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BAL Neutrophils, Serum Procalcitonin, and C-Reactive Protein To Predict Bacterial Infection in the Immunocompromised Host
CHEST
Original Research CHEST INFECTIONS
BAL Neutrophils, Serum Procalcitonin, and C-Reactive Protein To Predict Bacterial Infection in the Immunocompromised Host* Daiana Stolz, MD; Andreas Stulz; Beat Mu¨ller, MD; Alois Gratwohl, MD; and Michael Tamm, MD
Background: Bacterial pulmonary infection is a common life-threatening complication in immunocompromised patients. The results of BAL cultures are not immediately available, and their microbiological yield might be limited by empiric antibiotic prescriptions. We evaluated clinical signs and symptoms, leukocyte counts, C-reactive protein (CRP) levels, procalcitonin levels, and BAL fluid neutrophil percentages as potential markers for bacterial infection in a cohort of immunocompromised patients with pulmonary complications. Methods: One hundred seven consecutive patients who had been referred for bronchoscopy due to suspected pulmonary infection were included in this study. Based on clinical, laboratory, radiologic, microbiological, and histologic results, patients were classified as having proven bacterial infection (n ⴝ 27), possible bacterial infection (n ⴝ 11), and no bacterial infection (n ⴝ 69). Results: Most common underlying conditions were hematologic malignancy (n ⴝ 62) and solid organ transplantation (n ⴝ 20). Clinical parameters were similar in patients with and without bacterial infection (difference was not significant). The percentage of BAL fluid neutrophils had the highest area under the curve (0.818; 95% confidence interval [CI], 0.700 to 0.935; p < 0.001), followed by absolute neutrophil counts (0.797; 95% CI, 0.678 to 0.916; p < 0.001), procalcitonin level (0.746; 95% CI, 0.602 to 0.889; p ⴝ 0.001), and CRP level (0.688; 95% CI, 0.555 to 0.821; p ⴝ 0.015) to predict proven bacterial infection (in opposition to no or possible bacterial infection) in the receiver operating characteristic analysis. Conversely, neither infiltrates (p ⴝ 0.123) nor leukocyte counts (p ⴝ 0.429) were useful in diagnosing bacterial infection. The percentage of BAL fluid neutrophils and procalcitonin level were independent predictors of bacterial infection in the multivariate regression. Conclusions: Neutrophil percentage in BAL fluid, procalcitonin level, and CRP level might be potentially useful to differentiate bacterial infection from nonbacterial conditions in immunocompromised hosts with pulmonary complications. (CHEST 2007; 132:504 –514) Key words: biomarker; immunosuppression; stem cell transplantation Abbreviations: AUC ⫽ area under the curve; CI ⫽ confidence interval; IQR ⫽ interquartile range; OR ⫽ odds ratio; ROC ⫽ receiver operating characteristic
complications are a major cause of P ulmonary morbidity and mortality among immunocompromised patients.1–7 It has been suggested8,9 that clinical or radiologic pulmonary abnormalities warranting therapeutic consideration will develop in 30 to 60% of all immunocompromised patients. The accurate diagnosis of the underlying pulmonary disorder is pivotal as it influences medical therapy and out504
CRP ⫽ C-reactive
protein;
come.5,7,10 Although the lung is the organ that is most commonly affected by noninfectious abnormalities,11 the identification and severity assessment of bacterial infection is of particular interest, as it represents a major cause of mortality.12,13 Diagnostic bronchoscopy is routinely performed in immunocompromised patients.5,7,14,15 Because of the perceived severity of the baseline condition and Original Research
the worsened prognosis associated with a delay in antibiotic therapy, direct respiratory tract sampling usually occurs after antibiotic therapy has been instituted.16,17 The microbiological yield of BAL fluid cultures is therefore expected to be compromised, ranging widely from 15 to 93%.10,14,18,19 Differential cell counts of BAL fluid may serve as a complementary examination to microbiological studies. Herein, higher neutrophil counts have been reported in immunocompromised patients with bacterial pneumonia compared to those patients with no detectable pathogens.20 Circulating proinflammatory mediators such as C-reactive protein (CRP) and, more recently, procalcitonin, have been suggested to be predictive for invasive bacterial infection in the immunocompromised host.21–23 Some studies,24,25 but not all,26 investigating immunocompromised patients have shown that these patients are capable of producing high serum concentrations of both mediators during severe systemic bacterial infection. While there have been no interventional studies using CRP, procalcitonin was shown to safely support the decision to start antibiotic therapy in respiratory infections in nonimmunocompromised patients.27–29 However, in the immunocompromised host, it is thought that there is no sufficient evidence to base a therapeutic decision on.30 We hypothesize that BAL fluid neutrophils and serum biomarkers (CRP and procalcitonin) might be more useful than routinely used signs and symptoms for the diagnosis of bacterial infection in the immunocompromised host. Therefore, we performed a prospective, explorative, observational study to evaluate the diagnostic accuracy of clinical signs and symptoms, leukocyte counts, CRP levels, procalcitonin levels, and neutrophil percentages in BAL fluid *From the Clinics of Pneumology and Pulmonary Cell Research (Drs. Stolz, Stulz, and Tamm), Endocrinology, Diabetes, and Clinical Nutrition (Dr. Mu¨ller), and Hematology (Dr. Gratwohl), University Hospital Basel, Basel, Switzerland. The study was presented in part at the 16th Annual Congress of European Respiratory Society, Munich, 2006 and was honored with the Research Excellence Award in Respiratory Infections. Drs. Stolz and Mu¨ller have received payments from BRAHMS (the manufacturer of procalcitonin assays) to attend advisory board meetings and speaker engagements, or for research. Drs. Stulz, Gratwohl, and Tamm have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Manuscript received January 19, 2007; revision accepted April 18, 2007. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Daiana Stolz, MD, Assistant Professor, University of Massachusetts Medical School, 55 Lake Ave North, Worcester, MA 01655; e-mail: [email protected] DOI: 10.1378/chest.07-0175 www.chestjournal.org
as potential markers for bacterial infection in a cohort of immunocompromised patients with pulmonary complications.
Materials and Methods Patients This study was approved by the institutional review board and performed at the University Hospital Basel, a 784-bed tertiary care hospital located in Basel, Switzerland. One hundred seven consecutive hospitalized immunocompromised patients who were referred to the pulmonary division for diagnostic bronchoscopy within a period of 8 months in 2005 were included in this prospective cohort study. Eligibility criteria included the following: (1) immunocompromised state; (2) age ⬎ 18 years; (3) a decision by the pulmonary consultant to perform bronchoscopy due to suspected pulmonary infection; and (4) informed consent by the patient to undergo flexible bronchoscopy and related data analysis. Suspected pulmonary infection was defined by the presence of respiratory symptoms (eg, cough, sputum, and dyspnea), fever, and/or new or progressive radiologic findings, as judged by the attending physician. Immunocompromised state was defined by the following conditions: hematologic or other malignancy treated by high-dose chemotherapy and/or stem cell transplantation; solid organ transplantation; AIDS; long-term corticosteroid therapy (ie, ⱖ 20 mg/d prednisone equivalent for ⱖ 2 months); and current use of immunosuppressive or cytotoxic medication for indications other than organ or stem cell transplantation. Data Collection Data collection including demographics, underlying diseases, immunosuppressive drugs, antimicrobial treatment for suspected or documented infection, laboratory findings, and radiologic results were recorded at the time of bronchoscopy using a standardized study form. The collected data also included information related to bronchoscopy. Further data on final diagnosis, clinical outcome, and, if applicable, cause of death including autopsy results were collected after hospital discharge. A review of medical records was performed by two independent, boardcertified pulmonary specialists. Discrepancies were settled by consensus. Bronchoscopy Flexible bronchoscopy was performed with the patient under conscious sedation using hydrocodone and midazolam according to the British Thoracic Society guidelines.31–33 BAL was performed by the three installations of 50 mL each of a pyrogen-free, sterile, 0.9% NaCL solution over the working channel of the bronchoscope according to standard guidelines and as described earlier.14,34,35 In patients with diffuse pulmonary infiltrates, BAL was performed either in the right middle lobe or the lingula. For patients with focal lung infiltrates, BAL was performed in the pulmonary segment corresponding to the radiologic abnormality. BAL fluid was recovered by suction. Besides BAL, the choice of further sampling techniques used during bronchoscopy was at the pulmonologist’s discretion. Major complications were defined as major bleeding, worsening hypoxemia requiring endotracheal intubation, any adverse event requiring early discontinuation of the procedure, and death. Major bleeding was defined as the need for additional interventions such as the placement of a CHEST / 132 / 2 / AUGUST, 2007
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temporary bronchus-blocker, the application of a fibrin sealant, admission to a critical care unit, or the need for treatment with blood products.36 The microbiological diagnostic workup included a search for Legionella pneumophila, Chlamydia pneumoniae, Mycoplasma pneumoniae, and respiratory viruses (ie, herpes simplex virus, cytomegalovirus, respiratory syncytial virus, and adenovirus) by polymerase chain reaction, culture, or immunofluorescence. Appropriate stains and cultures for bacteria, mycobacteria, fungi, and Pneumocystis jiroveci were performed. Positive bacterial cultures were counted as the number of colony-forming units per milliliter, and identification and susceptibility tests were performed according to standard methods. Aspergillus infection was defined by the cytologic or histopathologic demonstration of the presence of Aspergillus or the isolation of Aspergillus in a respiratory specimen in the presence of a compatible clinical and radiographic pattern. Histologic lung biopsy specimens, recovered by transbronchial biopsy, endobronchial biopsy, videoassisted thoracic surgery, and autopsy, were obtained according to the clinical setting. Cytologic analysis of BAL fluid was performed with hematoxylin-eosin staining. Cell differentiation in BAL fluid was reported as absolute numbers and as a percentage of the total cell count.
Diagnostic Criteria Patients were examined, treated, and followed up according to the usual practice of the institution. Chest radiographs were performed in all cases, and CT scans were obtained as indicated by the treating physicians. Clinical diagnoses were determined from physician notes, hospital discharge summaries, laboratory studies, radiologic examinations, and pathologic reports. Severe neutropenia was defined as an absolute neutrophil count of ⬍ 0.5 ⫻ 109 cells/L. For the clinical diagnosis of noninfectious pulmonary complications, we used the criteria outlined in the definitions given in this paragraph. Nonspecific interstitial lung disease was defined as a pattern of interstitial chronic inflammation with type II pneumocyte hyperplasia and a varying degree of fibrosis with no evidence of lung infection, and without alternative histologic diagnosis.37 Organizing pneumonia was diagnosed by the presence of patchy intraluminal organizing fibrosis in distal airspaces with mild interstitial chronic inflammation and the preservation of lung architecture.37 Bronchiolitis obliterans syndrome was defined as progressive airflow limitation due to small airway obstruction after allogeneic stem cell transplantation or lung transplantation.38 Histology was characterized by constrictive bronchiolitis obliterans.1,39 Respiratory bronchiolitis was defined as a patchy pattern of dusty brown macrophages clustering and a patchy submucosal and peribronchiolar infiltrate of lymphocytes and histiocytes.37 Diffuse alveolar hemorrhage was defined by the presence of a widespread alveolar injury seen on a thoracic CT scan (as evidenced by multilobar infiltrates) and by BAL fluid returns becoming progressively bloodier or showing ⱖ 20% iron-laden macrophages in the absence of infection.40 Diffuse alveolar damage was defined as a pattern of acute lung injury, which was characterized by an exudative phase, with cell necrosis, edema, and hyaline membrane formation, and a proliferative phase with organizing interstitial fibrosis.37,41 Invasive pulmonary aspergillosis was diagnosed in the context of compatible clinical and radiographic features according to a consensus statement.42 Pulmonary edema was defined by bibasilar rales, radiologic evidence of pulmonary edema, and the resolution of symptoms by therapy with diuretic agents. Acute bronchitis was defined by the self-limited presence of acute cough associated with bronchial system erythema in the absence of infiltrates and bacterial infection. Granuloma was 506
defined by the typical appearance of small nodules (with or without calcification) as evidenced on a chest CT scan without change over time in the absence of bacterial or mycobacterial infection.
Diagnostic Groups Proven bacterial infection was diagnosed in cases with positive bacteriology results in the BAL fluid or histologic specimens (ie, a culture yielding a single pathogenic bacterial microorganism at the minimum concentration of 103 cfu/mL or any microorganism excluding mouth flora above the minimum concentration of 104 cfu/mL5; or the identification of Legionella spp, C pneumoniae, or M pneumoniae regardless of colony counts). Possible bacterial infection was characterized as a clinically defined infection without a proven microbial pathogen (ie, new infiltrate seen on the chest radiograph accompanied by respiratory symptoms, abnormal breath sounds on auscultation, leukocytosis or leukopenia; and no identification of bacterial, viral, or fungal pathogens in the respiratory tract, cultures, specific stains, polymerase chain reaction, or immunofluorescence, as appropriate). No bacterial infection was considered to be present when an alternative cause for pulmonary symptoms and/or infiltrates was established without evidence of bacteria in microbiological studies (ie, nonspecific interstitial lung disease, organizing pneumonia, bronchiolitis obliterans, graft-vs-host disease, respiratory bronchiolitis, diffuse alveolar hemorrhage, diffuse alveolar damage, invasive pulmonary aspergillosis, pulmonary edema, acute bronchitis, granuloma, Wegener granulomatosis, malignant pulmonary involvement, or fungal or viral infections). Cases fulfilling the diagnostic criteria for proven bacterial infection were classified as such, irrespective of the presence of any alternative causes for the pulmonary symptoms.
Measurement of CRP and Procalcitonin CRP levels, procalcitonin levels, and leukocyte counts were assessed on the day of bronchoscopy. Procalcitonin was measured using 100 L of serum by an ultrasensitive chemiluminometric assay (PCT sensitive LIA; Brahms AG; Hennigsdorf, Germany).43 The assay has a lowest standard of 0.005 ng/L and a functional assay sensitivity of 0.02 g/L, which is within the normal range of healthy persons.44 CRP was measured using an enzyme immunoassay having a detection limit of ⬍ 5 mg/dL in heparin plasma (Hitachi Instrument 917; Roche Diagnostics, Rotkreuz, Switzerland) using reagents (Wako Chemicals GmbH; Neuss, Germany) [detection limit, ⬍ 5 mg/dL].
Statistical Analysis Discrete variables are expressed as the count (percentage), and continuous variables are expressed as the mean ⫾ SD, unless otherwise stated. The frequency comparison was performed with the 2 test. Two-group comparisons of normally distributed data were performed using the Student t test. For data not normally distributed, the Mann-Whitney U test was used if only two groups were compared, and the Kruskal-Wallis one-way analysis of variance was used if more than two groups were being compared. To evaluate the relationship among procalcitonin level, CRP level, and BAL neutrophil percentage and proven bacterial infection, a logistic multivariate regression model analysis was performed. We log-transformed skewed variables for the regression analysis. We constructed receiver operating characteristic (ROC) curves and determined the area under the curve (AUC) Original Research
for the ROC. Significant predictors for bacterial infection (BAL neutrophil percentage log ⫻ procalcitonin log) were combined, and the predicted probability derived from logistic regression was used to construct a ROC curve. For these binary analyses, patients classified as having proven bacterial infection were plotted against the other diagnostic groups. Correlation analyses were performed by using Spearman rank correlation. Standard definitions of sensitivity, specificity, and likelihood ratio were used. The AUC was considered to be clinically useful if it was ⱖ 0.8.45 All statistical tests were two-tailed; a p value of ⬍ .05 was considered to be significant. Data were analyzed using a statistical software package (SPSS, version 14 for Windows; SPSS Inc; Chicago, IL).
Table 1—Underlying Diagnosis of 107 Immunocompromised Patients Underlying Diagnosis
Patients, No.
Hematologic disorders High-dose chemotherapy Acute myeloid leukemia Lymphoma Chronic myeloid leukemia Chronic lymphatic leukemia Multiple myeloma Acute lymphatic leukemia Acute myeloid leukemia plus lymphoma Lymphoma plus breast cancer Lymphoma plus heart transplant Allogeneic stem cell transplantation Acute myeloid leukemia Lymphoma Renal cell carcinoma Acute lymphatic leukemia Chronic lymphatic leukemia Multiple myeloma Polycythemia vera Myelodysplastic syndrome Autologous stem cell transplantation Acute myeloid leukemia Acute lymphatic leukemia Lymphoma Others Acute myeloid leukemia Myelodysplastic syndrome Polycythemia vera Solid organ transplants Kidney Lung Heart Lung plus kidney AIDS Solid organ malignancy Autoimmune disorders Rheumatoid arthritis Cryptogenic organizing pneumonia Respiratory bronchiolitis interstitial lung disease Panarteritis nodosa Sarcoidosis Allergic bronchopulmonary aspergillosis Connective tissue disease Wegener granulomatosis Bechet disease Polymyalgia rheumatica
62 29 10 7 4 3 1 1 1 1 1 26 14 4 3 1 1 1 1 1 3 1 1 1 4 2 1 1 20 10 6 1 3 8 2 15 3 2 2 2 1 1 1 1 1 1
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Results Baseline Characteristics of Patients Underlying conditions and baseline characteristics of the 107 patients are presented in Tables 1 and 2. Most common underlying conditions were hematologic malignancies that were treated by high dose chemotherapy alone (n ⫽ 29) or combined with allogeneic stem cell transplantation (n ⫽ 26) followed by solid organ transplantation (n ⫽ 20). Overall, 20 patients (18.7%) had neutropenia at the time of bronchoscopy. The median length of hospital stay before bronchoscopy was 2 days (interquartile range [IQR], 1 to 12.5). Fever and cough were the most commonly observed symptoms. Infiltrates were documented in the majority of cases (71%). The most common immunosuppressive medications used were steroids (43.9%), cyclosporine (30.8%), and mycophenolate mofetil (28.0%). A total of 78 patients (72.8%) received therapy with antibiotics for either prophylactic or therapeutic reasons before bronchoscopy. In patients receiving a therapeutic regimen, the median duration of antibiotic therapy at the time of bronchoscopy was 1 day
Table 2—Characteristics of 107 Patients at the Time of Bronchoscopy* Patient Characteristics Age, yr Male gender Agranulocytosis Symptoms Fever Cough Dyspnea Sputum Chills Chest radiograph/CT scan Infiltrates Laboratory parameters† Leukocytes, ⫻109 g/L CRP, mg/L Procalcitonin, ng/mL Immunosuppressive therapy Steroids Cyclosporine Mycophenolate Azathioprine Sirolimus Tacrolimus Antimicrobial therapy Antibacterial Antiviral Antifungal
Patients 52 (22–84) 67 (62.6) 20 (18.7) 60 (56.1) 60 (56.1) 56 (52.2) 34 (31.8) 14 (13.1) 76 (71.0) 6.22 (2.16–10.21) 48 (8–120) 0.102 (0.046–0.504) 47 (43.9) 33 (30.8) 30 (28.0) 10 (9.3) 6 (5.6) 3 (2.8) 78 (72.9) 39 (36.5) 32 (29.9)
*Values are given as mean (range) or No. (%), unless otherwise indicated. †Values are given as the median (IQR). CHEST / 132 / 2 / AUGUST, 2007
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Table 3—Laboratory Parameters in the Different Immunocompromised Patient Subgroups* Variables Leukocytes, ⫻10 g/L CRP, mg/L Procalcitonin, ng/mL BAL neutrophils % ⫻106 /L 9
Hematologic Disorders† (n ⫽ 64)
Solid Organ Transplants (n ⫽ 20)
HIV/AIDS (n ⫽ 8)
Autoimmune Disorders (n ⫽ 15)
p Value‡
3.28 (0.82–9.80) 48 (12–127) 0.12 (0.05–0.45)
7.36 (5.55–9.51) 33 (2-116) 0.10 (0.04–1.91)
4.60 (3.24–6.31) 41 (6–108) 0.14 (0.08–0.29)
11.74 (7.02–18.20) 30 (1–74) 0.06 (0.01–0.34)
0.001 0.422 0.228
12 (6–57) 39 (8–414)
21 (1–79) 44 (1–2500)
5 (1–16) 19 (4–205)
0.119 0.016
6 (1–18) 6 (1–24)
*Values are given as the median (IQR). †Including two patients who were undergoing chemotherapy for a solid organ malignancy. ‡By Kruskal-Wallis one-way analysis of variance comparing the four diagnostic groups.
(IQR, 1 to 4 days). Fifteen patients (19.2%) were receiving piperacillin/tazobactam, 7 patients (9.0%) cefepime, 4 patients (5.1%) meropenem, 3 patients (3.8%) ceftriaxone, 3 patients (3.8%) amoxicillin/ clavulanic acid (1 of those patients was also receiving prophylactic trimethoprim/sulfamethoxazole), 3 patients (3.8%) amikacin and cefepime, 3 patients (3.8%) piperacillin/tazobactam and cefepime, 2 patients (2.6%) clarithromycin, 2 patients (2.6%) piperacillin/tazobactam and levofloxacin, 2 patients (2.6%) obracin and cefepime, 2 patients (2.6%) amoxicillin/clavulanic acid and clarithromycin (1 of those patients was also receiving prophylactic trimethoprim/sulfamethoxazole), 2 patients (2.6%) piperacillin/tazobactam, cefepime, and amikacin, 1 patient (1.3%) trimethoprim/sulfamethoxazole, 1 patient (1.3%) levofloxacin, 1 patient (1.3%) imipenem and cilastatin, 1 patient (1.3%) vancomycin and cefepime, 1 patient (1.3%) piperacillin/tazobactam and vancomycin, 1 patient (1.3%) piperacillin/ tazobactam and meropenem, 1 patient (1.3%) ceftriaxone and clarithromycin, 1 patient (1.3%) cefepime and amikacin, and 1 patient (1.3%) rifampin and isoniazid and pyrazinamide. Furthermore, 20 patients (25.6%) were receiving trimethoprim/sulfamethoxazole prophylaxis, and 1 patient (1.3%) was receiving continuous therapy with clarithromycin as an antiinflammatory drug. Table 3 presents median values for leukocyte counts, CRP level, procalcitonin level, BAL fluid neutrophil percentage, and absolute counts in the different immunocompromised patient subgroups. While the median CRP level, procalcitonin level, and BAL fluid neutrophil percentage did not significantly differ in the different subgroups of immunocompromised patients, leukocyte counts and BAL fluid neutrophil absolute counts were significantly affected by the underlying immunocompromised status. Patients who were admitted to the hospital because of respiratory symptoms and were undergoing bronchoscopy within 24 h presented with lower procalcitonin levels (0.08 ng/mL; IQR, 0.03 to 0.23 508
ng/mL) compared to those patients who had a longer duration of symptoms during the hospital stay preceding bronchoscopy (0.17 ng/mL; IQR, 0.06 to 0.61 ng/mL; p ⫽ 0.045). Microbiological data for BAL fluid are presented in Table 4. Overall, 38 patients (35.5%) had a microbiological study result that was positive for bacteria, viruses, and/or fungi. The most common bacterial pathogens were Streptococcus pneumoniae, Pseudomonas aeruginosa, L pneumophila, and Enterococci. In addition to BAL fluid specimens, transbronchial biopsy specimens were obtained in 15 cases (14.0%) and endobronchial biopsy specimens in 3
Table 4 —Documentation of Bacteria, Viruses, and Fungi in the BAL Fluid of 107 Immunocompromised Patients Microorganisms
No.
Bacteria S pneumoniae S pneumoniae ⫹ Staphylococcus aureus ⫹ CMV S pneumoniae ⫹ Escherichia coli S pneumoniae ⫹ P jiroveci ⫹ CMV P aeruginosa P aeruginosa ⫹ CMV ⫹ HSV P aeruginosa ⫹ HSV L pneumophila S aureus Staphylococcus coag. negative ⫹ RSV Enterocci spp Enterocci spp ⫹ Klebsiella pneumoniae Enterobacter cloacae ⫹ HSV Haemophilus influenzae ⫹ CMV H influenzae ⫹ Mycobacterium xenopi Moraxella catarrhalis ⫹ RSV Others CMV CMV ⫹ P jiroveci HSV Mycobacterium tuberculosis Aspergillus fumigatus Zygomycetes
27 4 1 1 1 2 1 1 4 3 1 3 1 1 1 1 1 11 3 2 1 2 2 1
*CMV ⫽ cytomegalovirus; HSV ⫽ herpes simplex virus; RSV ⫽ respiratory syncytial virus. Original Research
Table 5—Distribution of Diagnostic Groups Among the Different Immunocompromised Patient Subgroups* Conditions
Proven Bacterial (n ⫽ 27)
Possible Bacterial (n ⫽ 11)
Nonbacterial (n ⫽ 69)
All† (n ⫽ 107)
Hematologic disorders‡ Solid organ transplants AIDS Autoimmune disorders
15 (23) 8 (40) 3 (37) 1 (7)
5 (8) 2 (10) 1 (13) 3 (20)
44 (69) 10 (50) 4 (50) 11 (73)
64 20 8 15
*Values are given as No. (%). †p ⫽ 0.285 comparing the three diagnostic groups. ‡Including two patients undergoing chemotherapy for solid-organ malignancy.
cases (2.8%). There were no major complications during bronchoscopy. Histologic pulmonary specimens obtained by video-assisted thoracic surgery were available in seven cases (6.5%). The in-hospital mortality rate was 5.6% (six cases). Autopsy results were available in four of these six cases. Distribution of Diagnostic Groups Proven bacterial infection was diagnosed in 27 patients (25%). In four patients (15%), the diagnosis was based on a polymerase chain reaction finding that was positive for L pneumophila, and in three patients (11%) bacterial growth in the BAL fluid was ⬎ 103 cfu/mL but ⬍ 104 cfu/mL (P aeruginosa, S pneumoniae, and Enterocci spp in one patient each). In one patient (4%), a negative finding for Staphylococcus coagulase. was found both in a BAL fluid specimen (⬎ 100,000 cfu/mL) and in blood culture. Gram stains on BAL fluid specimens failed to show evidence of bacteria in culture from 9 of 27 patients with proven bacterial infection. Eleven patients (11%) were classified as having possible bacterial infection, and a nonbacterial condition was identified in 69 patients (65%). The distribution of cases classified as proven, possible, and no bacterial infection within the different subgroups of immunocompromised patients is shown in Table 5. Among the 20 neutropenic patients, 4 (20%) had proven bacterial infection, 1 (5%) had possible bacterial infection, and 15 (75%) had no bacterial infection. Table 6 presents the final pulmonary diagnosis of the 69 patients considered to have a nonbacterial condition. The clinical parameters were similar in patients with and without bacterial infection (Table 7). Infiltrates were present significantly more often in patients with proven bacterial infection (89%) or possible bacterial infection (82%), compared to nonbacterial conditions (62%; p ⫽ 0.04). Table 8 presents leukocyte counts, CRP levels, procalcitonin levels, and BAL fluid neutrophil counts (absolute and percentage) in patients with proven bacterial infection, possible bacterial infection, and www.chestjournal.org
no bacterial infection. While there was a statistically significant difference among the three diagnostic groups, laboratory parameters and neutrophil counts in the BAL fluid were not significantly different in cases of proven and possible bacterial infection (difference not significant [determined by MannWhitney U test]). CRP and procalcitonin levels were similar in patients with proven or suspected (probable and possible) invasive pulmonary aspergillosis and in those patients in whom other nonbacterial conditions were identified (p ⫽ 0.221 and p ⫽ 0.162, respectively). There was no difference in CRP level, procalcitonin level, BAL fluid neutrophil percentage and absolute counts in patients with and without neutropenia and proven bacterial infection (difference not significant
Table 6 —Final Pulmonary Diagnosis of the 69 Patients Considered To Have a Nonbacterial Condition Causing Pulmonary Signs and Symptoms* Nonbacterial Conditions
Patients, No.
Nonspecific interstitial pneumonitis Organizing pneumonia Graft-vs-host disease Bronchiolitis obliterans Bronchiolitis obliterans ⫹ CMV infection Respiratory bronchiolitis Diffuse alveolar hemorrhage Diffuse alveolar damage Diffuse alveolar damage ⫹ possible IPA Diffuse alveolar damage ⫹ CMV infection Wegener granulomatosis Allergic bronchopulmonary aspergillosis Pulmonary lymphoma involvement Pulmonary edema IPA† Acute bronchitis P jiroveci ⫹ CMV infection Herpes simplex pneumonia Cytomegalovirus pneumonia M tuberculosis Granuloma
9 4 4 6 1 3 3 2 1 1 1 1 2 4 10 6 2 1 1 2 5
*IPA ⫽ invasive pulmonary aspergillosis. See Table 4 for abbreviation not used in the text. †Proven, one case; possible or probable, nine cases. CHEST / 132 / 2 / AUGUST, 2007
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Table 7—Signs, Symptoms, and Radiologic Findings in 107 Immunocompromised Patients, According to Diagnostic Group Classification* Variables
Proven Bacterial (%) (n ⫽ 27)
Possible Bacterial (n ⫽ 11)
Nonbacterial (n ⫽ 69)
All (n ⫽ 107)
p Value†
Cough Dyspnea Sputum Fever Infiltrates
16 (59) 13 (48) 9 (33) 19 (70) 24 (89)
9 (82) 7 (64) 4 (36) 8 (72) 9 (82)
35 (51) 36 (52) 21 (30) 33 (48) 43 (62)
60 (56) 56 (52) 34 (32) 60 (56) 76 (71)
0.144 0.686 0.907 0.068 0.040
*Values are given as No. (%), unless otherwise indicated. †Comparison of the three diagnostic groups by 2 test.
for all). Steroids and cyclosporin intake did not significantly affect BAL fluid neutrophil results. The median BAL fluid neutrophil count was 8% (IQR, 2 to 22.5%) in patients not receiving steroids compared to 10.5% (IQR, 4 to 27.5%) in patients receiving therapy with steroids (p ⫽ 0.414). Similarly, the median BAL neutrophil count was 10% (IQR, 3 to 37.5%) in patients not receiving therapy with cyclosporin compared to 8% (IQR, 2 to 22%) in patients receiving therapy with cyclosporin (p ⫽ 0.212). Similarly, median procalcitonin levels were not influenced by the following immunosuppressive drugs: steroids (n ⫽ 47; p ⫽ 0.673); cyclosporin (n ⫽ 33; p ⫽ 0.881); mycophenolate (n ⫽ 30 p ⫽ 0.603); azathioprine (n ⫽ 10; p ⫽ 0.996); sirolimus (n ⫽ 6; p ⫽ 0.096); and tacrolimus (n ⫽ 3.0; p ⫽ 0.166). There was a moderate correlation between procalcitonin and CRP levels (Spearman rho ⫽ 0.595; p ⬍ 0.001) and a poor negative correlation between procalcitonin levels and leukocyte counts (Spearman rho ⫽ ⫺0.213; p ⫽ 0.031). There was no correlation between procalcitonin levels and BAL neutrophil counts, both absolute and as a percentage (p ⫽ 0.204 and p ⫽ 0.171, respectively). Diagnostic Accuracy of Clinical and Laboratory Parameters To analyze the diagnostic accuracy of clinical and laboratory parameters to predict bacterial infection,
a ROC analysis was performed (Fig 1). The percentage of neutrophils in BAL fluid had the highest AUC (0.818; 95% confidence interval [CI], 0.700 to 0.935; p ⬍ 0.001), followed by absolute neutrophil counts (AUC, 0.797; 95% CI, 0.678 to 0.916; p ⬍ 0.001), procalcitonin level (AUC, 0.746; 95% CI, 0.602 to 0.889; p ⫽ 0.001), and CRP level (AUC, 0.688; 95% CI, 0.555 to 0.821; p ⫽ 0.015). The AUC was not statistically significant for infiltrates (AUC, 0.619; 95% CI, 0.484 to 0.754; p ⫽ 0.123) and leukocyte counts (AUC, 0.561; 95% CI, 0.403 to 0.719; p ⫽ 0.429). Compared to BAL fluid neutrophil percentage alone, the AUC for the combination of BAL fluid neutrophil percentage and either CRP level (AUC, 0.844; 95% CI, 0.737 to 0.951; p ⬍ 0.001) or procalcitonin level (AUC, 0.872; 95% CI, 0.778 to 0.965; p ⬍ 0.001) increased the AUC for the diagnosis of bacterial infection (Fig 2). However, this difference did not reach statistical significance for either situation (p ⫽ 0.078 and p ⫽ 0.118, respectively). The combination of BAL fluid neutrophil percentage with both CRP and procalcitonin levels did not further improve the AUC of the model. In a multivariate logistic regression model, the log-transformed percentage of neutrophils in BAL fluid (p ⫽ 0.001; odds ratio [OR], 2.508; 95% CI, 1.424 to 4.420) and the log-transformed procalcitonin level (p ⫽ 0.038; OR, 1.557; 95% CI, 1.025 to 2.364) proved to be independent factors predicting
Table 8 —Laboratory Parameters in the 107 Immunocompromised Patients, According to the Diagnostic Group Classification* Variables Leukocytes, ⫻10 g/L CRP mg/L Procalcitonin, ng/mL BAL neutrophils % ⫻106 cells/L 9
Proven Bacterial (n ⫽ 27)
Possible Bacterial (n ⫽ 11)
Nonbacterial (n ⫽ 69)
All (n ⫽ 107)
p Value†
8.22 (2.82–13.23) 109 (24–230) 0.66 (0.07–12.28)
10.21 (7.43–15.34) 108 (42–238) 0.32 (0.09–1.58)
5.50 (2.19–8.35) 17 (2–62) 0.08 (0.02–0.22)
6.22 (2.16–10.21) 48 (8–120) 0.10 (0.05–0.50)
0.048 ⬍ 0.001 0.001
8 (2–15) 10 (32–28)
9 (2–25) 11 (3–44)
59 (22–79) 150 (23–456)
10 (4–32) 5 (3–70)
0.001 0.004
*Values are given as the median (IQR), unless otherwise indicated. †By Kruskal-Wallis one-way analysis of variance comparing the three diagnostic groups. 510
Original Research
C-reactive protein BAL neutrophils (%) BAL neutrophils absolute Leukocytes counts Procalcitonin Infiltrates
Figure 1. ROC analysis for CRP level (AUC, 0.688; 95% CI, 0.555 to 0.821; p ⫽ 0.015), BAL fluid neutrophil counts by percentage (AUC, 0.818; 95% CI, 0.700 to 0.935; p ⬍ 0.001) and absolute numbers (AUC, 0.797; 95% CI, 0.678 to 0.916; p ⬍ 0.001), leukocyte count (AUC, 0.561, 95% CI, 0.403 to 0.719; p ⫽ 0.429), procalcitonin level (AUC, 0.746; 95% CI, 0.602 to 0.889; p ⫽ 0.001), and infiltrates (AUC, 0.619; 95% CI, 0.484 to 0.754; p ⫽ 0.123).
bacterial infection. We found no significance for log-transformed CRP level (p ⫽ 0.455; OR, 1.191; 95% CI, 0.752 to 1.887). Sensitivity, specificity, and positive and negative likelihood ratio point estimates for CRP level, procalcitonin level, and BAL fluid neutrophil percentage are presented in Table 9. At the threshold value of 20 mg/L, CRP level had a sensitivity of 84% and a specificity of 48%. Procalcitonin level had the highest specificity (84%) at the threshold value of 0.5 ng/mL. BAL fluid neutrophil percentage had the highest overall performance at the threshold of 15% (sensitivity, 84%; specificity, 77%). Discussion In this study, we found that clinical parameters were not useful for the differential diagnosis of
pulmonary complications in immunocompromised patients. In contrast, neutrophilia in the BAL fluid as well as increased serum levels of CRP and procalcitonin were significantly associated with bacterial pulmonary infection. The percentage of neutrophils in BAL fluid showed the best diagnostic accuracy for predicting bacterial infection in the ROC curve analysis, followed by procalcitonin level and CRP level. While the combination of BAL fluid neutrophil percentage and the level of either biomarker increased the AUC of the model, this improvement failed to reach statistical significance when compared to the use of BAL fluid neutrophil percentage alone. This suggests that the evaluation of BAL fluid still represent the best diagnostic modality in immunocompromised patients with pulmonary complications. However, if there are contraindications to performing BAL or bronchoscopy, and its results are not available within a reasonable time frame, the determination of the CRP or procalcitonin level might represent a feasible approach for gathering evidence of bacterial infection. Furthermore, as procalcitonin level proved to be an independent predictor of bacterial infection in a multivariate regression analysis, the combination of BAL fluid neutrophil percentage and procalcitonin level, including a costbenefit analysis, might warrant evaluation in future studies. Pulmonary bacterial infections in immunocompromised patients are a challenge to physicians as both clinical signs and radiologic appearance are nonspecific.46 BAL has been established as a reliable technique for the diagnosis of pulmonary infection in the immunocompromised host, specifically for detecting opportunistic infectious such as P jiroveci and also bacteria.14,15,47 Previous reports5,18,48 –50 have suggested that BAL might be capable of identifying bacterial pathogens in immunocompromised patients despite antibiotic therapy due to the high
Table 9 —Point Estimates for CRP, Procalcitonin, and BAL Fluid Neutrophil Counts To Diagnose Bacterial Infection* Variables CRP, mg/L 20 50 100 Procalcitonin, ng/mL 0.1 0.2 0.5 BAL fluid neutrophils, % 10 15 20
Sensitivity
Specificity
LHR⫹
LHR⫺
84% (70–94) 58% (43–74) 53% (37–66)
48% (42–50) 61% (56–66) 77% (72–82)
1.62 (1.21–1.89) 1.47 (0.98–2.18) 2.28 (1.32–3.77)
0.33 (0.12–0.71) 0.69 (0.40–1.02) 0.62 (0.41–0.88)
74% (58–86) 68% (51–80) 58% (44–71)
62% (57–67) 71% (66–77) 84% (79–88)
1.96 (1.35–2.57) 2.32 (1.48–3.29) 3.53 (2.05–6.13)
0.42 (0.21–0.74) 0.45 (0.27–0.75) 0.50 (0.31–0.71)
84% (70–94) 84% (70–94) 79% (64–88)
59% (54–62) 77% (72–80) 82% (77–86)
2.10 (1.51–2.45) 3.66 (2.56–4.78) 4.38 (2.77–6.35)
0.27 (0.10–0.56) 0.21 (0.07–0.41) 0.26 (0.14–0.48)
*Values are given as % (95% CI). LHR⫹ ⫽ positive likelihood ratio; LHR⫺ ⫽ negative likelihood ratio. www.chestjournal.org
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bacterial load in lower respiratory tract secretions or to the higher incidence of infection with virulent organisms that respond slowly to antimicrobial therapy. However, empiric antimicrobial therapy has been shown to impair the diagnostic yield of bronchoscopy in HIV-infected patients and in those with nosocomial infections.51,52 Alternatively, BAL fluid cytology has proved to be useful in the diagnosis of infectious pulmonary infiltrates in immunocompromised adults and children.20,46 Thereby, significantly higher total neutrophil cell counts and percentages were found in the group of patients in whom bacterial organisms were detected in BAL fluid, compared with the group of patients in whom no bacterial agent was detected.46 In accordance with previous studies,53–55 we found BAL fluid neutrophilia to be present in neutropenic patients, suggesting that even patients who are undergoing high-dose chemotherapy and stem cell transplantation with neutropenia can generate a local immune reaction in response to infectious agents. In the current study, neutrophilia in the BAL fluid at a threshold of 15% had a sensitivity of 84% and a specificity of 77% to predict bacterial infection. These data indicate that the differential cell count in BAL fluid may be of value in the differential diagnosis of pulmonary complications in immunocompromised hosts. The use of inflammatory biomarkers for the early detection of bacterial infection might be a useful approach for distinguishing febrile episodes and for guiding the choice of specific antibiotic therapies, even before culture results are available.23 The present findings illustrate that CRP and procalcitonin serum levels are significantly higher in patients with proven and possible bacterial infection, compared to those patients with a nonbacterial condition. Thus, circulating biomarkers might give evidence of bacterial infection even in those cases in which microbiology results turned negative due to antimicrobial therapy. Interestingly, the combination of BAL fluid neutrophils with serum biomarkers tended to improve the diagnostic accuracy of the ROC model, indicating that both parameters might have additive value. This is particularly important in the setting of immunocompromised patients due to the high morbidity and mortality if the infection is treated inappropriately or recognized too late. The fundamental goal of diagnostic bronchoscopy is to establish a specific diagnosis that will allow more targeted therapy and improve survival. While noninfectious pulmonary complications tend to be less common than infectious complications, fewer than half of potentially treatable, nonbacterial pulmonary infections have been reported to be diagnosed prior to death.56,57 The poor outcome of pulmonary complications in immunocompromised patients is 512
Figure 2. ROC analysis for a model combining BAL fluid neutrophil counts in percentages combined with CRP level (AUC, 0.844; 95% CI, 0.737 to 0.9551; p ⬍ 0.001) or procalcitonin level (AUC, 0.872; 95% CI, 0.778 to 0.965; p ⬍ 0.001).
claimed to be associated with the delay in the administration of specific drugs in the evolution of the illness.5 Hence, it is tempting to speculate that a diagnostic approach that rules out bacterial infection (eg, the determination of serum biomarkers) could also lead to an earlier diagnostic workup targeting noninfectious etiologies and, thus, to a better outcome. Several limitations of our study should also be noted. First, we have included a heterogeneous population of immunocompromised patients. While this diversity is routine for the pulmonary consultant in a tertiary care setting, we might have missed findings peculiar to a particular subpopulation of patients. Second, the majority of our study population was composed of patients with hematologic malignancies being treated with high-dose chemotherapy and/or allogeneic stem cell transplantation. This might explain the relatively high incidence of noninfectious pulmonary complications found in our cohort. It would be of additional clinical and scientific interest to evaluate the combination of BAL neutrophil counts with procalcitonin or CRP levels in larger subgroups of immunocompromised patients with a higher incidence of infectious complications, such as lung, kidney, heart, and liver transplant recipients. Third, we have included in the study only hospitalized patients who were treated in the medical ward. Because of the exclusion of critically ill patients requiring mechanical ventilation, mortality rates in our study were lower than those in previous reports. Fourth, we have evaluated clinical and laboratory parameters in regard to their diagnostic value on the day of bronchoscopy (not at the initiation of the symptoms), and the kinetics of both biomarkers have not been analyzed. Finally, we Original Research
cannot exclude the possibility that previous antibiotic therapy might have decreased the microbiological yield of BAL fluid specimens. However, 96% of patients (26 of 27 patients) with proven bacterial infection were receiving therapy with antibiotics at the time of bronchoscopy, and most patients were started on therapy with antibiotics within 24 h of undergoing bronchoscopy. Thus, due to the high bacterial load and slower antibiotic response observed in immunocompromised patients,5,18,48 –50 we believe that previous antibiotic therapy did not considerably influence the microbiological yield of BAL fluid specimens in our study. In summary, our findings indicate that BAL fluid neutrophil percentage alone or in combination with serum levels of procalcitonin or CRP at the time of bronchoscopy may potentially be used to guide diagnostic and therapeutic decisions in immunocompromised hosts with pulmonary complications.
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infectious complications part 2. Respiration 1999; 66:199 –207 14 Joos L, Chhajed PN, Wallner J, et al. Pulmonary infections diagnosed by BAL: a 12-year experience in 1066 immunocompromised patients. Respir Med 2006 15 Stover DE, Zaman MB, Hajdu SI, et al. Bronchoalveolar lavage in the diagnosis of diffuse pulmonary infiltrates in the immunosuppressed host. Ann Intern Med 1984; 101:1–7 16 Bodey GP, Rolston KV. Management of fever in neutropenic patients. J Infect Chemother 2001; 7:1–9 17 Pizzo PA. Fever in immunocompromised patients. N Engl J Med 1999; 341:893–900 18 Dunagan DP, Baker AM, Hurd DD, et al. Bronchoscopic evaluation of pulmonary infiltrates following bone marrow transplantation. Chest 1997; 111:135–141 19 White P, Bonacum JT, Miller CB. Utility of fiberoptic bronchoscopy in bone marrow transplant patients. Bone Marrow Transplant 1997; 20:681– 687 20 Sternberg RI, Baughman RP, Dohn MN, et al. Utility of bronchoalveolar lavage in assessing pneumonia in immunosuppressed renal transplant recipients. Am J Med 1993; 95:358 –364 21 Ortega M, Rovira M, Almela M, et al. Measurement of C-reactive protein in adults with febrile neutropenia after hematopoietic cell transplantation. Bone Marrow Transplant 2004; 33:741–744 22 Ortega M, Rovira M, Filella X, et al. Prospective evaluation of procalcitonin in adults with febrile neutropenia after haematopoietic stem cell transplantation. Br J Haematol 2004; 126:372–376 23 Persson L, Engervall P, Magnuson A, et al. Use of inflammatory markers for early detection of bacteraemia in patients with febrile neutropenia. Scand J Infect Dis 2004; 36:365–371 24 Bernard L, Ferriere F, Casassus P, et al. Procalcitonin as an early marker of bacterial infection in severely neutropenic febrile adults. Clin Infect Dis 1998; 27:914 –915 25 Engel A, Mack E, Kern P, et al. An analysis of interleukin-8, interleukin-6 and C-reactive protein serum concentrations to predict fever, Gram-negative bacteremia and complicated infection in neutropenic cancer patients. Infection 1998; 26:213–221 26 Svaldi M, Hirber J, Lanthaler AI, et al. Procalcitonin-reduced sensitivity and specificity in heavily leucopenic and immunosuppressed patients. Br J Haematol 2001; 115:53–57 27 Stolz D, Christ-Crain M, Bingisser R, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest 2007; 131:9 –19 28 Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med 2006; 174:84 –93 29 Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet 2004; 363:600 – 607 30 von Lilienfeld-Toal M, Schneider A, Orlopp K, et al. Change of procalcitonin predicts clinical outcome of febrile episodes in patients with hematological malignancies. Support Care Cancer 2006; 14:1241–1245 31 Stolz D, Chhajed PN, Leuppi J, et al. Nebulized lidocaine for flexible bronchoscopy: a randomized, double-blind, placebocontrolled trial. Chest 2005; 128:1756 –1760 32 Stolz D, Chhajed PN, Leuppi JD, et al. Cough suppression during flexible bronchoscopy using combined sedation with midazolam and hydrocodone: a randomised, double blind, placebo controlled trial. Thorax 2004; 59:773–776 CHEST / 132 / 2 / AUGUST, 2007
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33 British Thoracic Society Guidelines Committee. British Thoracic Society guidelines on diagnostic flexible bronchoscopy. Thorax 2001; 56(suppl):i1–21 34 European Society of Pneumology. Clinical guidelines and indications for bronchoalveolar lavage (BAL): report of the European Society of Pneumology Task Group on BAL. Eur Respir J 1990; 3:937–976 35 Tamm M, Traenkle P, Grilli B, et al. Pulmonary cytomegalovirus infection in immunocompromised patients. Chest 2001; 119:838 – 843 36 Herth FJ, Becker HD, Ernst A. Aspirin does not increase bleeding complications after transbronchial biopsy. Chest 2002; 122:1461–1464 37 American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias: this joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002; 165:277–304 38 Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002; 21:297–310 39 Afessa B, Litzow MR, Tefferi A. Bronchiolitis obliterans and other late onset non-infectious pulmonary complications in hematopoietic stem cell transplantation. Bone Marrow Transplant 2001; 28:425– 434 40 Afessa B, Tefferi A, Litzow MR, et al. Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 2002; 166:641– 645 41 Katzenstein AL, Bloor CM, Leibow AA. Diffuse alveolar damage: the role of oxygen, shock, and related factors; a review. Am J Pathol 1976; 85:209 –228 42 Ascioglu S, Rex JH, de Pauw B, et al. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 2002; 34:7–14 43 Linscheid P, Seboek D, Schaer DJ, et al. Expression and secretion of procalcitonin and calcitonin gene-related peptide by adherent monocytes and by macrophage-activated adipocytes. Crit Care Med 2004; 32:1715–1721 44 Nylen ES, Muller B, Becker KL, et al. The future diagnostic role of procalcitonin levels: the need for improved sensitivity. Clin Infect Dis 2003; 36:823– 824
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45 Metz CE. Basic principles of ROC analysis. Semin Nucl Med 1978; 8:283–298 46 Ratjen F, Costabel U, Havers W. Differential cytology of bronchoalveolar lavage fluid in immunosuppressed children with pulmonary infiltrates. Arch Dis Child 1996; 74:507–511 47 Xaubet A, Torres A, Marco F, et al. Pulmonary infiltrates in immunocompromised patients: diagnostic value of telescoping plugged catheter and bronchoalveolar lavage. Chest 1989; 95:130 –135 48 Kahn FW, Jones JM. Diagnosing bacterial respiratory infection by bronchoalveolar lavage. J Infect Dis 1987; 155:862– 869 49 von Eiff M, Zuhlsdorf M, Roos N, et al. Pulmonary infiltrates in patients with haematologic malignancies: clinical usefulness of non-invasive bronchoscopic procedures. Eur J Haematol 1995; 54:157–162 50 Eriksson BM, Dahl H, Wang FZ, et al. Diagnosis of pulmonary infections in immunocompromised patients by fiberoptic bronchoscopy with bronchoalveolar lavage and serology. Scand J Infect Dis 1996; 28:479 – 485 51 Gracia JD, Miravitlles M, Mayordomo C, et al. Empiric treatments impair the diagnostic yield of BAL in HIV-positive patients. Chest 1997; 111:1180 –1186 52 Souweine B, Veber B, Bedos JP, et al. Diagnostic accuracy of protected specimen brush and bronchoalveolar lavage in nosocomial pneumonia: impact of previous antimicrobial treatments. Crit Care Med 1998; 26:236 –244 53 Cordonnier C, Escudier E, Verra F, et al. Bronchoalveolar lavage during neutropenic episodes: diagnostic yield and cellular pattern. Eur Respir J 1994; 7:114 –120 54 Milburn HJ, Du Bois RM, Prentice HG, et al. Pneumonitis in bone marrow transplant recipients results from a local immune response. Clin Exp Immunol 1990; 81:232–237 55 Leskinen R, Taskinen E, Volin L, et al. Use of bronchoalveolar lavage cytology and determination of protein contents in pulmonary complications of bone marrow transplant recipients. Bone Marrow Transplant 1990; 5:241–245 56 Yokoi T, Hirabayashi N, Ito M, et al. Broncho-bronchiolitis obliterans as a complication of bone marrow transplantation: a clinicopathological study of eight autopsy cases: Nagoya BMT Group. Virchows Arch 1997; 431:275–282 57 Sharma S, Nadrous HF, Peters SG, et al. Pulmonary complications in adult blood and marrow transplant recipients: autopsy findings. Chest 2005; 128:1385–1392
Original Research
Original Research CHEST INFECTIONS
BAL Neutrophils, Serum Procalcitonin, and C-Reactive Protein To Predict Bacterial Infection in the Immunocompromised Host* Daiana Stolz, MD; Andreas Stulz; Beat Mu¨ller, MD; Alois Gratwohl, MD; and Michael Tamm, MD
Background: Bacterial pulmonary infection is a common life-threatening complication in immunocompromised patients. The results of BAL cultures are not immediately available, and their microbiological yield might be limited by empiric antibiotic prescriptions. We evaluated clinical signs and symptoms, leukocyte counts, C-reactive protein (CRP) levels, procalcitonin levels, and BAL fluid neutrophil percentages as potential markers for bacterial infection in a cohort of immunocompromised patients with pulmonary complications. Methods: One hundred seven consecutive patients who had been referred for bronchoscopy due to suspected pulmonary infection were included in this study. Based on clinical, laboratory, radiologic, microbiological, and histologic results, patients were classified as having proven bacterial infection (n ⴝ 27), possible bacterial infection (n ⴝ 11), and no bacterial infection (n ⴝ 69). Results: Most common underlying conditions were hematologic malignancy (n ⴝ 62) and solid organ transplantation (n ⴝ 20). Clinical parameters were similar in patients with and without bacterial infection (difference was not significant). The percentage of BAL fluid neutrophils had the highest area under the curve (0.818; 95% confidence interval [CI], 0.700 to 0.935; p < 0.001), followed by absolute neutrophil counts (0.797; 95% CI, 0.678 to 0.916; p < 0.001), procalcitonin level (0.746; 95% CI, 0.602 to 0.889; p ⴝ 0.001), and CRP level (0.688; 95% CI, 0.555 to 0.821; p ⴝ 0.015) to predict proven bacterial infection (in opposition to no or possible bacterial infection) in the receiver operating characteristic analysis. Conversely, neither infiltrates (p ⴝ 0.123) nor leukocyte counts (p ⴝ 0.429) were useful in diagnosing bacterial infection. The percentage of BAL fluid neutrophils and procalcitonin level were independent predictors of bacterial infection in the multivariate regression. Conclusions: Neutrophil percentage in BAL fluid, procalcitonin level, and CRP level might be potentially useful to differentiate bacterial infection from nonbacterial conditions in immunocompromised hosts with pulmonary complications. (CHEST 2007; 132:504 –514) Key words: biomarker; immunosuppression; stem cell transplantation Abbreviations: AUC ⫽ area under the curve; CI ⫽ confidence interval; IQR ⫽ interquartile range; OR ⫽ odds ratio; ROC ⫽ receiver operating characteristic
complications are a major cause of P ulmonary morbidity and mortality among immunocompromised patients.1–7 It has been suggested8,9 that clinical or radiologic pulmonary abnormalities warranting therapeutic consideration will develop in 30 to 60% of all immunocompromised patients. The accurate diagnosis of the underlying pulmonary disorder is pivotal as it influences medical therapy and out504
CRP ⫽ C-reactive
protein;
come.5,7,10 Although the lung is the organ that is most commonly affected by noninfectious abnormalities,11 the identification and severity assessment of bacterial infection is of particular interest, as it represents a major cause of mortality.12,13 Diagnostic bronchoscopy is routinely performed in immunocompromised patients.5,7,14,15 Because of the perceived severity of the baseline condition and Original Research
the worsened prognosis associated with a delay in antibiotic therapy, direct respiratory tract sampling usually occurs after antibiotic therapy has been instituted.16,17 The microbiological yield of BAL fluid cultures is therefore expected to be compromised, ranging widely from 15 to 93%.10,14,18,19 Differential cell counts of BAL fluid may serve as a complementary examination to microbiological studies. Herein, higher neutrophil counts have been reported in immunocompromised patients with bacterial pneumonia compared to those patients with no detectable pathogens.20 Circulating proinflammatory mediators such as C-reactive protein (CRP) and, more recently, procalcitonin, have been suggested to be predictive for invasive bacterial infection in the immunocompromised host.21–23 Some studies,24,25 but not all,26 investigating immunocompromised patients have shown that these patients are capable of producing high serum concentrations of both mediators during severe systemic bacterial infection. While there have been no interventional studies using CRP, procalcitonin was shown to safely support the decision to start antibiotic therapy in respiratory infections in nonimmunocompromised patients.27–29 However, in the immunocompromised host, it is thought that there is no sufficient evidence to base a therapeutic decision on.30 We hypothesize that BAL fluid neutrophils and serum biomarkers (CRP and procalcitonin) might be more useful than routinely used signs and symptoms for the diagnosis of bacterial infection in the immunocompromised host. Therefore, we performed a prospective, explorative, observational study to evaluate the diagnostic accuracy of clinical signs and symptoms, leukocyte counts, CRP levels, procalcitonin levels, and neutrophil percentages in BAL fluid *From the Clinics of Pneumology and Pulmonary Cell Research (Drs. Stolz, Stulz, and Tamm), Endocrinology, Diabetes, and Clinical Nutrition (Dr. Mu¨ller), and Hematology (Dr. Gratwohl), University Hospital Basel, Basel, Switzerland. The study was presented in part at the 16th Annual Congress of European Respiratory Society, Munich, 2006 and was honored with the Research Excellence Award in Respiratory Infections. Drs. Stolz and Mu¨ller have received payments from BRAHMS (the manufacturer of procalcitonin assays) to attend advisory board meetings and speaker engagements, or for research. Drs. Stulz, Gratwohl, and Tamm have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Manuscript received January 19, 2007; revision accepted April 18, 2007. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Daiana Stolz, MD, Assistant Professor, University of Massachusetts Medical School, 55 Lake Ave North, Worcester, MA 01655; e-mail: [email protected] DOI: 10.1378/chest.07-0175 www.chestjournal.org
as potential markers for bacterial infection in a cohort of immunocompromised patients with pulmonary complications.
Materials and Methods Patients This study was approved by the institutional review board and performed at the University Hospital Basel, a 784-bed tertiary care hospital located in Basel, Switzerland. One hundred seven consecutive hospitalized immunocompromised patients who were referred to the pulmonary division for diagnostic bronchoscopy within a period of 8 months in 2005 were included in this prospective cohort study. Eligibility criteria included the following: (1) immunocompromised state; (2) age ⬎ 18 years; (3) a decision by the pulmonary consultant to perform bronchoscopy due to suspected pulmonary infection; and (4) informed consent by the patient to undergo flexible bronchoscopy and related data analysis. Suspected pulmonary infection was defined by the presence of respiratory symptoms (eg, cough, sputum, and dyspnea), fever, and/or new or progressive radiologic findings, as judged by the attending physician. Immunocompromised state was defined by the following conditions: hematologic or other malignancy treated by high-dose chemotherapy and/or stem cell transplantation; solid organ transplantation; AIDS; long-term corticosteroid therapy (ie, ⱖ 20 mg/d prednisone equivalent for ⱖ 2 months); and current use of immunosuppressive or cytotoxic medication for indications other than organ or stem cell transplantation. Data Collection Data collection including demographics, underlying diseases, immunosuppressive drugs, antimicrobial treatment for suspected or documented infection, laboratory findings, and radiologic results were recorded at the time of bronchoscopy using a standardized study form. The collected data also included information related to bronchoscopy. Further data on final diagnosis, clinical outcome, and, if applicable, cause of death including autopsy results were collected after hospital discharge. A review of medical records was performed by two independent, boardcertified pulmonary specialists. Discrepancies were settled by consensus. Bronchoscopy Flexible bronchoscopy was performed with the patient under conscious sedation using hydrocodone and midazolam according to the British Thoracic Society guidelines.31–33 BAL was performed by the three installations of 50 mL each of a pyrogen-free, sterile, 0.9% NaCL solution over the working channel of the bronchoscope according to standard guidelines and as described earlier.14,34,35 In patients with diffuse pulmonary infiltrates, BAL was performed either in the right middle lobe or the lingula. For patients with focal lung infiltrates, BAL was performed in the pulmonary segment corresponding to the radiologic abnormality. BAL fluid was recovered by suction. Besides BAL, the choice of further sampling techniques used during bronchoscopy was at the pulmonologist’s discretion. Major complications were defined as major bleeding, worsening hypoxemia requiring endotracheal intubation, any adverse event requiring early discontinuation of the procedure, and death. Major bleeding was defined as the need for additional interventions such as the placement of a CHEST / 132 / 2 / AUGUST, 2007
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temporary bronchus-blocker, the application of a fibrin sealant, admission to a critical care unit, or the need for treatment with blood products.36 The microbiological diagnostic workup included a search for Legionella pneumophila, Chlamydia pneumoniae, Mycoplasma pneumoniae, and respiratory viruses (ie, herpes simplex virus, cytomegalovirus, respiratory syncytial virus, and adenovirus) by polymerase chain reaction, culture, or immunofluorescence. Appropriate stains and cultures for bacteria, mycobacteria, fungi, and Pneumocystis jiroveci were performed. Positive bacterial cultures were counted as the number of colony-forming units per milliliter, and identification and susceptibility tests were performed according to standard methods. Aspergillus infection was defined by the cytologic or histopathologic demonstration of the presence of Aspergillus or the isolation of Aspergillus in a respiratory specimen in the presence of a compatible clinical and radiographic pattern. Histologic lung biopsy specimens, recovered by transbronchial biopsy, endobronchial biopsy, videoassisted thoracic surgery, and autopsy, were obtained according to the clinical setting. Cytologic analysis of BAL fluid was performed with hematoxylin-eosin staining. Cell differentiation in BAL fluid was reported as absolute numbers and as a percentage of the total cell count.
Diagnostic Criteria Patients were examined, treated, and followed up according to the usual practice of the institution. Chest radiographs were performed in all cases, and CT scans were obtained as indicated by the treating physicians. Clinical diagnoses were determined from physician notes, hospital discharge summaries, laboratory studies, radiologic examinations, and pathologic reports. Severe neutropenia was defined as an absolute neutrophil count of ⬍ 0.5 ⫻ 109 cells/L. For the clinical diagnosis of noninfectious pulmonary complications, we used the criteria outlined in the definitions given in this paragraph. Nonspecific interstitial lung disease was defined as a pattern of interstitial chronic inflammation with type II pneumocyte hyperplasia and a varying degree of fibrosis with no evidence of lung infection, and without alternative histologic diagnosis.37 Organizing pneumonia was diagnosed by the presence of patchy intraluminal organizing fibrosis in distal airspaces with mild interstitial chronic inflammation and the preservation of lung architecture.37 Bronchiolitis obliterans syndrome was defined as progressive airflow limitation due to small airway obstruction after allogeneic stem cell transplantation or lung transplantation.38 Histology was characterized by constrictive bronchiolitis obliterans.1,39 Respiratory bronchiolitis was defined as a patchy pattern of dusty brown macrophages clustering and a patchy submucosal and peribronchiolar infiltrate of lymphocytes and histiocytes.37 Diffuse alveolar hemorrhage was defined by the presence of a widespread alveolar injury seen on a thoracic CT scan (as evidenced by multilobar infiltrates) and by BAL fluid returns becoming progressively bloodier or showing ⱖ 20% iron-laden macrophages in the absence of infection.40 Diffuse alveolar damage was defined as a pattern of acute lung injury, which was characterized by an exudative phase, with cell necrosis, edema, and hyaline membrane formation, and a proliferative phase with organizing interstitial fibrosis.37,41 Invasive pulmonary aspergillosis was diagnosed in the context of compatible clinical and radiographic features according to a consensus statement.42 Pulmonary edema was defined by bibasilar rales, radiologic evidence of pulmonary edema, and the resolution of symptoms by therapy with diuretic agents. Acute bronchitis was defined by the self-limited presence of acute cough associated with bronchial system erythema in the absence of infiltrates and bacterial infection. Granuloma was 506
defined by the typical appearance of small nodules (with or without calcification) as evidenced on a chest CT scan without change over time in the absence of bacterial or mycobacterial infection.
Diagnostic Groups Proven bacterial infection was diagnosed in cases with positive bacteriology results in the BAL fluid or histologic specimens (ie, a culture yielding a single pathogenic bacterial microorganism at the minimum concentration of 103 cfu/mL or any microorganism excluding mouth flora above the minimum concentration of 104 cfu/mL5; or the identification of Legionella spp, C pneumoniae, or M pneumoniae regardless of colony counts). Possible bacterial infection was characterized as a clinically defined infection without a proven microbial pathogen (ie, new infiltrate seen on the chest radiograph accompanied by respiratory symptoms, abnormal breath sounds on auscultation, leukocytosis or leukopenia; and no identification of bacterial, viral, or fungal pathogens in the respiratory tract, cultures, specific stains, polymerase chain reaction, or immunofluorescence, as appropriate). No bacterial infection was considered to be present when an alternative cause for pulmonary symptoms and/or infiltrates was established without evidence of bacteria in microbiological studies (ie, nonspecific interstitial lung disease, organizing pneumonia, bronchiolitis obliterans, graft-vs-host disease, respiratory bronchiolitis, diffuse alveolar hemorrhage, diffuse alveolar damage, invasive pulmonary aspergillosis, pulmonary edema, acute bronchitis, granuloma, Wegener granulomatosis, malignant pulmonary involvement, or fungal or viral infections). Cases fulfilling the diagnostic criteria for proven bacterial infection were classified as such, irrespective of the presence of any alternative causes for the pulmonary symptoms.
Measurement of CRP and Procalcitonin CRP levels, procalcitonin levels, and leukocyte counts were assessed on the day of bronchoscopy. Procalcitonin was measured using 100 L of serum by an ultrasensitive chemiluminometric assay (PCT sensitive LIA; Brahms AG; Hennigsdorf, Germany).43 The assay has a lowest standard of 0.005 ng/L and a functional assay sensitivity of 0.02 g/L, which is within the normal range of healthy persons.44 CRP was measured using an enzyme immunoassay having a detection limit of ⬍ 5 mg/dL in heparin plasma (Hitachi Instrument 917; Roche Diagnostics, Rotkreuz, Switzerland) using reagents (Wako Chemicals GmbH; Neuss, Germany) [detection limit, ⬍ 5 mg/dL].
Statistical Analysis Discrete variables are expressed as the count (percentage), and continuous variables are expressed as the mean ⫾ SD, unless otherwise stated. The frequency comparison was performed with the 2 test. Two-group comparisons of normally distributed data were performed using the Student t test. For data not normally distributed, the Mann-Whitney U test was used if only two groups were compared, and the Kruskal-Wallis one-way analysis of variance was used if more than two groups were being compared. To evaluate the relationship among procalcitonin level, CRP level, and BAL neutrophil percentage and proven bacterial infection, a logistic multivariate regression model analysis was performed. We log-transformed skewed variables for the regression analysis. We constructed receiver operating characteristic (ROC) curves and determined the area under the curve (AUC) Original Research
for the ROC. Significant predictors for bacterial infection (BAL neutrophil percentage log ⫻ procalcitonin log) were combined, and the predicted probability derived from logistic regression was used to construct a ROC curve. For these binary analyses, patients classified as having proven bacterial infection were plotted against the other diagnostic groups. Correlation analyses were performed by using Spearman rank correlation. Standard definitions of sensitivity, specificity, and likelihood ratio were used. The AUC was considered to be clinically useful if it was ⱖ 0.8.45 All statistical tests were two-tailed; a p value of ⬍ .05 was considered to be significant. Data were analyzed using a statistical software package (SPSS, version 14 for Windows; SPSS Inc; Chicago, IL).
Table 1—Underlying Diagnosis of 107 Immunocompromised Patients Underlying Diagnosis
Patients, No.
Hematologic disorders High-dose chemotherapy Acute myeloid leukemia Lymphoma Chronic myeloid leukemia Chronic lymphatic leukemia Multiple myeloma Acute lymphatic leukemia Acute myeloid leukemia plus lymphoma Lymphoma plus breast cancer Lymphoma plus heart transplant Allogeneic stem cell transplantation Acute myeloid leukemia Lymphoma Renal cell carcinoma Acute lymphatic leukemia Chronic lymphatic leukemia Multiple myeloma Polycythemia vera Myelodysplastic syndrome Autologous stem cell transplantation Acute myeloid leukemia Acute lymphatic leukemia Lymphoma Others Acute myeloid leukemia Myelodysplastic syndrome Polycythemia vera Solid organ transplants Kidney Lung Heart Lung plus kidney AIDS Solid organ malignancy Autoimmune disorders Rheumatoid arthritis Cryptogenic organizing pneumonia Respiratory bronchiolitis interstitial lung disease Panarteritis nodosa Sarcoidosis Allergic bronchopulmonary aspergillosis Connective tissue disease Wegener granulomatosis Bechet disease Polymyalgia rheumatica
62 29 10 7 4 3 1 1 1 1 1 26 14 4 3 1 1 1 1 1 3 1 1 1 4 2 1 1 20 10 6 1 3 8 2 15 3 2 2 2 1 1 1 1 1 1
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Results Baseline Characteristics of Patients Underlying conditions and baseline characteristics of the 107 patients are presented in Tables 1 and 2. Most common underlying conditions were hematologic malignancies that were treated by high dose chemotherapy alone (n ⫽ 29) or combined with allogeneic stem cell transplantation (n ⫽ 26) followed by solid organ transplantation (n ⫽ 20). Overall, 20 patients (18.7%) had neutropenia at the time of bronchoscopy. The median length of hospital stay before bronchoscopy was 2 days (interquartile range [IQR], 1 to 12.5). Fever and cough were the most commonly observed symptoms. Infiltrates were documented in the majority of cases (71%). The most common immunosuppressive medications used were steroids (43.9%), cyclosporine (30.8%), and mycophenolate mofetil (28.0%). A total of 78 patients (72.8%) received therapy with antibiotics for either prophylactic or therapeutic reasons before bronchoscopy. In patients receiving a therapeutic regimen, the median duration of antibiotic therapy at the time of bronchoscopy was 1 day
Table 2—Characteristics of 107 Patients at the Time of Bronchoscopy* Patient Characteristics Age, yr Male gender Agranulocytosis Symptoms Fever Cough Dyspnea Sputum Chills Chest radiograph/CT scan Infiltrates Laboratory parameters† Leukocytes, ⫻109 g/L CRP, mg/L Procalcitonin, ng/mL Immunosuppressive therapy Steroids Cyclosporine Mycophenolate Azathioprine Sirolimus Tacrolimus Antimicrobial therapy Antibacterial Antiviral Antifungal
Patients 52 (22–84) 67 (62.6) 20 (18.7) 60 (56.1) 60 (56.1) 56 (52.2) 34 (31.8) 14 (13.1) 76 (71.0) 6.22 (2.16–10.21) 48 (8–120) 0.102 (0.046–0.504) 47 (43.9) 33 (30.8) 30 (28.0) 10 (9.3) 6 (5.6) 3 (2.8) 78 (72.9) 39 (36.5) 32 (29.9)
*Values are given as mean (range) or No. (%), unless otherwise indicated. †Values are given as the median (IQR). CHEST / 132 / 2 / AUGUST, 2007
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Table 3—Laboratory Parameters in the Different Immunocompromised Patient Subgroups* Variables Leukocytes, ⫻10 g/L CRP, mg/L Procalcitonin, ng/mL BAL neutrophils % ⫻106 /L 9
Hematologic Disorders† (n ⫽ 64)
Solid Organ Transplants (n ⫽ 20)
HIV/AIDS (n ⫽ 8)
Autoimmune Disorders (n ⫽ 15)
p Value‡
3.28 (0.82–9.80) 48 (12–127) 0.12 (0.05–0.45)
7.36 (5.55–9.51) 33 (2-116) 0.10 (0.04–1.91)
4.60 (3.24–6.31) 41 (6–108) 0.14 (0.08–0.29)
11.74 (7.02–18.20) 30 (1–74) 0.06 (0.01–0.34)
0.001 0.422 0.228
12 (6–57) 39 (8–414)
21 (1–79) 44 (1–2500)
5 (1–16) 19 (4–205)
0.119 0.016
6 (1–18) 6 (1–24)
*Values are given as the median (IQR). †Including two patients who were undergoing chemotherapy for a solid organ malignancy. ‡By Kruskal-Wallis one-way analysis of variance comparing the four diagnostic groups.
(IQR, 1 to 4 days). Fifteen patients (19.2%) were receiving piperacillin/tazobactam, 7 patients (9.0%) cefepime, 4 patients (5.1%) meropenem, 3 patients (3.8%) ceftriaxone, 3 patients (3.8%) amoxicillin/ clavulanic acid (1 of those patients was also receiving prophylactic trimethoprim/sulfamethoxazole), 3 patients (3.8%) amikacin and cefepime, 3 patients (3.8%) piperacillin/tazobactam and cefepime, 2 patients (2.6%) clarithromycin, 2 patients (2.6%) piperacillin/tazobactam and levofloxacin, 2 patients (2.6%) obracin and cefepime, 2 patients (2.6%) amoxicillin/clavulanic acid and clarithromycin (1 of those patients was also receiving prophylactic trimethoprim/sulfamethoxazole), 2 patients (2.6%) piperacillin/tazobactam, cefepime, and amikacin, 1 patient (1.3%) trimethoprim/sulfamethoxazole, 1 patient (1.3%) levofloxacin, 1 patient (1.3%) imipenem and cilastatin, 1 patient (1.3%) vancomycin and cefepime, 1 patient (1.3%) piperacillin/tazobactam and vancomycin, 1 patient (1.3%) piperacillin/ tazobactam and meropenem, 1 patient (1.3%) ceftriaxone and clarithromycin, 1 patient (1.3%) cefepime and amikacin, and 1 patient (1.3%) rifampin and isoniazid and pyrazinamide. Furthermore, 20 patients (25.6%) were receiving trimethoprim/sulfamethoxazole prophylaxis, and 1 patient (1.3%) was receiving continuous therapy with clarithromycin as an antiinflammatory drug. Table 3 presents median values for leukocyte counts, CRP level, procalcitonin level, BAL fluid neutrophil percentage, and absolute counts in the different immunocompromised patient subgroups. While the median CRP level, procalcitonin level, and BAL fluid neutrophil percentage did not significantly differ in the different subgroups of immunocompromised patients, leukocyte counts and BAL fluid neutrophil absolute counts were significantly affected by the underlying immunocompromised status. Patients who were admitted to the hospital because of respiratory symptoms and were undergoing bronchoscopy within 24 h presented with lower procalcitonin levels (0.08 ng/mL; IQR, 0.03 to 0.23 508
ng/mL) compared to those patients who had a longer duration of symptoms during the hospital stay preceding bronchoscopy (0.17 ng/mL; IQR, 0.06 to 0.61 ng/mL; p ⫽ 0.045). Microbiological data for BAL fluid are presented in Table 4. Overall, 38 patients (35.5%) had a microbiological study result that was positive for bacteria, viruses, and/or fungi. The most common bacterial pathogens were Streptococcus pneumoniae, Pseudomonas aeruginosa, L pneumophila, and Enterococci. In addition to BAL fluid specimens, transbronchial biopsy specimens were obtained in 15 cases (14.0%) and endobronchial biopsy specimens in 3
Table 4 —Documentation of Bacteria, Viruses, and Fungi in the BAL Fluid of 107 Immunocompromised Patients Microorganisms
No.
Bacteria S pneumoniae S pneumoniae ⫹ Staphylococcus aureus ⫹ CMV S pneumoniae ⫹ Escherichia coli S pneumoniae ⫹ P jiroveci ⫹ CMV P aeruginosa P aeruginosa ⫹ CMV ⫹ HSV P aeruginosa ⫹ HSV L pneumophila S aureus Staphylococcus coag. negative ⫹ RSV Enterocci spp Enterocci spp ⫹ Klebsiella pneumoniae Enterobacter cloacae ⫹ HSV Haemophilus influenzae ⫹ CMV H influenzae ⫹ Mycobacterium xenopi Moraxella catarrhalis ⫹ RSV Others CMV CMV ⫹ P jiroveci HSV Mycobacterium tuberculosis Aspergillus fumigatus Zygomycetes
27 4 1 1 1 2 1 1 4 3 1 3 1 1 1 1 1 11 3 2 1 2 2 1
*CMV ⫽ cytomegalovirus; HSV ⫽ herpes simplex virus; RSV ⫽ respiratory syncytial virus. Original Research
Table 5—Distribution of Diagnostic Groups Among the Different Immunocompromised Patient Subgroups* Conditions
Proven Bacterial (n ⫽ 27)
Possible Bacterial (n ⫽ 11)
Nonbacterial (n ⫽ 69)
All† (n ⫽ 107)
Hematologic disorders‡ Solid organ transplants AIDS Autoimmune disorders
15 (23) 8 (40) 3 (37) 1 (7)
5 (8) 2 (10) 1 (13) 3 (20)
44 (69) 10 (50) 4 (50) 11 (73)
64 20 8 15
*Values are given as No. (%). †p ⫽ 0.285 comparing the three diagnostic groups. ‡Including two patients undergoing chemotherapy for solid-organ malignancy.
cases (2.8%). There were no major complications during bronchoscopy. Histologic pulmonary specimens obtained by video-assisted thoracic surgery were available in seven cases (6.5%). The in-hospital mortality rate was 5.6% (six cases). Autopsy results were available in four of these six cases. Distribution of Diagnostic Groups Proven bacterial infection was diagnosed in 27 patients (25%). In four patients (15%), the diagnosis was based on a polymerase chain reaction finding that was positive for L pneumophila, and in three patients (11%) bacterial growth in the BAL fluid was ⬎ 103 cfu/mL but ⬍ 104 cfu/mL (P aeruginosa, S pneumoniae, and Enterocci spp in one patient each). In one patient (4%), a negative finding for Staphylococcus coagulase. was found both in a BAL fluid specimen (⬎ 100,000 cfu/mL) and in blood culture. Gram stains on BAL fluid specimens failed to show evidence of bacteria in culture from 9 of 27 patients with proven bacterial infection. Eleven patients (11%) were classified as having possible bacterial infection, and a nonbacterial condition was identified in 69 patients (65%). The distribution of cases classified as proven, possible, and no bacterial infection within the different subgroups of immunocompromised patients is shown in Table 5. Among the 20 neutropenic patients, 4 (20%) had proven bacterial infection, 1 (5%) had possible bacterial infection, and 15 (75%) had no bacterial infection. Table 6 presents the final pulmonary diagnosis of the 69 patients considered to have a nonbacterial condition. The clinical parameters were similar in patients with and without bacterial infection (Table 7). Infiltrates were present significantly more often in patients with proven bacterial infection (89%) or possible bacterial infection (82%), compared to nonbacterial conditions (62%; p ⫽ 0.04). Table 8 presents leukocyte counts, CRP levels, procalcitonin levels, and BAL fluid neutrophil counts (absolute and percentage) in patients with proven bacterial infection, possible bacterial infection, and www.chestjournal.org
no bacterial infection. While there was a statistically significant difference among the three diagnostic groups, laboratory parameters and neutrophil counts in the BAL fluid were not significantly different in cases of proven and possible bacterial infection (difference not significant [determined by MannWhitney U test]). CRP and procalcitonin levels were similar in patients with proven or suspected (probable and possible) invasive pulmonary aspergillosis and in those patients in whom other nonbacterial conditions were identified (p ⫽ 0.221 and p ⫽ 0.162, respectively). There was no difference in CRP level, procalcitonin level, BAL fluid neutrophil percentage and absolute counts in patients with and without neutropenia and proven bacterial infection (difference not significant
Table 6 —Final Pulmonary Diagnosis of the 69 Patients Considered To Have a Nonbacterial Condition Causing Pulmonary Signs and Symptoms* Nonbacterial Conditions
Patients, No.
Nonspecific interstitial pneumonitis Organizing pneumonia Graft-vs-host disease Bronchiolitis obliterans Bronchiolitis obliterans ⫹ CMV infection Respiratory bronchiolitis Diffuse alveolar hemorrhage Diffuse alveolar damage Diffuse alveolar damage ⫹ possible IPA Diffuse alveolar damage ⫹ CMV infection Wegener granulomatosis Allergic bronchopulmonary aspergillosis Pulmonary lymphoma involvement Pulmonary edema IPA† Acute bronchitis P jiroveci ⫹ CMV infection Herpes simplex pneumonia Cytomegalovirus pneumonia M tuberculosis Granuloma
9 4 4 6 1 3 3 2 1 1 1 1 2 4 10 6 2 1 1 2 5
*IPA ⫽ invasive pulmonary aspergillosis. See Table 4 for abbreviation not used in the text. †Proven, one case; possible or probable, nine cases. CHEST / 132 / 2 / AUGUST, 2007
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Table 7—Signs, Symptoms, and Radiologic Findings in 107 Immunocompromised Patients, According to Diagnostic Group Classification* Variables
Proven Bacterial (%) (n ⫽ 27)
Possible Bacterial (n ⫽ 11)
Nonbacterial (n ⫽ 69)
All (n ⫽ 107)
p Value†
Cough Dyspnea Sputum Fever Infiltrates
16 (59) 13 (48) 9 (33) 19 (70) 24 (89)
9 (82) 7 (64) 4 (36) 8 (72) 9 (82)
35 (51) 36 (52) 21 (30) 33 (48) 43 (62)
60 (56) 56 (52) 34 (32) 60 (56) 76 (71)
0.144 0.686 0.907 0.068 0.040
*Values are given as No. (%), unless otherwise indicated. †Comparison of the three diagnostic groups by 2 test.
for all). Steroids and cyclosporin intake did not significantly affect BAL fluid neutrophil results. The median BAL fluid neutrophil count was 8% (IQR, 2 to 22.5%) in patients not receiving steroids compared to 10.5% (IQR, 4 to 27.5%) in patients receiving therapy with steroids (p ⫽ 0.414). Similarly, the median BAL neutrophil count was 10% (IQR, 3 to 37.5%) in patients not receiving therapy with cyclosporin compared to 8% (IQR, 2 to 22%) in patients receiving therapy with cyclosporin (p ⫽ 0.212). Similarly, median procalcitonin levels were not influenced by the following immunosuppressive drugs: steroids (n ⫽ 47; p ⫽ 0.673); cyclosporin (n ⫽ 33; p ⫽ 0.881); mycophenolate (n ⫽ 30 p ⫽ 0.603); azathioprine (n ⫽ 10; p ⫽ 0.996); sirolimus (n ⫽ 6; p ⫽ 0.096); and tacrolimus (n ⫽ 3.0; p ⫽ 0.166). There was a moderate correlation between procalcitonin and CRP levels (Spearman rho ⫽ 0.595; p ⬍ 0.001) and a poor negative correlation between procalcitonin levels and leukocyte counts (Spearman rho ⫽ ⫺0.213; p ⫽ 0.031). There was no correlation between procalcitonin levels and BAL neutrophil counts, both absolute and as a percentage (p ⫽ 0.204 and p ⫽ 0.171, respectively). Diagnostic Accuracy of Clinical and Laboratory Parameters To analyze the diagnostic accuracy of clinical and laboratory parameters to predict bacterial infection,
a ROC analysis was performed (Fig 1). The percentage of neutrophils in BAL fluid had the highest AUC (0.818; 95% confidence interval [CI], 0.700 to 0.935; p ⬍ 0.001), followed by absolute neutrophil counts (AUC, 0.797; 95% CI, 0.678 to 0.916; p ⬍ 0.001), procalcitonin level (AUC, 0.746; 95% CI, 0.602 to 0.889; p ⫽ 0.001), and CRP level (AUC, 0.688; 95% CI, 0.555 to 0.821; p ⫽ 0.015). The AUC was not statistically significant for infiltrates (AUC, 0.619; 95% CI, 0.484 to 0.754; p ⫽ 0.123) and leukocyte counts (AUC, 0.561; 95% CI, 0.403 to 0.719; p ⫽ 0.429). Compared to BAL fluid neutrophil percentage alone, the AUC for the combination of BAL fluid neutrophil percentage and either CRP level (AUC, 0.844; 95% CI, 0.737 to 0.951; p ⬍ 0.001) or procalcitonin level (AUC, 0.872; 95% CI, 0.778 to 0.965; p ⬍ 0.001) increased the AUC for the diagnosis of bacterial infection (Fig 2). However, this difference did not reach statistical significance for either situation (p ⫽ 0.078 and p ⫽ 0.118, respectively). The combination of BAL fluid neutrophil percentage with both CRP and procalcitonin levels did not further improve the AUC of the model. In a multivariate logistic regression model, the log-transformed percentage of neutrophils in BAL fluid (p ⫽ 0.001; odds ratio [OR], 2.508; 95% CI, 1.424 to 4.420) and the log-transformed procalcitonin level (p ⫽ 0.038; OR, 1.557; 95% CI, 1.025 to 2.364) proved to be independent factors predicting
Table 8 —Laboratory Parameters in the 107 Immunocompromised Patients, According to the Diagnostic Group Classification* Variables Leukocytes, ⫻10 g/L CRP mg/L Procalcitonin, ng/mL BAL neutrophils % ⫻106 cells/L 9
Proven Bacterial (n ⫽ 27)
Possible Bacterial (n ⫽ 11)
Nonbacterial (n ⫽ 69)
All (n ⫽ 107)
p Value†
8.22 (2.82–13.23) 109 (24–230) 0.66 (0.07–12.28)
10.21 (7.43–15.34) 108 (42–238) 0.32 (0.09–1.58)
5.50 (2.19–8.35) 17 (2–62) 0.08 (0.02–0.22)
6.22 (2.16–10.21) 48 (8–120) 0.10 (0.05–0.50)
0.048 ⬍ 0.001 0.001
8 (2–15) 10 (32–28)
9 (2–25) 11 (3–44)
59 (22–79) 150 (23–456)
10 (4–32) 5 (3–70)
0.001 0.004
*Values are given as the median (IQR), unless otherwise indicated. †By Kruskal-Wallis one-way analysis of variance comparing the three diagnostic groups. 510
Original Research
C-reactive protein BAL neutrophils (%) BAL neutrophils absolute Leukocytes counts Procalcitonin Infiltrates
Figure 1. ROC analysis for CRP level (AUC, 0.688; 95% CI, 0.555 to 0.821; p ⫽ 0.015), BAL fluid neutrophil counts by percentage (AUC, 0.818; 95% CI, 0.700 to 0.935; p ⬍ 0.001) and absolute numbers (AUC, 0.797; 95% CI, 0.678 to 0.916; p ⬍ 0.001), leukocyte count (AUC, 0.561, 95% CI, 0.403 to 0.719; p ⫽ 0.429), procalcitonin level (AUC, 0.746; 95% CI, 0.602 to 0.889; p ⫽ 0.001), and infiltrates (AUC, 0.619; 95% CI, 0.484 to 0.754; p ⫽ 0.123).
bacterial infection. We found no significance for log-transformed CRP level (p ⫽ 0.455; OR, 1.191; 95% CI, 0.752 to 1.887). Sensitivity, specificity, and positive and negative likelihood ratio point estimates for CRP level, procalcitonin level, and BAL fluid neutrophil percentage are presented in Table 9. At the threshold value of 20 mg/L, CRP level had a sensitivity of 84% and a specificity of 48%. Procalcitonin level had the highest specificity (84%) at the threshold value of 0.5 ng/mL. BAL fluid neutrophil percentage had the highest overall performance at the threshold of 15% (sensitivity, 84%; specificity, 77%). Discussion In this study, we found that clinical parameters were not useful for the differential diagnosis of
pulmonary complications in immunocompromised patients. In contrast, neutrophilia in the BAL fluid as well as increased serum levels of CRP and procalcitonin were significantly associated with bacterial pulmonary infection. The percentage of neutrophils in BAL fluid showed the best diagnostic accuracy for predicting bacterial infection in the ROC curve analysis, followed by procalcitonin level and CRP level. While the combination of BAL fluid neutrophil percentage and the level of either biomarker increased the AUC of the model, this improvement failed to reach statistical significance when compared to the use of BAL fluid neutrophil percentage alone. This suggests that the evaluation of BAL fluid still represent the best diagnostic modality in immunocompromised patients with pulmonary complications. However, if there are contraindications to performing BAL or bronchoscopy, and its results are not available within a reasonable time frame, the determination of the CRP or procalcitonin level might represent a feasible approach for gathering evidence of bacterial infection. Furthermore, as procalcitonin level proved to be an independent predictor of bacterial infection in a multivariate regression analysis, the combination of BAL fluid neutrophil percentage and procalcitonin level, including a costbenefit analysis, might warrant evaluation in future studies. Pulmonary bacterial infections in immunocompromised patients are a challenge to physicians as both clinical signs and radiologic appearance are nonspecific.46 BAL has been established as a reliable technique for the diagnosis of pulmonary infection in the immunocompromised host, specifically for detecting opportunistic infectious such as P jiroveci and also bacteria.14,15,47 Previous reports5,18,48 –50 have suggested that BAL might be capable of identifying bacterial pathogens in immunocompromised patients despite antibiotic therapy due to the high
Table 9 —Point Estimates for CRP, Procalcitonin, and BAL Fluid Neutrophil Counts To Diagnose Bacterial Infection* Variables CRP, mg/L 20 50 100 Procalcitonin, ng/mL 0.1 0.2 0.5 BAL fluid neutrophils, % 10 15 20
Sensitivity
Specificity
LHR⫹
LHR⫺
84% (70–94) 58% (43–74) 53% (37–66)
48% (42–50) 61% (56–66) 77% (72–82)
1.62 (1.21–1.89) 1.47 (0.98–2.18) 2.28 (1.32–3.77)
0.33 (0.12–0.71) 0.69 (0.40–1.02) 0.62 (0.41–0.88)
74% (58–86) 68% (51–80) 58% (44–71)
62% (57–67) 71% (66–77) 84% (79–88)
1.96 (1.35–2.57) 2.32 (1.48–3.29) 3.53 (2.05–6.13)
0.42 (0.21–0.74) 0.45 (0.27–0.75) 0.50 (0.31–0.71)
84% (70–94) 84% (70–94) 79% (64–88)
59% (54–62) 77% (72–80) 82% (77–86)
2.10 (1.51–2.45) 3.66 (2.56–4.78) 4.38 (2.77–6.35)
0.27 (0.10–0.56) 0.21 (0.07–0.41) 0.26 (0.14–0.48)
*Values are given as % (95% CI). LHR⫹ ⫽ positive likelihood ratio; LHR⫺ ⫽ negative likelihood ratio. www.chestjournal.org
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bacterial load in lower respiratory tract secretions or to the higher incidence of infection with virulent organisms that respond slowly to antimicrobial therapy. However, empiric antimicrobial therapy has been shown to impair the diagnostic yield of bronchoscopy in HIV-infected patients and in those with nosocomial infections.51,52 Alternatively, BAL fluid cytology has proved to be useful in the diagnosis of infectious pulmonary infiltrates in immunocompromised adults and children.20,46 Thereby, significantly higher total neutrophil cell counts and percentages were found in the group of patients in whom bacterial organisms were detected in BAL fluid, compared with the group of patients in whom no bacterial agent was detected.46 In accordance with previous studies,53–55 we found BAL fluid neutrophilia to be present in neutropenic patients, suggesting that even patients who are undergoing high-dose chemotherapy and stem cell transplantation with neutropenia can generate a local immune reaction in response to infectious agents. In the current study, neutrophilia in the BAL fluid at a threshold of 15% had a sensitivity of 84% and a specificity of 77% to predict bacterial infection. These data indicate that the differential cell count in BAL fluid may be of value in the differential diagnosis of pulmonary complications in immunocompromised hosts. The use of inflammatory biomarkers for the early detection of bacterial infection might be a useful approach for distinguishing febrile episodes and for guiding the choice of specific antibiotic therapies, even before culture results are available.23 The present findings illustrate that CRP and procalcitonin serum levels are significantly higher in patients with proven and possible bacterial infection, compared to those patients with a nonbacterial condition. Thus, circulating biomarkers might give evidence of bacterial infection even in those cases in which microbiology results turned negative due to antimicrobial therapy. Interestingly, the combination of BAL fluid neutrophils with serum biomarkers tended to improve the diagnostic accuracy of the ROC model, indicating that both parameters might have additive value. This is particularly important in the setting of immunocompromised patients due to the high morbidity and mortality if the infection is treated inappropriately or recognized too late. The fundamental goal of diagnostic bronchoscopy is to establish a specific diagnosis that will allow more targeted therapy and improve survival. While noninfectious pulmonary complications tend to be less common than infectious complications, fewer than half of potentially treatable, nonbacterial pulmonary infections have been reported to be diagnosed prior to death.56,57 The poor outcome of pulmonary complications in immunocompromised patients is 512
Figure 2. ROC analysis for a model combining BAL fluid neutrophil counts in percentages combined with CRP level (AUC, 0.844; 95% CI, 0.737 to 0.9551; p ⬍ 0.001) or procalcitonin level (AUC, 0.872; 95% CI, 0.778 to 0.965; p ⬍ 0.001).
claimed to be associated with the delay in the administration of specific drugs in the evolution of the illness.5 Hence, it is tempting to speculate that a diagnostic approach that rules out bacterial infection (eg, the determination of serum biomarkers) could also lead to an earlier diagnostic workup targeting noninfectious etiologies and, thus, to a better outcome. Several limitations of our study should also be noted. First, we have included a heterogeneous population of immunocompromised patients. While this diversity is routine for the pulmonary consultant in a tertiary care setting, we might have missed findings peculiar to a particular subpopulation of patients. Second, the majority of our study population was composed of patients with hematologic malignancies being treated with high-dose chemotherapy and/or allogeneic stem cell transplantation. This might explain the relatively high incidence of noninfectious pulmonary complications found in our cohort. It would be of additional clinical and scientific interest to evaluate the combination of BAL neutrophil counts with procalcitonin or CRP levels in larger subgroups of immunocompromised patients with a higher incidence of infectious complications, such as lung, kidney, heart, and liver transplant recipients. Third, we have included in the study only hospitalized patients who were treated in the medical ward. Because of the exclusion of critically ill patients requiring mechanical ventilation, mortality rates in our study were lower than those in previous reports. Fourth, we have evaluated clinical and laboratory parameters in regard to their diagnostic value on the day of bronchoscopy (not at the initiation of the symptoms), and the kinetics of both biomarkers have not been analyzed. Finally, we Original Research
cannot exclude the possibility that previous antibiotic therapy might have decreased the microbiological yield of BAL fluid specimens. However, 96% of patients (26 of 27 patients) with proven bacterial infection were receiving therapy with antibiotics at the time of bronchoscopy, and most patients were started on therapy with antibiotics within 24 h of undergoing bronchoscopy. Thus, due to the high bacterial load and slower antibiotic response observed in immunocompromised patients,5,18,48 –50 we believe that previous antibiotic therapy did not considerably influence the microbiological yield of BAL fluid specimens in our study. In summary, our findings indicate that BAL fluid neutrophil percentage alone or in combination with serum levels of procalcitonin or CRP at the time of bronchoscopy may potentially be used to guide diagnostic and therapeutic decisions in immunocompromised hosts with pulmonary complications.
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