–Grunwald–Giemsa, Papanicolaou, and Perls methods. A 400 differential cell count was performed. To detect neutral fat, an additional smear was stained using the Oil Red O method, as described previously (14). A 100-macrophage cell count was performed in blind fashion by two anatomopathologists (E.L. and D.D.). Pulmonary fat embolism was diagnosed if more than 5% of the macrophages were stained with Oil Red O. This cutoff point had been determined in our previous study using two control groups (14).

Statistical Analysis
Agreement between measurements was tested and graphically displayed as suggested by Bland and Altman (assuming that 95% of the differences between measures were smaller than two SDs) (24). Correlations were tested by Spearman's rank correlation coefficient. Differences between groups were first assessed by the Kruskall–Wallis test and when significant, by the Mann–Whitney U test (StatView processor; SAS Institute Inc., Cary, NC).

Additional details concerning the methods used are provided in an online supplement.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Study 1: Sputum versus BAL
The contents of IS and BAL samples collected during ACS were compared in 20 adult patients with sickle cell disease. Patients' baseline characteristics are shown in Table 1 . The IS procedure was well tolerated by all 20 patients. Before performing IS, analgesia was optimized, to ensure good thoracic expansion without pain. The procedure was performed between 24 and 48 hours after admission, so that patients would be free of pain when it began.


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  		TABLE 1. Baseline characteristics of patients with sickle cell disease

 
All BAL and IS samples were negative for bacterial culture. Representative cytologic samples stained with May–Grunwald–Giemsa and Oil Red O are displayed in Figure 1 . Samples were not representative of alveolar samples in one case for BAL and not representative of bronchial samples in two cases for IS.



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  		Figure 1. Low-power view showing the cells present in a representative induced sputum sample from a patient with acute chest syndrome. (A) May–Grunwald–Giemsa staining. (B) Oil Red O (ORO)–staining of a similar sample. Squamous cells are easily detectable (asterisk), and neutral fat droplets form globular refringent inclusions stained by ORO in alveolar macrophages (arrow).

 
A detailed comparison of the cytologic results for IS and BAL is given in Table E1 in the online supplement.

As previously reported for normal patients and patients with asthma (25), IS contained a larger total of nonsquamous cells than BAL fluid (p = 0.0001), a lower percentage of macrophages (p = 0.002), a higher percentage of polymorphonuclear cells (p = 0.002), and a lower percentage of lymphocytes (p = 0.004). However, the percentages of lipid-laden macrophages were not different in BAL and IS samples, and there was even a correlation between the numbers of Oil Red O–stained macrophages in BAL and IS samples ({rho} = 0.657, p < 0.018). Lastly, the agreement between the counts of these macrophages in each type of sample seemed acceptable, as indicated by the Bland–Altman graph (Figure 2) . We chose the same cutoff point for the percentages of Oil Red O–stained macrophages in IS and BAL to obtain the minimum number of false-negative results. This gave a sensitivity of 83%, a specificity of 50%, a positive predictive value of 91%, and a negative predictive value of 33%.



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  		Figure 2. Representation of the agreement between the percentages of ORO-stained macrophages (ORO + macrophages [Mac]) in 17 samples of bronchoalveolar lavage (BAL) and induced sputum (IS), according to Bland and Altman. Differences between IS and BAL samples are plotted as a function of the mean of two values. Solid line represents mean difference; dashed lines represent limits of ± 2 SD of mean difference.

 
Study 2: Sputum Samples from 60 Patients Suffering from Sickle Cell Disease with ACS and 10 Control Patients without ACS
Our next step was a prospective study of the results of IS performed during consecutive ACS episodes in 60 adult patients with sickle cell disease (ACS+) and in 10 control patients without ACS (ACS-). Patients' baseline and clinical characteristics are shown in Table 1 and were not different in the two groups. The IS collection procedure was well tolerated by 57 patients but induced exacerbation of asthma in one patient and of chest pain in two patients. Of the 60 ACS+ samples, 13 could not be analyzed (failure of the technique of sputum production in 2 patients, and salivary contamination of samples in 11). One patient in the control group was unable to produce IS. Bacterial studies showed two positive samples in the ACS group: one for Escherichia coli and one for Streptococcus Pneumoniae.

The cell content of IS samples (Table 2) was compared in patients with ACS and those without ACS. The samples collected during ACS episodes contained higher percentages of eosinophils and Oil Red O–stained macrophages than the control samples. In the latter, the proportion of these macrophages never exceeded 3%. The choice of the cutoff point at 5% gave a diagnosis of pulmonary fat embolism in 29 of the 47 patients with ACS and none of the 9 control patients.


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  		TABLE 2. Cytologic analysis of induced sputum samples from patients suffering from sickle cell disease with and without acute chest syndrome and from patients suffering from acute chest syndrome with and without pulmonary fat embolism

 
We also compared the cell content of samples from patients suffering from ACS with and without pulmonary fat embolism (Table 2). The total number of nonsquamous cells was significantly lower in patients with pulmonary fat embolism (p < 0.0009), and we found a correlation between the total number of cells and the percentage of Oil Red O–stained macrophages. The percentages of polymorphonuclear cells also tended to be lower in pulmonary fat embolism. In addition, we found a significant increase in the protein content of IS samples from patients suffering from ACS with pulmonary fat embolism and a correlation between the total number of cells and the protein level.

Comparison of Clinical Characteristics, Outcome, and IS Contents in Patients with ACS
We compared the characteristics of ACS events in patients with or without Oil Red O–stained macrophages (Table 3) . Compared with patients suffering from ACS without pulmonary fat embolism, those with pulmonary fat embolism had more extrathoracic concomitant pain (76 vs. 50%, p < 10-8), more neurologic symptoms (7 vs. 0%, p < 10-8), a lower differential platelet count (-49 ± 121 vs. +85 ± 229, p < 0.04), and a higher frequency of abnormal transaminase values (28 vs. 17%, p < 0.01). However, no difference was seen for outcome or length of hospital stay. Note that no deaths occurred during the period of the study.


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  		TABLE 3. Comparison of clinical characteristics and outcome of acute chest syndrome events in patients with and without oil red o–stained macrophages

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
ACS is a multifactorial syndrome, and its recommended treatments include hydration, oxygenation, and analgesia. Transfusions or exchange transfusions are also recommended for patients with severe hypoxia. Although infectious agents have not often been found in adults, antibiotherapy is commonly recommended. Fiberoptic bronchoscopy is the gold standard test for airway infectious disease and pulmonary fat embolism in episodes of ACS, but it causes discomfort to the patient and is not without risk. In a study by Vichinsky and coworkers, complications of bronchoscopy occurred in 28 patients (13%), 8 of whom required endotracheal intubation (13). We developed the technique of IS to obtain a less invasive method of diagnosing airway infectious disease and pulmonary fat embolism during ACS.

In the present investigation, IS was performed successfully in 57/60 cases (95%), which can mainly be attributed to careful management of pain in our patients. Because the quality of sputum is highly dependent on patient cooperation, the analgesia was important. Note that very few patients experienced complications due to the procedure for obtaining IS. However, the cytologic results could not be interpreted in 13 samples. Although this is a high failure rate for a diagnostic tool, it is far lower than the 42% of uninterpretable samples reported for non-IS by the National Acute Chest Syndrome Study Group (13).

In recent years, the method of IS has been used by a large number of groups to monitor airway inflammation. Interpretation of the results of IS requires knowledge of the normal values for the same population. Two studies recently aimed to define reference values for total and differential cell counts in IS from healthy, adult nonsmokers (25, 26). Although reference values for patients with sickle cell disease have not yet been reported, the present data from our control patients are very close to the normal values cited in these two publications. If confirmed, this will be of great clinical interest for the interpretation of IS in such patients. However, these results require confirmation in patients with sickle cell disease without any symptoms and during a nonpulmonary vasoocclusive crisis. The number of cells per milliliter was smaller in our patients than in other series (1.800 vs. 2.70 0 x 103 total cell count of nonsquamous cells per milliliter), but this was probably due to the processing of the whole expectorate and not of a selected portion (26). Note that less than 20% of our patients were current or previous smokers.

Differential cell numbers did not change in patients with ACS, even when we distinguished between IS samples from patients with and without pulmonary fat embolism. This contrasts with our results for BAL fluid, in which more polymorphonuclear cells and lymphocytes were found in patients suffering from sickle cell disease with ACS than in those without ACS and in which a strong correlation existed between the percentages of Oil red O + stained macrophages and polymorphonuclear cells (14, 20). Discrepancies between the results of BAL and IS have already been observed in patients with asthma, chronic obstructive pulmonary disease, and sarcoidosis, partly because of the different areas of lung sampled. We postulate that the total cell counts were lower in patients suffering from ACS with pulmonary fat embolism than in those without ACS because the inflammatory exudates in these cases are mainly located in the level of pulmonary alveoli. The protein level is very high in such patients, and some rose dramatically, by more than 50 g per liter. The presence of a local inflammatory exudate suggests that fat embolism involves a different lung injury from the one caused by ACS without pulmonary fat embolism. This is corroborated by our previous data on BAL showing different cytologic profiles for episodes of ACS with and without fat embolism (14, 20). We also found a very high level of protein in BAL fluid supernatants (unpublished data), again suggesting that the inflammatory exudate is mainly located in the alveolar region. In some patients this exudative process induced a productive yellow sputum, which may explain the relative decrease in total cell counts per milliliter in our IS data. It would be very interesting to compare the lung inflammation markers and plasmatic biomarkers associated with the ACS events described in the literature, such as sPLA2, endothelin 1, adhesion molecules, and nitric oxide metabolites (27–32).

Lastly, the high proportion (78%) of ACS samples with Oil Red O–stained macrophages in the present series was a feature suggestive of pulmonary fat embolism. Previous authors have attempted to diagnose pulmonary fat storage by sputum examination, tracheobronchial washing, or BAL, to detect the presence of lipids in macrophages (14, 17, 33). However, for pulmonary fat embolism, only descriptive data concerning BAL have been reported. In a previous study, our group demonstrated a good correlation between the presence of lipid-laden macrophages in BAL and episodes of ACS with clinical characteristics suggestive of pulmonary fat embolism (14). Here, we showed that the presence of lipid-laden macrophages in IS was associated with a high frequency of extrathoracic pain, neurologic abnormalities, and low platelet counts. These results, together with the correlation between the results of BAL and IS, indicate that the percentage of lipid-laden macrophages is a reliable tool for the diagnosis of fat embolism. We also confirmed, in a large number of successive adult patients with sickle cell disease, the high frequency of the pulmonary fat embolism described in previous studies of adults and children (13, 20). There is no specific treatment for pulmonary fat embolism, and the detection of lipid-laden macrophages did not prompt us to modify our standard of care for these patients. However, it may be helpful in the near future to study the effect of disease-specific therapeutic agents targeted at this syndrome, and to determine more precisely the different causes of ACS. Regarding diagnosis, the present findings indicate that IS may constitute a simple and useful tool for detecting a specific cause of ACS, i.e., fat embolism, in adult patients with sickle cell disease.


   Acknowledgments
 
The authors are grateful to the physiotherapists and staff of the Intensive Care Unit of the Henri Mondor hospital who participated in the study and the System Assistance Medicale Company, which provided the nebulizer device.


   FOOTNOTES
 
Presented in part at the American Thoracic Society International Conference, San Francisco, May 2001.

This article has an online supplement, which is accessible from the current issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: E.L. has no declared conflict of interest; A.H has no declared conflict of interest; D.B. has no declared conflict of interest; F.G. has no declared conflict of interest; A.S. has no declared conflict of interest; D.D. has no declared conflict of interest; L.B. has no declared conflict of interest; B.H. has no declared conflict of interest; B.G. has no declared conflict of interest; B.M. has no declared conflict of interest.

Received in original form February 6, 2003; accepted in final form September 5, 2003


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 METHODS
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 DISCUSSION
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