bronchoscopy A Prospective Study of Fever and Bacteremia After Flexible Fiberoptic Bronchoscopy in Children* Elie Picard, MD; Shepard Schwartz, MD; Shmuel Goldberg, MD; Tzipporah Glick, MD; Yael Villa, PhD; and Eitan Kerem, MD Study objectives: To assess the incidence of fever and bacteremia after fiberoptic bronchoscopy in immunocompetent children. Design: Prospective study. Patients: Immunocompetent children undergoing fiberoptic bronchoscopy between January 1997 and June 1998. Measurements and results: Ninety-one children were included in the study. Forty-four children (48%) developed fever within 24 h following bronchoscopy. Bacteremia was not detected in any of the cases at the time of the fever. Children who developed fever were younger than those who remained afebrile (mean age, 2.4 3.6 years vs 4.2 3.7 years; p 0.025). In the fever group, 66% of the bronchoscopies were considered abnormal, compared to 45% in the nonfever group (p 0.04). Of the fever group, 40.5% of BAL fluid cultures had significant bacterial growth, significantly higher compared to the nonfever group (13.2%; p 0.006). Of the 80 patients in whom BAL was performed, fever occurred in 52.5% compared to only 18.2% in those who did not have BAL (p 0.03). BAL fluid content of cell count, lipid-laden macrophages, and interleukin-8 were not significantly different in both groups. In a logistic regression analysis, the significant predictors for developing fever were positive bacterial culture (relative risk, 5.1; 95% confidence interval, 1.6 to 16.4; p 0.007) and abnormal bronchoscopic findings (relative risk, 3.1, 95% confidence interval, 1.2 to 8.3; p 0.02). When age < 2 years was included in the model, this factor became highly significant (relative risk, 5.01; 95% confidence interval, 1.83 to 13.75; p < 0.002). Conclusions: Fever following fiberoptic bronchoscopy is a common event in immunocompetent children and is not associated with bacteremia. Risks to develop this complication are age < 2 years, positive bacterial cultures in BAL fluid, and abnormal bronchoscopic findings. (CHEST 2000; 117:573 577) Key words: adverse events; bacteremia; bronchoscopy; children; fever Abbreviations: BALF BAL fluid; FB fiberoptic bronchoscopy; IL interleukin; LLM lipid-laden macrophages *From the Department of Pediatrics and Pediatric Respiratory Medicine (Drs. Picard, Schwartz, Goldberg, and Kerem), Shaare Zedek Medical Center, Jerusalem; the Department of Pathology (Dr. Glick), Shaare Zedek Medical Center, Jerusalem; and the School of Mathematical Sciences (Dr. Villa), Tel Aviv University, Tel Aviv, Israel. Manuscript received May 4, 1999; revision accepted September 8, 1999. Correspondence to: Eitan Kerem MD, Department of Pediatrics, Pediatric Respiratory Medicine, Shaare Zedek Medical Center, Hebrew University Medical School, Jerusalem 91031, Israel; e-mail: ek@cc.huji.ac.il Fiberoptic bronchoscopy (FB) is a relatively simple and well-tolerated procedure that can provide both diagnostic and therapeutic benefits. It is considered to be a relatively safe procedure. Serious complications such as arrhythmia, bleeding, bronchospasm, pneumonia, and pneumothorax occur rarely. 1 4 In contrast, fever within the first 24 h after bronchoscopy has been frequently reported in adults, 5 and has also been observed in children. 6,7 In adults, the reported frequency of this complication CHEST / 117 / 2/ FEBRUARY, 2000 573
ranges, according to the different reports, from 0 to 50%. 8 12 However, in children, the incidence of fever following FB has not been prospectively assessed. There have been some reports of bacteremia and sepsis following bronchoscopy among adults, most of them with impaired immunity. 13 17 We recently cared for an immunodeficient child who developed fulminant pneumococcal sepsis following FB. 18 These sporadic reports support the hypothesis that in immunodeficient patients fever after bronchoscopy may be related to bacteremia. However in immunocompetent hosts, it has been suggested that postbronchoscopy fever is not due to bacteremia but rather to the release of pyrogenic mediators. 19 21 The purpose of this prospective study was to assess the frequency of fever and bacteremia following FB in immunocompetent children, and to identify possible risk factors for the development of these complications. Materials and Methods Children undergoing FB between January 1997 and June 1998 in the Pediatric Respiratory Unit at the Shaare Zedek Medical Center were enrolled in the study. Exclusion criteria were as follows: immunocompromised state, concurrent treatment with antibiotics or systemic steroids, fever 38 C during the 48 h prior to bronchoscopy, or bronchoscopy performed late in the day rendering strict follow-up impossible. Informed consent was obtained from the parents of each patient enrolled in the study. All bronchoscopies were performed with an Olympus bronchoscope (model BF-3C20, or BF-P200 for the older children). Sedation was achieved with IV fentanyl, 1 to 2 g/kg, and/or midazolam, 0.1 to 0.2 mg/kg. All patients received IV atropine, 0.01 mg/kg, with a minimal dose of 0.1 mg. After local lubrication with lignocain HCl 2% ointment, the bronchoscope was inserted through the nasal passages and advanced through the vocal cords into the tracheobronchial tree. Lidocaine 1% was atomized for topical anesthesia through the channel of the bronchoscope as needed up to a maximal dose of 7 mg/kg. BAL was performed in all cases where an infectious agent was searched or if purulent secretions were disclosed by FB. BAL was also done for lipidladen macrophages (LLM) scoring when aspirations were suspected according to the symptoms and underlying diseases or in particular situations with high incidences of gastroesophageal reflux. 22,23 The BAL was usually performed in the right lower lobe except in cases with known localized pathology elsewhere. Three aliquots of 1 ml/kg of 0.9% sterile saline solution at room temperature were instilled through the working channel after wedging the bronchus. Fluid was recovered by manual suction through a sterile specimen trap. The BAL fluid (BALF) was obtained by a nonprotected fashion. The average yield for obtaining BAL fluid was approximately 30%. All BALF specimens were tested in our microbiology laboratory for quantitative bacterial culture and for cell count. In accordance with previous reports, we considered the growth of one bacteria at a concentration 10 4 cfu/ml as diagnostic of a lower airway infection. 24,25 When LLM were required, the specimens were stained with Oil-red-O, and an index as described by Colombo and Hallberg 26 was assigned. An index of 90 was considered positive. Testing of the BALF concentration for the proinflammatory cytokines interleukin (IL)-8 by commercial enzymelinked immunosorbent assay kits became available in the middle of the study. Therefore, IL-8 concentration were measured in only 34 patients. After the procedure, patients were observed by our registered nurse for at least 4 h with monitoring of body temperature. We considered fever as an elevation of body temperature measured rectally or orally 38 C. A single specimen of blood was sent for culture (both aerobic and anaerobic) in all patients who developed fever during the observation period. Patients who remained afebrile were discharged home once they were fully awake, with instructions to return immediately to the emergency department if fever occurred within 24 h of the bronchoscopy. These instructions included regular head feelings and temperature measurements if necessary. In the emergency department, they were examined by a physician and a blood culture was drawn even if temperature measurement in the emergency department returned spontaneously to normal. After 48 h, one of the researchers contacted the family in order to ascertain that all episodes of fever were indeed reported. Statistical Analysis Two sample t tests and 2 tests were performed in the univariate analysis for continuous and discrete variables as appropriate. The nonparametric Mann-Whitney test was used in order to compare the values of BAL cells in each group since this variable was not normally distributed. Odds ratios and 95% confidence intervals were calculated to evaluate the risk of different parameters in developing fever. Multivariate logistic regression was performed in order to assess the contribution of each variable to the development of fever. Results Of the 130 children who underwent FB in our department during the study period, 91 were entered in the study. Those excluded either had fever before the procedure, were receiving antibiotic therapy, or were immunodeficient. Indications for FB included stridor (19 cases), BAL for bacteriology and cytology (19 cases), upper airway obstruction (14 cases), recurrent pneumonia (11 cases), suspected foreign body aspiration (9 cases), atelectasis (9 cases), persistent wheezing (5 cases), hoarse voice (3 cases), and hemoptysis (2 cases). Of the 91 children, 44 children (48%) developed fever during the first 24 h following bronchoscopy. All blood culture specimens collected from the 44 febrile children were sterile. Patient demographic data, FB findings, and microorganisms isolated from BALF are summarized in Table 1. Among the 80 children who had BAL, fever occurred in 42 children (52.5%) compared to 2 of the 11 children (18%) who did not undergo BAL (relative risk, 5.0; 95% confidence interval, 1.01 to 24.48; p 0.03). The average age in the fever group (2.4 3.6 years) was significantly younger than that of the nonfever group (4.2 3.7 years; p 0.025). Sixty-three percent of children 2 years old developed fever, compared to only 30% of children 2 years old (relative risk, 2.2; 95% confidence interval, 1.3 to 3.7; p 0.002). Abnormal 574 Bronchoscopy
Table 1 Clinical Data of the Study Patients (n 91)* Groups Underlying Disease, No. Broncoscopic Findings, No. Microorganisms in BAL, No. Fever (n 44) No fever (n 47) *S/P status post. None 20 Normal 15 S pneumoniae 6 Mental retardation 9 Adenoidal hypertrophy 8 H influenzae 5 Cystic fibrosis 6 Tracheomalacia 5 Staphylococcus aureus 2 S/P prematurity 3 Laryngomalacia 5 Branhamella catarrhalis 2 Chronic lung disease 3 Purulent secretions 5 Haemophilus parainfluenzae 1 Congenital heart disease 1 Bronchomalacia 1 Streptococcus group A 1 Others 2 Others 5 None 25 Culture not done 2 None 29 Normal 26 H influenzae 5 Chronic lung disease 4 Purulent secretions 3 None 33 Asthma 3 Bronchomalacia 2 Culture not done 9 Cystic fibrosis 3 Tracheomalacia 2 Mental retardation 3 Adenoidal hypertrophy 5 S/P prematurity 1 Laryngomalacia 2 Others 4 Foreign body 1 Others 6 bronchoscopic findings were more common in the fever group (65.9%) than in the nonfever group (44.7%; relative risk, 2.4; 95% confidence interval, 1.03 to 5.59; p 0.04). Although mean BAL cell count in the fever group (3.7 9.7 10 6 /ml) was higher than in the nonfever group (1.3 3.9 10 6 / ml), the difference was not statistically significant (p 0.4). There was a significantly higher prevalence of bacterial growth in BALF among the fever group of patients (40.5%), as compared to the nonfever group of patients (13.2%; relative risk, 4.5; 95% confidence interval, 1.46 to 13.81; p 0.006). Streptococcus pneumoniae and Haemophilus influenzae were the predominant isolates from the BALF of patients in the fever group. In the nonfever group, H influenzae was the only isolate. The presence of LLM was not associated with fever. The Oil-Red-O staining was positive in 17 of 32 patients in the fever group (53.1%) and in 23 of 33 patients in the nonfever group (69.7%; p 0.2). The mean index of positivity of LLM in the fever group was 129 80 and did not differ significantly from the mean index of the nonfever group (107 63; p 0.4). IL-8 was measured in BALF of 34 patients. The average IL-8 concentration in BALF of 19 patients from the fever group was 1,308 pg/ml 837, higher but not statistically different from the average of 921 pg/ml 658 found among 15 patients from the nonfever group (p 0.15). A comparison of the findings in the two groups are summarized in Table 2. We performed a logistic regression analysis including in the model the variables that were significantly associated with fever: age, BAL, presence of positive bacterial culture, and abnormal findings in bronchoscopy. Only positive bacterial culture (relative risk, 5.1; 95% confidence interval, 1.6 to 16.4; p 0.007) and abnormal bronchoscopic findings (relative risk, 3.1; 95% confidence interval, 1.2 to 8.3; p 0.02) were found to be significant predictors. However, when we included in the model age 2 years vs age 2 years, this variable became very significant (relative risk, 5.01; 95% confidence interval, 1.83 to 13.75; p 0.002) followed by positive bacterial culture (relative risk, 4.72; 95% confidence interval, 1.41 to 15.79; p 0.02). Discussion In this prospective study, nearly half of the children who underwent FB developed fever within 24 h after the procedure. Postbronchoscopy fever was Table 2 Comparison of Clinical Findings Between Children With and Without Fever* Findings Fever No Fever p Value Patients, No. 44 47 Gender, F/M 12/32 18/29 NS Age, yr 2.4 3.6 4.2 3.7 0.025 Abnormal bronchoscopy, % 66 45 0.04 Positive culture, % 40.5 13.2 0.006 BALF cell count, 10 6 /ml 3.7 9.6 1.3 3.9 NS Positive lipid stain, % 53.1 69.7 0.2 Index of LLM 129 80 107 63 0.4 IL-8 levels, pg/ml 1308 837 921 658 0.15 *Data are presented as mean SD unless otherwise indicated; NS not significant. CHEST / 117 / 2/ FEBRUARY, 2000 575
associated with younger age (mainly 2 years), presence of significant bacterial growth from BALF, and abnormal bronchoscopic findings. Bacteremia was not detected in any of the cases in our study. Furthermore, recurrent aspiration was not found to be a risk factor for developing fever. To the best of our knowledge, no prospective study of fever after FB in children has been previously published. Fever after FB is a well-known adverse reaction in adults. 5 However, its real incidence is variable according to different reports. Fever was associated with FB in 2.5% of the 281 procedures reported by Strumpf et al, 12 and in 16% of the 100 FB cases reported by Pereira et al. 9 Fever after FB and BAL was also found in 21% 10 and in 50% 11 of healthy volunteers. By contrast, none of the 43 patients reported by Kane et al 8 developed fever after FB. Our study indicates that fever following FB is common in children and occurs even more frequently than in adults. The mechanism of the development of fever after bronchoscopy is unclear. It has been suggested that it is a result of transient bacteremia. However, the reports on the occurrence of bacteremia following FB are mainly in immunocompromised patients. 13,18 Furthermore, in prospective studies in immunocompetent patients, bacteremia has been rarely found. Smith et al 27 reported only one case of bacteremia among 50 adults following FB. In none of the 143 patients reported by Kane et al 8 and Pereira et al 9 was bacteremia detected after FB. These findings are confirmed in our pediatric study, in which all blood cultures obtained in all febrile patients at the time of fever yielded no bacterial growth. Recently it has been proposed that post-fb fever is caused by BAL-induced release of cytokines from the alveolar cells. 20,28 Standiford et al 20 reported a sharp increase of serum levels of tumor necrosis factor following bronchoscopy. Krause et al 28 demonstrated a rise in IL-1, IL-6, and tumor necrosis factor- in the serum of febrile patients 6 h following FB. This elevation was significantly greater among febrile patients. These findings suggest that during FB inflammatory cells release cytokines that act as endogenous mediators of fever 29 and cause the subsequent fever. The absence of bacteremia during the fever in our study may support these previous impressions. We found that children who did not undergo BAL also developed fever, although its incidence was significantly lower. The mechanism of fever when BAL was not performed is probably similar to that when BAL is performed. In the absence of BAL, the trigger of cytokine release might be lower and could be due to the lidocaine instillation 28 or other physical irritation, such as suctioning through the bronchoscope. IL-8, another known marker of inflammation, is produced mainly by macrophages and is involved in inflammation and cell migration. It is a particularly powerful inducer of chemotaxis of the neutrophils, 30 as in their recruitment in the alveolar structures after an acute lung inflammation. 31 Furthermore in a recent study performed on volunteers, there was an increased concentration of IL-8 in BALF 4 h after an initial lavage procedure. 32 We hypothesized that higher levels of IL-8 prior to the procedure may be found in future febrile patients and may suggest the presence of preexisting inflammation. Our hypothesis was supported by the fact that Krause et al 28 reported higher serum levels of IL-1 prior to FB in the patients who develop fever afterwards. We indeed detected higher BALF levels of IL-8 in the fever group compared to the nonfever group, although this difference did not reach statistical significance. The reason for the lack of statistical significance in the IL-8 level between the two groups may be due to the small number of BAL samples analyzed for IL-8, or because it was not being measured at the time of fever and in the serum, as was done in other studies. The reason for the higher incidence of fever after FB among children and in particular among those 2 years of age in our study is unclear. The amount of saline solution instilled during the procedure was based on body weight and therefore would not be a factor. A previous study demonstrated higher cell counts and greater neutrophil concentrations in BALF of healthy children 3 years of age in comparison to older children. 33 Similarly in immunocompetent patients, the total number of cells in the alveoli increase in the presence of infection. 34 Furthermore, serum IL-6 concentrations and macrophage counts found in BALF of patients with fever following FB have been shown to correlate. 28 It is possible that when BAL is performed in an infected or inflamed area in infants, more pyrogenic cytokines are released. This may also account for our finding of a higher incidence of fever among those with significant bacterial growth in BALF specimens, and with bronchoscopic abnormalities. We conclude that fever is a frequent adverse event after FB in children. Young age (especially 2 years), bacterial growth from BALF, and abnormal FB findings are risk factors for subsequent fever. Bacteremia does not appear to occur following FB in immunocompetent children. Parents and patients should be informed about this frequent complication and receive appropriate medical instructions. Fur- 576 Bronchoscopy
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