Etiology and Clinical Characteristics of Community-Acquired Pneumonia with Airway Malacia in Children

Etiology and Clinical Characteristics of Community-Acquired Pneumonia with Airway Malacia in... Abstract Objective The objective of this article is to study the etiology of community-acquired pneumonia in children with airway malacia. Methods We retrospectively reviewed the medical records of 428 pneumonia patients. All patients underwent bronchoscopy, and bronchoalveolar lavage samples were processed for microbiological assessment. Results In a total of 428 cases reviewed, 60 were found to have airway malacia. Pathogens were identified in 44 of the 60 specimens (73.3%), with 32 being single-pathogen infections. The most common pathogen was respiratory syncytial virus (RSV; 20%). Mixed-pathogen infections were observed in 12 patients. Airway malacia patients were younger than those without malacia (10.5 vs. 50 months, respectively; p < 0.001). Compared with those without airway malacia, wheezing, cyanosis and admission to the pediatric intensive care unit were more common in children with airway malacia and their hospital stay was longer. Conclusion RSV was the most common pathogen in those with airway malacia. Airway malacia was found to aggravate infectious pneumonia. children, community-acquired pneumonia, airway malacia, pathogen INTRODUCTION Protracted or recurrent pneumonia poses a significant challenge to the pediatricians. Children with airway malacia often have protracted courses of airway infections because dynamic airway collapse during coughing results in impaired mucociliary clearance and retention of tracheobronchial secretions [1–3]. Zhang et al. found that underlying diseases, such as airway abnormalities, are associated with severe acute lower respiratory infections [4]. Furthermore, Gokdemir et al. [5] found that malacia disorders were the most common causes (7.0%) of persistent and recurrent pneumonia. Previous studies have focused on the association among recurrent wheeze, chronic cough and airway malacia, with few reports focusing on the etiologic organisms responsible for recurrent or persistent pneumonia with airway malacia. In a study by Boogaard et al. [5], recurrent lower respiratory tract infections were found in 60 of 96 (63%) patients with airway malacia, and in 77.9% of the children with malacia, at least one pathogen was cultured. A more recent investigation by De Baets et al. [6] reported that 56% of the children reviewed with persistent respiratory symptoms had a positive bronchoalveolar lavage culture. These findings suggest protracted bacterial infection as a possible cause of persistent respiratory symptoms. Little is known about the pathogens and clinical features in protracted and recurrent pneumonia patients with airway malacia. The aim of this study was to determine the pathogens and clinical manifestations of protracted and recurrent pneumonia in children with airway malacia, and to compare these with pneumonia in children with no airway malacia to provide a basis for a reasonable choice of antibiotic. MATERIALS AND METHODS Patients This study was retrospectively conducted on patients with protracted or recurrent pneumonia who were admitted to the Department of Respiratory Disease at the Children’s Hospital Soochow University, China, from January 2014 to December 2015. Protracted pneumonia is defined as a lower respiratory tract infection persisting for ≥30 days; recurrent pneumonia is defined as at least two pneumonia episodes within 1 year [5]. Patients with congenital heart disease, immune deficiency, neuromuscular disease or foreign body aspiration were excluded from the study. Bronchoscopy BAL fluid (BALF) samples were taken from all patients and assessed for respiratory pathogens. ‘Laryngomalacia’ is the inward collapse of the supraglottic structures of the glottis on inspiration, causing airway obstruction. ‘Tracheomalacia’ is a tracheal deformity at the end of expiration, maintained during spontaneous respiration but that can be altered by the passage of the bronchoscope or positive airway pressure. ‘Bronchomalacia’ is the appearance of a deformity in the right or left mainstem bronchi and/or their respective divisions at the lobar or segmental level. Tracheomalacia and/or bronchomalacia can be classified as mild (less than one-third invagination), moderate (one-third to one-half invagination) or severe (more than four-fifth invagination) [7]. For BALF collection, the bronchoscope was inserted into the bronchus and three samples in 1.0 ml/kg normal saline solution were taken. Indications for bronchoscopy include unexplained hemoptysis or chronic excitant cough, pulmonary atelectasis, local stridor, tracheal and bronchial pulmonary hypoplasia and deformity, pulmonary diffuse disease and protracted or recurrent pulmonary infections. Contraindications for bronchoscopy include severe arrhythmia, cardiac failure, severe respiratory failure, severe bleeding tendency and coagulation dysfunction [8]. Detection of pathogens Direct immunofluorescence was used to detect syncytial viral infection (respiratory syncytial virus, RSV), influenza virus A, influenza virus B, parainfluenza virus (PIV) I, PIV II, PIV III and adenovirus (ADV). All assay kits were purchased from Chemicon International, Inc. (Billerica, MA, USA), and all staining procedures were done according to the manufacturer’s instructions. Immunostained preparations were viewed using a Leica 020-518.500 fluorescence microscope (Leica Microsystems, Wetzlar, Germany). Detection of the human metapneumovirus gene The primer sequences for human metapneumovirus (HMPV) were 5ʹ-AACCGTGTACTAAGTGATGCACTC-3ʹ; antisense, 5ʹ-CATTGTTTGACCGGCCCCATAA-3ʹ. HMPV was assayed by fluorescent real-time polymerase chain reaction (RT-PCR) using the iCycler RT-PCR system (Bio-Rad, Hercules, CA, USA). The cyclic temperature settings were 94.0 °C, 30 s; 56.0 °C, 30 s; 72.0 °C, 30 s and were amplified by 40 cycles. Detection of the human bocavirus gene The primer sequences for the human bocavirus (HBoV) gene were HBoV-F: 5ʹ-TGACATTCAACTACCAACAACCTG-3ʹ; HBoV-R: 5ʹ-CAGATCCTTTTCCTCCTCCAATAC-3ʹ; and HBoV-probe: AGCACCACAAAACACCTCAGGGG-TAMRA. HBoV-DNA was detected by RT-PCR. The cyclic temperature settings were 94.0 °C, 30 s; 56.0 °C, 30 s; 72.0 °C, 30 s and were amplified by 40 cycles. Detection of the human rhinovirus gene The primer sequences for human rhinovirus (HRV) were HRV-F: TGG ACA GGG TGT GAA GAG C; HRV-R: CAA AGT AGT CGG TCC CAT CC; and HRV-probe: FAM-TCC TCC GGC CCC TGA ATG-TAMRA. HRV-DNA was detected by RT-PCR. The cyclic temperature settings were 95.0 °C, 5.0 min; 95.0 °C, 15 s; 60.0 °C, 30 s and were amplified by 40 cycles. Detection of bacteria We prepared cultures for quantitative analysis to assess the presence of common aerobic and anaerobic bacteria. Selected media (e.g. Columbia AGAR blood plate, chocolate tablet) were inoculated and placed in a carbon dioxide incubator (50 ml/l) (YAMATO, Ltd, Tokyo, Japan) at 35.0 °C for 18∼24 h. Bacteria were identified based on the characteristics of their colonies, Gram staining, microscopic performance and biochemical reaction. C-reactive protein detection Blood samples were taken from each patient and were measured using the XE–2000i Automated Hematology System (SYSMEX, Kobe, Japan); C-reactive protein (CRP) was detected by immune scattering turbidimetry using the HITACHI 7600-010 automatic biochemical analyzer (Hitachi, Ltd., Tokyo, Japan). Serology testing for Mycoplasma pneumoniae and Chlamydophila pneumonia The presence of specific IgM and IgG antibodies against Mycoplasma pneumoniae (MP) was investigated in serum samples of patients using a commercial ELISA kit (Serion ELISA classic M. pneumoniae IgG/IgM, Institute Virion/Serion, Germany). IgA and IgG antibodies against Chlamydophila pneumoniae were detected with Serion ELISA classic C. pneumoniae IgA/IgG kits. Statistical analyses All data were analyzed using PASW 20.0. Comparisons among groups were performed using the Chi-squared test. Fisher’s exact probability test was used to analyze data that did not meet the requirements for the Chi-squared test. Data that were not normally distributed were compared using the Mann–Whitney U test. Here, p < 0.05 was considered statistically significant. RESULTS Patient characteristics The records of 428 patients were examined for the study. In all, 60 suffered from airway malacia (Table 1); the remaining 368 patients were used as the control group. There were 43 (71.6%) males and 17 (28.3%) females. Seventeen patients (28.3%) were <6.0 months old, 16 (26.7%) were from 6 months to 1.0 year old, 18 (30%) were from 1.0 to 3.0 years old, 5 (8.3%) were from 3.0 to 5.0 years old and 4 (6.7%) were >5.0 years old. The control group (n = 368) was composed of 199 (54.1%) males and 169 (45.9%) females. Patients whose parents refused bronchoscopy and those patients with bronchoscopy contraindications were excluded from the study. The number of patients whose parents refused bronchoscopy was 45. Two patients were with bronchoscopy contraindications. The diagnoses in this group were recurrent/protracted pneumonia (n = 22), bronchial asthma (n = 9), Bordetella pertussis-like symptoms (n = 9), gastroesophageal reflux (n = 2), atelectasis (n = 2), pleural effusion (n = 1), respiratory failure (n = 1) and heart failure (n = 1). Table 1 Airway malacia in patients with community-acquired pneumonia Airway malacia Cases (n) Laryngomalacia 7 Mild tracheomalacia 11 Mild bronchomalacia 23 Moderate bronchomalacia 14 Severe bronchomalacia 1 Laryngotracheobronchomalacia 2 Laryngomalacia and bronchomalacia 1 Laryngotracheomalacia 1 Airway malacia Cases (n) Laryngomalacia 7 Mild tracheomalacia 11 Mild bronchomalacia 23 Moderate bronchomalacia 14 Severe bronchomalacia 1 Laryngotracheobronchomalacia 2 Laryngomalacia and bronchomalacia 1 Laryngotracheomalacia 1 Table 1 Airway malacia in patients with community-acquired pneumonia Airway malacia Cases (n) Laryngomalacia 7 Mild tracheomalacia 11 Mild bronchomalacia 23 Moderate bronchomalacia 14 Severe bronchomalacia 1 Laryngotracheobronchomalacia 2 Laryngomalacia and bronchomalacia 1 Laryngotracheomalacia 1 Airway malacia Cases (n) Laryngomalacia 7 Mild tracheomalacia 11 Mild bronchomalacia 23 Moderate bronchomalacia 14 Severe bronchomalacia 1 Laryngotracheobronchomalacia 2 Laryngomalacia and bronchomalacia 1 Laryngotracheomalacia 1 Pathogens Pathogens were identified in 44 of 60 (73.3%) specimens from patients with airway malacia, of which 32 were single-pathogen infections. RSV was the most common single pathogen affecting 12 cases (37.5%). The most common mixed-pathogen infection was MP + RSV (25.0%) in 12 patients (Table 2). Table 2 Pathogens identified from patients with airway malacia Pathogen Cases (n) Single-pathogen  RSV 12  MP 7  SP 5  PIV III 2  HRV 3  Enterobacter aerogenes 2  Haemophilus influenzae 1 Mixed-pathogen  MP + RSV 12  PIV III + MP 2  SP + HRV 1  HRV+ KP 1  Gram-positive coccus + MP 1  MP + HRV 1  HI + MP 1  SP + MP + HRV 1  Gram-positive coccus + MP + HBoV 1 Pathogen Cases (n) Single-pathogen  RSV 12  MP 7  SP 5  PIV III 2  HRV 3  Enterobacter aerogenes 2  Haemophilus influenzae 1 Mixed-pathogen  MP + RSV 12  PIV III + MP 2  SP + HRV 1  HRV+ KP 1  Gram-positive coccus + MP 1  MP + HRV 1  HI + MP 1  SP + MP + HRV 1  Gram-positive coccus + MP + HBoV 1 Table 2 Pathogens identified from patients with airway malacia Pathogen Cases (n) Single-pathogen  RSV 12  MP 7  SP 5  PIV III 2  HRV 3  Enterobacter aerogenes 2  Haemophilus influenzae 1 Mixed-pathogen  MP + RSV 12  PIV III + MP 2  SP + HRV 1  HRV+ KP 1  Gram-positive coccus + MP 1  MP + HRV 1  HI + MP 1  SP + MP + HRV 1  Gram-positive coccus + MP + HBoV 1 Pathogen Cases (n) Single-pathogen  RSV 12  MP 7  SP 5  PIV III 2  HRV 3  Enterobacter aerogenes 2  Haemophilus influenzae 1 Mixed-pathogen  MP + RSV 12  PIV III + MP 2  SP + HRV 1  HRV+ KP 1  Gram-positive coccus + MP 1  MP + HRV 1  HI + MP 1  SP + MP + HRV 1  Gram-positive coccus + MP + HBoV 1 Pathogens were identified in 249 of 368 specimens with no airway malacia (67.7%) of which 188 were single-pathogen infections. MP was the most common single pathogen affecting 153 cases (81.4%). The most common mixed-pathogen infections were MP + SP (14.8%) in nine patients and MP + Gram-positive coccus (14.8%) in nine patients (Table 3). Table 3 Pathogens identified from patients with no airway malacia Pathogen Cases (n) Single-pathogen  MP 153  SP 10  RSV 5  ADV 3  HBoV 2  PIV III 1  InFA 2  CP 1  PA 3  Enterobacter aerogenes 2  Haemophilus influenzae 3  Gram-positive coccus 1  Moraxella catarrhalis 1 Mixed-pathogen  MP + RSV 6  MP + InFA 3  MP + InFB 2  HRV + SP 1  HRV + KP 1  MP + PA 1  RSV + HBoV 3  Enterococcus + MP 2  MP + Escherichia coli 3  MP + HBoV 3  MP + SP 9  Gram-positive coccus + MP 9  MP + HI 2  RSV + HI 2  MP + CP 3  Neisseria bacteria + MP 1  MP + SA 2  MP + Stenotrophomonas maltophilia 1  SP + HI 1  MP + RSV + SP 2  MP + RSV + HI 1  MP + PinfIII + Enterobacter aerogenes 1 Pathogen Cases (n) Single-pathogen  MP 153  SP 10  RSV 5  ADV 3  HBoV 2  PIV III 1  InFA 2  CP 1  PA 3  Enterobacter aerogenes 2  Haemophilus influenzae 3  Gram-positive coccus 1  Moraxella catarrhalis 1 Mixed-pathogen  MP + RSV 6  MP + InFA 3  MP + InFB 2  HRV + SP 1  HRV + KP 1  MP + PA 1  RSV + HBoV 3  Enterococcus + MP 2  MP + Escherichia coli 3  MP + HBoV 3  MP + SP 9  Gram-positive coccus + MP 9  MP + HI 2  RSV + HI 2  MP + CP 3  Neisseria bacteria + MP 1  MP + SA 2  MP + Stenotrophomonas maltophilia 1  SP + HI 1  MP + RSV + SP 2  MP + RSV + HI 1  MP + PinfIII + Enterobacter aerogenes 1 Table 3 Pathogens identified from patients with no airway malacia Pathogen Cases (n) Single-pathogen  MP 153  SP 10  RSV 5  ADV 3  HBoV 2  PIV III 1  InFA 2  CP 1  PA 3  Enterobacter aerogenes 2  Haemophilus influenzae 3  Gram-positive coccus 1  Moraxella catarrhalis 1 Mixed-pathogen  MP + RSV 6  MP + InFA 3  MP + InFB 2  HRV + SP 1  HRV + KP 1  MP + PA 1  RSV + HBoV 3  Enterococcus + MP 2  MP + Escherichia coli 3  MP + HBoV 3  MP + SP 9  Gram-positive coccus + MP 9  MP + HI 2  RSV + HI 2  MP + CP 3  Neisseria bacteria + MP 1  MP + SA 2  MP + Stenotrophomonas maltophilia 1  SP + HI 1  MP + RSV + SP 2  MP + RSV + HI 1  MP + PinfIII + Enterobacter aerogenes 1 Pathogen Cases (n) Single-pathogen  MP 153  SP 10  RSV 5  ADV 3  HBoV 2  PIV III 1  InFA 2  CP 1  PA 3  Enterobacter aerogenes 2  Haemophilus influenzae 3  Gram-positive coccus 1  Moraxella catarrhalis 1 Mixed-pathogen  MP + RSV 6  MP + InFA 3  MP + InFB 2  HRV + SP 1  HRV + KP 1  MP + PA 1  RSV + HBoV 3  Enterococcus + MP 2  MP + Escherichia coli 3  MP + HBoV 3  MP + SP 9  Gram-positive coccus + MP 9  MP + HI 2  RSV + HI 2  MP + CP 3  Neisseria bacteria + MP 1  MP + SA 2  MP + Stenotrophomonas maltophilia 1  SP + HI 1  MP + RSV + SP 2  MP + RSV + HI 1  MP + PinfIII + Enterobacter aerogenes 1 Comparison of clinical features of CAP patients with and without airway malacia Airway malacia patients were younger than those without malacia (10.5 vs. 50 months, p < .001). The proportion of males with airway malacia was higher than that of females (73.7% vs. 26.7%, p = 0.005). Wheezing, cyanosis and admission to pediatric intensive care unit (PICU) were more common in children with airway malacia (68.3% vs. 30.9%, p < 0.001; 8.3% vs. 0.8%, p = 0.002; 11.7% vs. 3.5%, p = 0.013). The average hospital stay was longer in children with airway malacia (10 days vs. 8.0 days, p = 0.004). MP (81.4%) was the most common single pathogen in CAP patients without airway malacia while virus (56.3%) was the most common pathogen with airway malacia (Table 4). Table 4 Demographic and clinical features of community-acquired pneumonia with or without airway malacia Characteristics No airway deformity (n = 368), n (%) Airway deformity (n = 60) n (%) X2/Z test p Mean age (months) 50.0 (21.0–85.0) 10.5 (4.75–24.25) Z = 7.372 <0.001 Sex  Male 199 (54.1) 44 (73.3)  Female 169 (45.9) 16 (26.7) X2 = 7.796 0.005 Symptom  Cough 357 (97) 59 (98.3) 1.0  Wheezing 114 (30.9) 41 (68.3) X2 = 31.164 <0.001  Fever 252 (68.5) 24 (40) X2 = 18.269 <0.001  Dyspnea 26 (7.1) 8 (13.3) X2 = 2.27 0.132  Cyanosis 3 (0.8) 5 (8.3) 0.002 Physical examination  Lung wheezing rales 114 (30.9) 41 (68.3) X2 = 31.164 <0.001  Lung moisture rales 11 (39.2) 12 (9.3) X2 = 29.359 <0.001 Lab tests WBC (×109) 9.0445 (6.59–13.02) 10.83 (8.0795–15.65) Z = 2.769 0.006 CRP (mg/l) 1.04 (0.2–9.02) 1.03 (0.135–2.915) Z = 1.194 0.233 PICU admission 13 (3.5) 7 (11.7) 0.013 Hospital stay (days) 8.0 (6.0–11.0) 10.0 (7.0–16.0) Z = 2.912 0.004 Cellularity of BALF  Neutrophil (%) 40.0 (15.0–74.0) 39.0 (19.5–67.5) Z = 0.433 0.665  Lymphocyte (%) 3.0 (2.0–7.0) 4.0 (2.0–7.0) Z = 2.157 0.031  Macrophage (%) 51.0 (19.0–81.0) 55.0 (21.5–73.0) Z = 0.23 0.818  Eosinophil (%) 0.0 (0.0–1.0) 0 (0–1.0) Z = 0.151 0.88 Positive pathogen of BALF 249 (67.7) 44 (73.3) X2 = 0.768 0.381  One pathogen 188 (75.5) 32 (72.7) X2 = 0.104 0.747   Mycoplasma pneumoniae 153 (81.4) 6 (18.8) X2 = 10.138 <0.001   Bacteria 21 (11.2) 8 (25) 0.057   Virus 13 (6.9) 18 (56.3) X2 = 25.436 <0.001   Chlamydia pneumoniae 1 (0.5) 0 (0) 1.0  Two pathogens 57 (22.9) 10 (22.7) X2 = 0.054 0.816   MP + CP 3 (5.3) 0 (0) 1.0   MP + virus 15 (26.3) 6 (60) 0.097   MP + bacteria 32 (54.4) 2 (20) 0.292   Virus + bacteria 2 (3.5) 2 (20) 0.096   Two viruses 4 (7) 0 (0) 1.0   Two bacteria 1 (3.5) 0 (0) 1.0  Three pathogens 4 (3.6) 2 (4.5) 0.2   MP + virus + bacteria 3 (75) 2 (100) 0.146   MP + virus + virus 1 (25) 0 (0) 1.0 Characteristics No airway deformity (n = 368), n (%) Airway deformity (n = 60) n (%) X2/Z test p Mean age (months) 50.0 (21.0–85.0) 10.5 (4.75–24.25) Z = 7.372 <0.001 Sex  Male 199 (54.1) 44 (73.3)  Female 169 (45.9) 16 (26.7) X2 = 7.796 0.005 Symptom  Cough 357 (97) 59 (98.3) 1.0  Wheezing 114 (30.9) 41 (68.3) X2 = 31.164 <0.001  Fever 252 (68.5) 24 (40) X2 = 18.269 <0.001  Dyspnea 26 (7.1) 8 (13.3) X2 = 2.27 0.132  Cyanosis 3 (0.8) 5 (8.3) 0.002 Physical examination  Lung wheezing rales 114 (30.9) 41 (68.3) X2 = 31.164 <0.001  Lung moisture rales 11 (39.2) 12 (9.3) X2 = 29.359 <0.001 Lab tests WBC (×109) 9.0445 (6.59–13.02) 10.83 (8.0795–15.65) Z = 2.769 0.006 CRP (mg/l) 1.04 (0.2–9.02) 1.03 (0.135–2.915) Z = 1.194 0.233 PICU admission 13 (3.5) 7 (11.7) 0.013 Hospital stay (days) 8.0 (6.0–11.0) 10.0 (7.0–16.0) Z = 2.912 0.004 Cellularity of BALF  Neutrophil (%) 40.0 (15.0–74.0) 39.0 (19.5–67.5) Z = 0.433 0.665  Lymphocyte (%) 3.0 (2.0–7.0) 4.0 (2.0–7.0) Z = 2.157 0.031  Macrophage (%) 51.0 (19.0–81.0) 55.0 (21.5–73.0) Z = 0.23 0.818  Eosinophil (%) 0.0 (0.0–1.0) 0 (0–1.0) Z = 0.151 0.88 Positive pathogen of BALF 249 (67.7) 44 (73.3) X2 = 0.768 0.381  One pathogen 188 (75.5) 32 (72.7) X2 = 0.104 0.747   Mycoplasma pneumoniae 153 (81.4) 6 (18.8) X2 = 10.138 <0.001   Bacteria 21 (11.2) 8 (25) 0.057   Virus 13 (6.9) 18 (56.3) X2 = 25.436 <0.001   Chlamydia pneumoniae 1 (0.5) 0 (0) 1.0  Two pathogens 57 (22.9) 10 (22.7) X2 = 0.054 0.816   MP + CP 3 (5.3) 0 (0) 1.0   MP + virus 15 (26.3) 6 (60) 0.097   MP + bacteria 32 (54.4) 2 (20) 0.292   Virus + bacteria 2 (3.5) 2 (20) 0.096   Two viruses 4 (7) 0 (0) 1.0   Two bacteria 1 (3.5) 0 (0) 1.0  Three pathogens 4 (3.6) 2 (4.5) 0.2   MP + virus + bacteria 3 (75) 2 (100) 0.146   MP + virus + virus 1 (25) 0 (0) 1.0 Note: Red: Fisher’s exact test; M (P25–P75): Mann–Whitney U-test. Table 4 Demographic and clinical features of community-acquired pneumonia with or without airway malacia Characteristics No airway deformity (n = 368), n (%) Airway deformity (n = 60) n (%) X2/Z test p Mean age (months) 50.0 (21.0–85.0) 10.5 (4.75–24.25) Z = 7.372 <0.001 Sex  Male 199 (54.1) 44 (73.3)  Female 169 (45.9) 16 (26.7) X2 = 7.796 0.005 Symptom  Cough 357 (97) 59 (98.3) 1.0  Wheezing 114 (30.9) 41 (68.3) X2 = 31.164 <0.001  Fever 252 (68.5) 24 (40) X2 = 18.269 <0.001  Dyspnea 26 (7.1) 8 (13.3) X2 = 2.27 0.132  Cyanosis 3 (0.8) 5 (8.3) 0.002 Physical examination  Lung wheezing rales 114 (30.9) 41 (68.3) X2 = 31.164 <0.001  Lung moisture rales 11 (39.2) 12 (9.3) X2 = 29.359 <0.001 Lab tests WBC (×109) 9.0445 (6.59–13.02) 10.83 (8.0795–15.65) Z = 2.769 0.006 CRP (mg/l) 1.04 (0.2–9.02) 1.03 (0.135–2.915) Z = 1.194 0.233 PICU admission 13 (3.5) 7 (11.7) 0.013 Hospital stay (days) 8.0 (6.0–11.0) 10.0 (7.0–16.0) Z = 2.912 0.004 Cellularity of BALF  Neutrophil (%) 40.0 (15.0–74.0) 39.0 (19.5–67.5) Z = 0.433 0.665  Lymphocyte (%) 3.0 (2.0–7.0) 4.0 (2.0–7.0) Z = 2.157 0.031  Macrophage (%) 51.0 (19.0–81.0) 55.0 (21.5–73.0) Z = 0.23 0.818  Eosinophil (%) 0.0 (0.0–1.0) 0 (0–1.0) Z = 0.151 0.88 Positive pathogen of BALF 249 (67.7) 44 (73.3) X2 = 0.768 0.381  One pathogen 188 (75.5) 32 (72.7) X2 = 0.104 0.747   Mycoplasma pneumoniae 153 (81.4) 6 (18.8) X2 = 10.138 <0.001   Bacteria 21 (11.2) 8 (25) 0.057   Virus 13 (6.9) 18 (56.3) X2 = 25.436 <0.001   Chlamydia pneumoniae 1 (0.5) 0 (0) 1.0  Two pathogens 57 (22.9) 10 (22.7) X2 = 0.054 0.816   MP + CP 3 (5.3) 0 (0) 1.0   MP + virus 15 (26.3) 6 (60) 0.097   MP + bacteria 32 (54.4) 2 (20) 0.292   Virus + bacteria 2 (3.5) 2 (20) 0.096   Two viruses 4 (7) 0 (0) 1.0   Two bacteria 1 (3.5) 0 (0) 1.0  Three pathogens 4 (3.6) 2 (4.5) 0.2   MP + virus + bacteria 3 (75) 2 (100) 0.146   MP + virus + virus 1 (25) 0 (0) 1.0 Characteristics No airway deformity (n = 368), n (%) Airway deformity (n = 60) n (%) X2/Z test p Mean age (months) 50.0 (21.0–85.0) 10.5 (4.75–24.25) Z = 7.372 <0.001 Sex  Male 199 (54.1) 44 (73.3)  Female 169 (45.9) 16 (26.7) X2 = 7.796 0.005 Symptom  Cough 357 (97) 59 (98.3) 1.0  Wheezing 114 (30.9) 41 (68.3) X2 = 31.164 <0.001  Fever 252 (68.5) 24 (40) X2 = 18.269 <0.001  Dyspnea 26 (7.1) 8 (13.3) X2 = 2.27 0.132  Cyanosis 3 (0.8) 5 (8.3) 0.002 Physical examination  Lung wheezing rales 114 (30.9) 41 (68.3) X2 = 31.164 <0.001  Lung moisture rales 11 (39.2) 12 (9.3) X2 = 29.359 <0.001 Lab tests WBC (×109) 9.0445 (6.59–13.02) 10.83 (8.0795–15.65) Z = 2.769 0.006 CRP (mg/l) 1.04 (0.2–9.02) 1.03 (0.135–2.915) Z = 1.194 0.233 PICU admission 13 (3.5) 7 (11.7) 0.013 Hospital stay (days) 8.0 (6.0–11.0) 10.0 (7.0–16.0) Z = 2.912 0.004 Cellularity of BALF  Neutrophil (%) 40.0 (15.0–74.0) 39.0 (19.5–67.5) Z = 0.433 0.665  Lymphocyte (%) 3.0 (2.0–7.0) 4.0 (2.0–7.0) Z = 2.157 0.031  Macrophage (%) 51.0 (19.0–81.0) 55.0 (21.5–73.0) Z = 0.23 0.818  Eosinophil (%) 0.0 (0.0–1.0) 0 (0–1.0) Z = 0.151 0.88 Positive pathogen of BALF 249 (67.7) 44 (73.3) X2 = 0.768 0.381  One pathogen 188 (75.5) 32 (72.7) X2 = 0.104 0.747   Mycoplasma pneumoniae 153 (81.4) 6 (18.8) X2 = 10.138 <0.001   Bacteria 21 (11.2) 8 (25) 0.057   Virus 13 (6.9) 18 (56.3) X2 = 25.436 <0.001   Chlamydia pneumoniae 1 (0.5) 0 (0) 1.0  Two pathogens 57 (22.9) 10 (22.7) X2 = 0.054 0.816   MP + CP 3 (5.3) 0 (0) 1.0   MP + virus 15 (26.3) 6 (60) 0.097   MP + bacteria 32 (54.4) 2 (20) 0.292   Virus + bacteria 2 (3.5) 2 (20) 0.096   Two viruses 4 (7) 0 (0) 1.0   Two bacteria 1 (3.5) 0 (0) 1.0  Three pathogens 4 (3.6) 2 (4.5) 0.2   MP + virus + bacteria 3 (75) 2 (100) 0.146   MP + virus + virus 1 (25) 0 (0) 1.0 Note: Red: Fisher’s exact test; M (P25–P75): Mann–Whitney U-test. Comparison of clinical features of single- and mixed-pathogen infection in CAP patients without airway malacia Of those CAP patients without airway malacia, the proportion of males with mixed-pathogen infections was higher than that of females. CRP was higher in those with mixed-pathogen infections without airway malacia than in those with single-pathogen infections (Table 5). Table 5 Demographic and clinical features of single-pathogen and mixed-pathogen infections in community-acquired pneumonia without airway malacia Characteristics Single-pathogen infection (n = 188), n (%) Mixed-pathogen infection (n = 61) n (%) X2/Z test p Mean age (months) 49.5 (23.0–80.75) 53.0 (19.0–83.25) Z = 0.535 0.593 Sex  Male 93 (54.1) 44 (73.3)  Female 95 (45.9) 17 (26.7) X2 = 9.558 0.002 Symptom  Cough 183 (97.3) 59 (96.7) 0.681  Wheezing 60 (31.9) 21 (34.4) X2 = 0.132 0.716  Fever 127 (67.6) 46 (75.4) X2 = 1.341 0.247  Dyspnea 7 (3.7) 6 (9.8) 0.092  Cyanosis 3 (1.6) 0 (0) 1.0 Physical examination  Lung wheezing rales 58 (30.9) 21 (34.4) X2 = 0.272 0.602  Lung moisture rales 115 (61.2) 33 (54.1) X2 = 0.955 0.328 Lab tests WBC (×109) 8.93 (6.555–13.09) 8.86 (6.77–15.28) Z = 0.422 0.673 CRP (mg/l) 0.41 (0.1–1.65) 3.7045 (0.275–12.515) Z = 3.49 0.001 PICU admission 6 (3.2) 3 (4.9) 0.693 Hospital stay (days) 9.0 (7.0–12.0) 8.0 (6.0–10.0) Z = 1.6 0.11 Characteristics Single-pathogen infection (n = 188), n (%) Mixed-pathogen infection (n = 61) n (%) X2/Z test p Mean age (months) 49.5 (23.0–80.75) 53.0 (19.0–83.25) Z = 0.535 0.593 Sex  Male 93 (54.1) 44 (73.3)  Female 95 (45.9) 17 (26.7) X2 = 9.558 0.002 Symptom  Cough 183 (97.3) 59 (96.7) 0.681  Wheezing 60 (31.9) 21 (34.4) X2 = 0.132 0.716  Fever 127 (67.6) 46 (75.4) X2 = 1.341 0.247  Dyspnea 7 (3.7) 6 (9.8) 0.092  Cyanosis 3 (1.6) 0 (0) 1.0 Physical examination  Lung wheezing rales 58 (30.9) 21 (34.4) X2 = 0.272 0.602  Lung moisture rales 115 (61.2) 33 (54.1) X2 = 0.955 0.328 Lab tests WBC (×109) 8.93 (6.555–13.09) 8.86 (6.77–15.28) Z = 0.422 0.673 CRP (mg/l) 0.41 (0.1–1.65) 3.7045 (0.275–12.515) Z = 3.49 0.001 PICU admission 6 (3.2) 3 (4.9) 0.693 Hospital stay (days) 9.0 (7.0–12.0) 8.0 (6.0–10.0) Z = 1.6 0.11 Note: Red: Fisher’s exact test. Table 5 Demographic and clinical features of single-pathogen and mixed-pathogen infections in community-acquired pneumonia without airway malacia Characteristics Single-pathogen infection (n = 188), n (%) Mixed-pathogen infection (n = 61) n (%) X2/Z test p Mean age (months) 49.5 (23.0–80.75) 53.0 (19.0–83.25) Z = 0.535 0.593 Sex  Male 93 (54.1) 44 (73.3)  Female 95 (45.9) 17 (26.7) X2 = 9.558 0.002 Symptom  Cough 183 (97.3) 59 (96.7) 0.681  Wheezing 60 (31.9) 21 (34.4) X2 = 0.132 0.716  Fever 127 (67.6) 46 (75.4) X2 = 1.341 0.247  Dyspnea 7 (3.7) 6 (9.8) 0.092  Cyanosis 3 (1.6) 0 (0) 1.0 Physical examination  Lung wheezing rales 58 (30.9) 21 (34.4) X2 = 0.272 0.602  Lung moisture rales 115 (61.2) 33 (54.1) X2 = 0.955 0.328 Lab tests WBC (×109) 8.93 (6.555–13.09) 8.86 (6.77–15.28) Z = 0.422 0.673 CRP (mg/l) 0.41 (0.1–1.65) 3.7045 (0.275–12.515) Z = 3.49 0.001 PICU admission 6 (3.2) 3 (4.9) 0.693 Hospital stay (days) 9.0 (7.0–12.0) 8.0 (6.0–10.0) Z = 1.6 0.11 Characteristics Single-pathogen infection (n = 188), n (%) Mixed-pathogen infection (n = 61) n (%) X2/Z test p Mean age (months) 49.5 (23.0–80.75) 53.0 (19.0–83.25) Z = 0.535 0.593 Sex  Male 93 (54.1) 44 (73.3)  Female 95 (45.9) 17 (26.7) X2 = 9.558 0.002 Symptom  Cough 183 (97.3) 59 (96.7) 0.681  Wheezing 60 (31.9) 21 (34.4) X2 = 0.132 0.716  Fever 127 (67.6) 46 (75.4) X2 = 1.341 0.247  Dyspnea 7 (3.7) 6 (9.8) 0.092  Cyanosis 3 (1.6) 0 (0) 1.0 Physical examination  Lung wheezing rales 58 (30.9) 21 (34.4) X2 = 0.272 0.602  Lung moisture rales 115 (61.2) 33 (54.1) X2 = 0.955 0.328 Lab tests WBC (×109) 8.93 (6.555–13.09) 8.86 (6.77–15.28) Z = 0.422 0.673 CRP (mg/l) 0.41 (0.1–1.65) 3.7045 (0.275–12.515) Z = 3.49 0.001 PICU admission 6 (3.2) 3 (4.9) 0.693 Hospital stay (days) 9.0 (7.0–12.0) 8.0 (6.0–10.0) Z = 1.6 0.11 Note: Red: Fisher’s exact test. Comparison of clinical features of single- and mixed-pathogen infections in CAP with airway malacia There was no significant difference in clinical characteristics, such as age, fever, wheezing, dyspnea, cyanosis, admission to PICU and hospital stay, between patients with single-pathogen infections and those with mixed-pathogen infections in CAP with airway malacia (Table 6). Table 6 Demographic and clinical features of single-pathogen and mixed-pathogen infections in CAP patients with airway malacia Characteristics Single-pathogen infection (n = 32), n (%) Mixed-pathogen infection (n = 12), n (%) X2/Z test p Mean age (months) 10.5 (4.0–23.0) 7.5 (4.5–14.5) Z = 0.158 0.874 Sex  Male 24 (75) 9 (75)  Female 8 (25) 3 (25) 1.0 Symptom  Cough 31 (96.8) 12 (100) 1.0  Wheezing 20 (62.5) 10 (83.3) 0.282  Fever 12 (37.5) 4 (41.7) 1.0  Dyspnea 6 (18.8) 2 (16.7) 1.0  Cyanosis 3 (9.4) 2 (16.7) 0.603 Physical examination  Lung wheezing rales 18 (56.3) 8 (66.7) 0.733  Lung moisture rales 23 (71.8) 11 (91.7) 0.241 Lab tests WBC (×109) 10.05 (7.96–13.51) 13.07 (9.04–18.44) Z = 1.814 0.07 CRP (mg/l) 1.84 (0.115–3.2775) 1.94 (0.275–6.1675) Z = 0.514 0.607 PICU admission 5 (15.6) 2 (16.7) 1.0 Hospital stay (days) 9.0 (7.25–15.0) 12.5 (8.5–17.0) Z = 1.23 0.219 Characteristics Single-pathogen infection (n = 32), n (%) Mixed-pathogen infection (n = 12), n (%) X2/Z test p Mean age (months) 10.5 (4.0–23.0) 7.5 (4.5–14.5) Z = 0.158 0.874 Sex  Male 24 (75) 9 (75)  Female 8 (25) 3 (25) 1.0 Symptom  Cough 31 (96.8) 12 (100) 1.0  Wheezing 20 (62.5) 10 (83.3) 0.282  Fever 12 (37.5) 4 (41.7) 1.0  Dyspnea 6 (18.8) 2 (16.7) 1.0  Cyanosis 3 (9.4) 2 (16.7) 0.603 Physical examination  Lung wheezing rales 18 (56.3) 8 (66.7) 0.733  Lung moisture rales 23 (71.8) 11 (91.7) 0.241 Lab tests WBC (×109) 10.05 (7.96–13.51) 13.07 (9.04–18.44) Z = 1.814 0.07 CRP (mg/l) 1.84 (0.115–3.2775) 1.94 (0.275–6.1675) Z = 0.514 0.607 PICU admission 5 (15.6) 2 (16.7) 1.0 Hospital stay (days) 9.0 (7.25–15.0) 12.5 (8.5–17.0) Z = 1.23 0.219 Note: Red: Fisher’s exact test. Table 6 Demographic and clinical features of single-pathogen and mixed-pathogen infections in CAP patients with airway malacia Characteristics Single-pathogen infection (n = 32), n (%) Mixed-pathogen infection (n = 12), n (%) X2/Z test p Mean age (months) 10.5 (4.0–23.0) 7.5 (4.5–14.5) Z = 0.158 0.874 Sex  Male 24 (75) 9 (75)  Female 8 (25) 3 (25) 1.0 Symptom  Cough 31 (96.8) 12 (100) 1.0  Wheezing 20 (62.5) 10 (83.3) 0.282  Fever 12 (37.5) 4 (41.7) 1.0  Dyspnea 6 (18.8) 2 (16.7) 1.0  Cyanosis 3 (9.4) 2 (16.7) 0.603 Physical examination  Lung wheezing rales 18 (56.3) 8 (66.7) 0.733  Lung moisture rales 23 (71.8) 11 (91.7) 0.241 Lab tests WBC (×109) 10.05 (7.96–13.51) 13.07 (9.04–18.44) Z = 1.814 0.07 CRP (mg/l) 1.84 (0.115–3.2775) 1.94 (0.275–6.1675) Z = 0.514 0.607 PICU admission 5 (15.6) 2 (16.7) 1.0 Hospital stay (days) 9.0 (7.25–15.0) 12.5 (8.5–17.0) Z = 1.23 0.219 Characteristics Single-pathogen infection (n = 32), n (%) Mixed-pathogen infection (n = 12), n (%) X2/Z test p Mean age (months) 10.5 (4.0–23.0) 7.5 (4.5–14.5) Z = 0.158 0.874 Sex  Male 24 (75) 9 (75)  Female 8 (25) 3 (25) 1.0 Symptom  Cough 31 (96.8) 12 (100) 1.0  Wheezing 20 (62.5) 10 (83.3) 0.282  Fever 12 (37.5) 4 (41.7) 1.0  Dyspnea 6 (18.8) 2 (16.7) 1.0  Cyanosis 3 (9.4) 2 (16.7) 0.603 Physical examination  Lung wheezing rales 18 (56.3) 8 (66.7) 0.733  Lung moisture rales 23 (71.8) 11 (91.7) 0.241 Lab tests WBC (×109) 10.05 (7.96–13.51) 13.07 (9.04–18.44) Z = 1.814 0.07 CRP (mg/l) 1.84 (0.115–3.2775) 1.94 (0.275–6.1675) Z = 0.514 0.607 PICU admission 5 (15.6) 2 (16.7) 1.0 Hospital stay (days) 9.0 (7.25–15.0) 12.5 (8.5–17.0) Z = 1.23 0.219 Note: Red: Fisher’s exact test. Associations between severity of airway malacia and PICU stay and duration of hospitalization No statistically significant associations between severity of airway malacia and PICU admission and duration of hospitalization were observed in the airway malacia group (Table 7). Table 7 Associations between severity of airway malacia and admission to the PICU and duration of hospitalization Characteristics Mild malacia (n = 43) Moderate malacia (n = 14) Severe malacia (n = 3) Kruskal–Wallis/Fisher p PICU admission 6 (13.9) 0 (0) 1 (33.3) 2.064 >0.05 Duration of hospitalization 12.23 ± 6.34 9.5 ± 5.56 12.0 ± 11.36 3.565 >0.05 Characteristics Mild malacia (n = 43) Moderate malacia (n = 14) Severe malacia (n = 3) Kruskal–Wallis/Fisher p PICU admission 6 (13.9) 0 (0) 1 (33.3) 2.064 >0.05 Duration of hospitalization 12.23 ± 6.34 9.5 ± 5.56 12.0 ± 11.36 3.565 >0.05 Table 7 Associations between severity of airway malacia and admission to the PICU and duration of hospitalization Characteristics Mild malacia (n = 43) Moderate malacia (n = 14) Severe malacia (n = 3) Kruskal–Wallis/Fisher p PICU admission 6 (13.9) 0 (0) 1 (33.3) 2.064 >0.05 Duration of hospitalization 12.23 ± 6.34 9.5 ± 5.56 12.0 ± 11.36 3.565 >0.05 Characteristics Mild malacia (n = 43) Moderate malacia (n = 14) Severe malacia (n = 3) Kruskal–Wallis/Fisher p PICU admission 6 (13.9) 0 (0) 1 (33.3) 2.064 >0.05 Duration of hospitalization 12.23 ± 6.34 9.5 ± 5.56 12.0 ± 11.36 3.565 >0.05 DISCUSSION Current management of lower respiratory tract infections in children with airway malacia, which includes liberal use of antibiotics and physiotherapy, is not evidence based [9]; therefore, determining the correct pathogen is particularly important for determining the correct treatment. This is the first study examining the etiology of pneumonia with airway malacia in China. Of the 60 protracted and recurrent CAP cases with airway malacia, with a positive pathogen detection rate of 73.3%, we found RSV to be the most common pathogen, followed by SP and MP. However, in CAP patients without airway malacia, MP was the most common pathogen, the results of which are different from those of previous reports of 10–40% [10, 11]. In addition, RSV and MP incidences were higher than those in previous reports [12, 13]. De Baets et al. [6] studied 124 children with persistent respiratory symptoms and fiberoptic bronchoscopy with BAL were performed; they found that 47% of cases had structural abnormality of the central airways, 56% of BAL samples tested positive for bacterial culture with Moraxella catarrhalis (51%), HI (28%), SP (13%), Staphylococcus aureus (10%). The pathogen detection rate was higher than that in our study, and the pathogen was different. In those patients with tracheobronchomalacia, which lack specific clinical symptoms, Pan et al. [14] studied 459 cases of children with airway malacia and found chronic cough and wheezing to be the main clinical manifestations, accompanied by difficulty in breathing, fever and sputum production. In the present study, we found that wheezing and cyanosis were common in patients with airway malacia. Patients with airway malacia had higher rates of admission to PICU and longer hospital stays, suggesting that airway malacia aggravated the disease. However, no significant associations between severity of airway malacia and PICU admission and duration of hospitalization were observed. Our study was consistent with Masters et al. [15], who reported that children with malacia have an increased disease severity and a tendency for delayed recovery. Whether mixed-pathogen infection increases the severity of pneumonia remains controversial. Some studies showed that viruses and bacteria in a mixed-pathogen infection prolongs hospitalization and increases the risk of admission to PICU [16–19]. However, other studies have shown no significant difference between average hospital stay, hospitalization rates and mortality when comparing mixed-pathogen infections with single-pathogen infections in patients with pneumonia [20–22]. In our study, we found the CRP level was higher in the mixed-pathogen infection group. The rate of admission to PICU and the length of hospital stay showed no obvious differences between the two groups, indicating that mixed-pathogen infections have no relationship to protracted and recurrent CAP patient mortality. CONCLUSIONS This study found that airway malacia is the underlying cause predisposing to persistence or recurrence of pneumonia in children; co-existing airway malacia did aggravate the disease. RSV was the most common pathogen, and mixed-pathogen infection accounted for 20% of infections. Thus, when treating children with protract and recurrent pneumonia who do not respond to antibiotics treatment, clinicians should consider airway malacia as a possible precipitant and perform a bronchoscopy. Study Limitations This study had some limitations. First, it was a retrospective study. Second, it was a single-center study. Third, there was no study of potential fungal pathogens. Finally, there was a certain selection bias because patients who refused bronchoscopy were not included in the study. ACKNOWLEDGEMENTS This work was supported by a grant from the National Natural Science Foundation of China (No. 81573167). Funding This work was supported by National Natural Science Foundation of China (81573167), Science and Technology Projects of Jiangsu Province (2017657) and Science and Technology Projects of Suzhou (SYS201436). References 1 Lodha R , Kabra SK. Recurrent/persistent pneumonia . Indian Pediatr 2000 ; 37 : 1085 – 92 . Google Scholar PubMed 2 Ozdemir O , Sari S , Bakirtas A , et al. Underlying diseases of recurrent pneumonia in Turkish children . Turk J Med Sci 2010 ; 40 : 25 – 30 . 3 Lodha R , Puranik M , Natchu UC , et al. Recurrent pneumonia in children: clinical profile and underlying causes . Acta Paediatr 2002 ; 91 : 1170 – 3 . Google Scholar CrossRef Search ADS PubMed 4 Zhang XB , Liu LJ , Qian LL. Clinical characteristics and risk factors of severe respiratory syncytial virus-associated acute lower respiratory tract infections in hospitalized infants . World J Pediatr 2014 ; 10 : 360 – 4 . Google Scholar CrossRef Search ADS PubMed 5 Gokdemir Y , Cakir E , Kut A , et al. Bronchoscopic evaluation of unexplained recurrent and persistent pneumonia in children . J Paediatr Child Health 2013 ; 49 : 204 – 7 . Google Scholar CrossRef Search ADS PubMed 6 De Baets F , De Schutter I , Aarts C. Malacia, inflammation and bronchoalveolar lavage culture in children with persistent respiratory symptoms . Eur Respir J 2012 ; 39 : 392 – 5 . Google Scholar CrossRef Search ADS PubMed 7 Carden KA , Boiselle PM , Waltz DA , et al. Tracheomalacia and tracheobronchomalacia in children and adults: an in-depth review . Chest 2005 ; 127 : 984 – 1005 . Google Scholar CrossRef Search ADS PubMed 8 Subspecialty Group of Respiratory Diseases, The Society of Pediatrics, Chinese Medical Association , et al. Guidelines for management of community acquired pneumonia in children (the revised edition of 2013) (I) [in Chinese]. Zhonghua Er Ke Za Zhi 2013 ; 51 : 745 – 52 . PubMed 9 Boogaard R , de Jongste JC , Vaessen-Verberne AA. Recombinant human DNase in children with airway malacia and lower respiratory tract infection . Pediatr Pulmonol 2009 ; 44 : 962 – 9 . Google Scholar CrossRef Search ADS PubMed 10 Vervloet LA , Marguet C , Camargos PA. Infection by Mycoplasma pneumoniae and its importance as an etiological agent in childhood comm unity-acquired pneumonia[J] . Braz J Infect Dis 2007 ; 11 : 507 – 14 . Google Scholar CrossRef Search ADS PubMed 11 Eun BW , Kim NH , Choi EH , et al. Mycoplasma pneumoniae in Korean children: the epidmiology of pneumonia over an 18-year period [J] . J Infect 2008 ; 56 : 326 – 31 . Google Scholar CrossRef Search ADS PubMed 12 Bezerra PG , Britto MC , Correia JB , et al. Viral and atypical bacterial detection in acute respiratory infection in children under five years[J] . PLoS One 2011 ; 6 : e18928 . Google Scholar CrossRef Search ADS PubMed 13 Feikin DR , Njenga MK , Bigogo G , et al. Etiology and Incidence of viral and bacterial acute respiratory illness among older children and adults in rural western Kenya, 2007-2010 . PLoS One 2012 ; 7 : e43656 . Google Scholar CrossRef Search ADS PubMed 14 Pan W , Peng D , Luo J , et al. Clinical features of airway malacia a retrospective analysis of 459 patients . Int J Clin Exp Med ; 7 : 3005 – 12 . PubMed 15 Masters IB , Zimmerman PV , Pandeya N , et al. Quantified tracheobronchomalacia disorders and their clinical profiles in children . Chest 2008 ; 133 : 461 – 7 . Google Scholar CrossRef Search ADS PubMed 16 Kurz H , Gopfrich H , Huber K , et al. Spectrum of pathogens of in-patient children and youths with community acquired pneumonia: a 3 year survey of a community hospital in Vienna, Austria . Wien Klin Wochenschr 2013 ; 125 : 674 – 9 . Google Scholar CrossRef Search ADS PubMed 17 Ghani AS , Morrow BM , Hardie DR , et al. An investigation into the prevalence and outcome of patients admitted to a pediatric intensive care unit with viral respiratory tract infections in Cape Town, South Africa . Pediatr Crit Care Med 2012 ; 13 : e275 – 81 . Google Scholar CrossRef Search ADS PubMed 18 Resch B , Gusenleitner W , Mueller WD. Risk of concurrent bacterial infection in preterm infants hospitalized due to respiratory syncytial virus infection . Acta Paediatr 2007 ; 96 : 495 – 8 . Google Scholar CrossRef Search ADS PubMed 19 Marria AM , Mariana E , Antoni T. Viral pneumonia . Cur Opin Infect Dis 2009 ; 22 : 143 – 7 . Google Scholar CrossRef Search ADS 20 Chen CJ , Lin PY , Tsai MH , et al. Etiology of community-acquired pneumonia in hospitalized children in northern Taiwan . Pediatr Infect Dis J 2012 ; 31 : e196 – 201 . Google Scholar CrossRef Search ADS PubMed 21 DeSchutter I , DeWachter E , Crokaert F , et al. Microbiology of bronchoalveolar lavage fluid in children with acute nonresponding or recurrent community-acquired pneumonia: identification of nontypical Haemophilus infuenzae as a major pathogen . Clin Infect Dis 2011 ; 52 : 1437 – 44 . Google Scholar CrossRef Search ADS PubMed 22 Vu HT , Yoshida LM , Suzuki M , et al. Association between nasopharyngeal load of Streptococcus pneumoniae, viral coinfection, and radiologically confirmed pneumonia in Vietnamese children . Pediatr Infect Dis J 2011 ; 30 : 11 – 18 . Google Scholar CrossRef Search ADS PubMed © The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Tropical Pediatrics Oxford University Press

Etiology and Clinical Characteristics of Community-Acquired Pneumonia with Airway Malacia in Children

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Oxford University Press
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© The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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0142-6338
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1465-3664
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10.1093/tropej/fmx071
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Abstract

Abstract Objective The objective of this article is to study the etiology of community-acquired pneumonia in children with airway malacia. Methods We retrospectively reviewed the medical records of 428 pneumonia patients. All patients underwent bronchoscopy, and bronchoalveolar lavage samples were processed for microbiological assessment. Results In a total of 428 cases reviewed, 60 were found to have airway malacia. Pathogens were identified in 44 of the 60 specimens (73.3%), with 32 being single-pathogen infections. The most common pathogen was respiratory syncytial virus (RSV; 20%). Mixed-pathogen infections were observed in 12 patients. Airway malacia patients were younger than those without malacia (10.5 vs. 50 months, respectively; p < 0.001). Compared with those without airway malacia, wheezing, cyanosis and admission to the pediatric intensive care unit were more common in children with airway malacia and their hospital stay was longer. Conclusion RSV was the most common pathogen in those with airway malacia. Airway malacia was found to aggravate infectious pneumonia. children, community-acquired pneumonia, airway malacia, pathogen INTRODUCTION Protracted or recurrent pneumonia poses a significant challenge to the pediatricians. Children with airway malacia often have protracted courses of airway infections because dynamic airway collapse during coughing results in impaired mucociliary clearance and retention of tracheobronchial secretions [1–3]. Zhang et al. found that underlying diseases, such as airway abnormalities, are associated with severe acute lower respiratory infections [4]. Furthermore, Gokdemir et al. [5] found that malacia disorders were the most common causes (7.0%) of persistent and recurrent pneumonia. Previous studies have focused on the association among recurrent wheeze, chronic cough and airway malacia, with few reports focusing on the etiologic organisms responsible for recurrent or persistent pneumonia with airway malacia. In a study by Boogaard et al. [5], recurrent lower respiratory tract infections were found in 60 of 96 (63%) patients with airway malacia, and in 77.9% of the children with malacia, at least one pathogen was cultured. A more recent investigation by De Baets et al. [6] reported that 56% of the children reviewed with persistent respiratory symptoms had a positive bronchoalveolar lavage culture. These findings suggest protracted bacterial infection as a possible cause of persistent respiratory symptoms. Little is known about the pathogens and clinical features in protracted and recurrent pneumonia patients with airway malacia. The aim of this study was to determine the pathogens and clinical manifestations of protracted and recurrent pneumonia in children with airway malacia, and to compare these with pneumonia in children with no airway malacia to provide a basis for a reasonable choice of antibiotic. MATERIALS AND METHODS Patients This study was retrospectively conducted on patients with protracted or recurrent pneumonia who were admitted to the Department of Respiratory Disease at the Children’s Hospital Soochow University, China, from January 2014 to December 2015. Protracted pneumonia is defined as a lower respiratory tract infection persisting for ≥30 days; recurrent pneumonia is defined as at least two pneumonia episodes within 1 year [5]. Patients with congenital heart disease, immune deficiency, neuromuscular disease or foreign body aspiration were excluded from the study. Bronchoscopy BAL fluid (BALF) samples were taken from all patients and assessed for respiratory pathogens. ‘Laryngomalacia’ is the inward collapse of the supraglottic structures of the glottis on inspiration, causing airway obstruction. ‘Tracheomalacia’ is a tracheal deformity at the end of expiration, maintained during spontaneous respiration but that can be altered by the passage of the bronchoscope or positive airway pressure. ‘Bronchomalacia’ is the appearance of a deformity in the right or left mainstem bronchi and/or their respective divisions at the lobar or segmental level. Tracheomalacia and/or bronchomalacia can be classified as mild (less than one-third invagination), moderate (one-third to one-half invagination) or severe (more than four-fifth invagination) [7]. For BALF collection, the bronchoscope was inserted into the bronchus and three samples in 1.0 ml/kg normal saline solution were taken. Indications for bronchoscopy include unexplained hemoptysis or chronic excitant cough, pulmonary atelectasis, local stridor, tracheal and bronchial pulmonary hypoplasia and deformity, pulmonary diffuse disease and protracted or recurrent pulmonary infections. Contraindications for bronchoscopy include severe arrhythmia, cardiac failure, severe respiratory failure, severe bleeding tendency and coagulation dysfunction [8]. Detection of pathogens Direct immunofluorescence was used to detect syncytial viral infection (respiratory syncytial virus, RSV), influenza virus A, influenza virus B, parainfluenza virus (PIV) I, PIV II, PIV III and adenovirus (ADV). All assay kits were purchased from Chemicon International, Inc. (Billerica, MA, USA), and all staining procedures were done according to the manufacturer’s instructions. Immunostained preparations were viewed using a Leica 020-518.500 fluorescence microscope (Leica Microsystems, Wetzlar, Germany). Detection of the human metapneumovirus gene The primer sequences for human metapneumovirus (HMPV) were 5ʹ-AACCGTGTACTAAGTGATGCACTC-3ʹ; antisense, 5ʹ-CATTGTTTGACCGGCCCCATAA-3ʹ. HMPV was assayed by fluorescent real-time polymerase chain reaction (RT-PCR) using the iCycler RT-PCR system (Bio-Rad, Hercules, CA, USA). The cyclic temperature settings were 94.0 °C, 30 s; 56.0 °C, 30 s; 72.0 °C, 30 s and were amplified by 40 cycles. Detection of the human bocavirus gene The primer sequences for the human bocavirus (HBoV) gene were HBoV-F: 5ʹ-TGACATTCAACTACCAACAACCTG-3ʹ; HBoV-R: 5ʹ-CAGATCCTTTTCCTCCTCCAATAC-3ʹ; and HBoV-probe: AGCACCACAAAACACCTCAGGGG-TAMRA. HBoV-DNA was detected by RT-PCR. The cyclic temperature settings were 94.0 °C, 30 s; 56.0 °C, 30 s; 72.0 °C, 30 s and were amplified by 40 cycles. Detection of the human rhinovirus gene The primer sequences for human rhinovirus (HRV) were HRV-F: TGG ACA GGG TGT GAA GAG C; HRV-R: CAA AGT AGT CGG TCC CAT CC; and HRV-probe: FAM-TCC TCC GGC CCC TGA ATG-TAMRA. HRV-DNA was detected by RT-PCR. The cyclic temperature settings were 95.0 °C, 5.0 min; 95.0 °C, 15 s; 60.0 °C, 30 s and were amplified by 40 cycles. Detection of bacteria We prepared cultures for quantitative analysis to assess the presence of common aerobic and anaerobic bacteria. Selected media (e.g. Columbia AGAR blood plate, chocolate tablet) were inoculated and placed in a carbon dioxide incubator (50 ml/l) (YAMATO, Ltd, Tokyo, Japan) at 35.0 °C for 18∼24 h. Bacteria were identified based on the characteristics of their colonies, Gram staining, microscopic performance and biochemical reaction. C-reactive protein detection Blood samples were taken from each patient and were measured using the XE–2000i Automated Hematology System (SYSMEX, Kobe, Japan); C-reactive protein (CRP) was detected by immune scattering turbidimetry using the HITACHI 7600-010 automatic biochemical analyzer (Hitachi, Ltd., Tokyo, Japan). Serology testing for Mycoplasma pneumoniae and Chlamydophila pneumonia The presence of specific IgM and IgG antibodies against Mycoplasma pneumoniae (MP) was investigated in serum samples of patients using a commercial ELISA kit (Serion ELISA classic M. pneumoniae IgG/IgM, Institute Virion/Serion, Germany). IgA and IgG antibodies against Chlamydophila pneumoniae were detected with Serion ELISA classic C. pneumoniae IgA/IgG kits. Statistical analyses All data were analyzed using PASW 20.0. Comparisons among groups were performed using the Chi-squared test. Fisher’s exact probability test was used to analyze data that did not meet the requirements for the Chi-squared test. Data that were not normally distributed were compared using the Mann–Whitney U test. Here, p < 0.05 was considered statistically significant. RESULTS Patient characteristics The records of 428 patients were examined for the study. In all, 60 suffered from airway malacia (Table 1); the remaining 368 patients were used as the control group. There were 43 (71.6%) males and 17 (28.3%) females. Seventeen patients (28.3%) were <6.0 months old, 16 (26.7%) were from 6 months to 1.0 year old, 18 (30%) were from 1.0 to 3.0 years old, 5 (8.3%) were from 3.0 to 5.0 years old and 4 (6.7%) were >5.0 years old. The control group (n = 368) was composed of 199 (54.1%) males and 169 (45.9%) females. Patients whose parents refused bronchoscopy and those patients with bronchoscopy contraindications were excluded from the study. The number of patients whose parents refused bronchoscopy was 45. Two patients were with bronchoscopy contraindications. The diagnoses in this group were recurrent/protracted pneumonia (n = 22), bronchial asthma (n = 9), Bordetella pertussis-like symptoms (n = 9), gastroesophageal reflux (n = 2), atelectasis (n = 2), pleural effusion (n = 1), respiratory failure (n = 1) and heart failure (n = 1). Table 1 Airway malacia in patients with community-acquired pneumonia Airway malacia Cases (n) Laryngomalacia 7 Mild tracheomalacia 11 Mild bronchomalacia 23 Moderate bronchomalacia 14 Severe bronchomalacia 1 Laryngotracheobronchomalacia 2 Laryngomalacia and bronchomalacia 1 Laryngotracheomalacia 1 Airway malacia Cases (n) Laryngomalacia 7 Mild tracheomalacia 11 Mild bronchomalacia 23 Moderate bronchomalacia 14 Severe bronchomalacia 1 Laryngotracheobronchomalacia 2 Laryngomalacia and bronchomalacia 1 Laryngotracheomalacia 1 Table 1 Airway malacia in patients with community-acquired pneumonia Airway malacia Cases (n) Laryngomalacia 7 Mild tracheomalacia 11 Mild bronchomalacia 23 Moderate bronchomalacia 14 Severe bronchomalacia 1 Laryngotracheobronchomalacia 2 Laryngomalacia and bronchomalacia 1 Laryngotracheomalacia 1 Airway malacia Cases (n) Laryngomalacia 7 Mild tracheomalacia 11 Mild bronchomalacia 23 Moderate bronchomalacia 14 Severe bronchomalacia 1 Laryngotracheobronchomalacia 2 Laryngomalacia and bronchomalacia 1 Laryngotracheomalacia 1 Pathogens Pathogens were identified in 44 of 60 (73.3%) specimens from patients with airway malacia, of which 32 were single-pathogen infections. RSV was the most common single pathogen affecting 12 cases (37.5%). The most common mixed-pathogen infection was MP + RSV (25.0%) in 12 patients (Table 2). Table 2 Pathogens identified from patients with airway malacia Pathogen Cases (n) Single-pathogen  RSV 12  MP 7  SP 5  PIV III 2  HRV 3  Enterobacter aerogenes 2  Haemophilus influenzae 1 Mixed-pathogen  MP + RSV 12  PIV III + MP 2  SP + HRV 1  HRV+ KP 1  Gram-positive coccus + MP 1  MP + HRV 1  HI + MP 1  SP + MP + HRV 1  Gram-positive coccus + MP + HBoV 1 Pathogen Cases (n) Single-pathogen  RSV 12  MP 7  SP 5  PIV III 2  HRV 3  Enterobacter aerogenes 2  Haemophilus influenzae 1 Mixed-pathogen  MP + RSV 12  PIV III + MP 2  SP + HRV 1  HRV+ KP 1  Gram-positive coccus + MP 1  MP + HRV 1  HI + MP 1  SP + MP + HRV 1  Gram-positive coccus + MP + HBoV 1 Table 2 Pathogens identified from patients with airway malacia Pathogen Cases (n) Single-pathogen  RSV 12  MP 7  SP 5  PIV III 2  HRV 3  Enterobacter aerogenes 2  Haemophilus influenzae 1 Mixed-pathogen  MP + RSV 12  PIV III + MP 2  SP + HRV 1  HRV+ KP 1  Gram-positive coccus + MP 1  MP + HRV 1  HI + MP 1  SP + MP + HRV 1  Gram-positive coccus + MP + HBoV 1 Pathogen Cases (n) Single-pathogen  RSV 12  MP 7  SP 5  PIV III 2  HRV 3  Enterobacter aerogenes 2  Haemophilus influenzae 1 Mixed-pathogen  MP + RSV 12  PIV III + MP 2  SP + HRV 1  HRV+ KP 1  Gram-positive coccus + MP 1  MP + HRV 1  HI + MP 1  SP + MP + HRV 1  Gram-positive coccus + MP + HBoV 1 Pathogens were identified in 249 of 368 specimens with no airway malacia (67.7%) of which 188 were single-pathogen infections. MP was the most common single pathogen affecting 153 cases (81.4%). The most common mixed-pathogen infections were MP + SP (14.8%) in nine patients and MP + Gram-positive coccus (14.8%) in nine patients (Table 3). Table 3 Pathogens identified from patients with no airway malacia Pathogen Cases (n) Single-pathogen  MP 153  SP 10  RSV 5  ADV 3  HBoV 2  PIV III 1  InFA 2  CP 1  PA 3  Enterobacter aerogenes 2  Haemophilus influenzae 3  Gram-positive coccus 1  Moraxella catarrhalis 1 Mixed-pathogen  MP + RSV 6  MP + InFA 3  MP + InFB 2  HRV + SP 1  HRV + KP 1  MP + PA 1  RSV + HBoV 3  Enterococcus + MP 2  MP + Escherichia coli 3  MP + HBoV 3  MP + SP 9  Gram-positive coccus + MP 9  MP + HI 2  RSV + HI 2  MP + CP 3  Neisseria bacteria + MP 1  MP + SA 2  MP + Stenotrophomonas maltophilia 1  SP + HI 1  MP + RSV + SP 2  MP + RSV + HI 1  MP + PinfIII + Enterobacter aerogenes 1 Pathogen Cases (n) Single-pathogen  MP 153  SP 10  RSV 5  ADV 3  HBoV 2  PIV III 1  InFA 2  CP 1  PA 3  Enterobacter aerogenes 2  Haemophilus influenzae 3  Gram-positive coccus 1  Moraxella catarrhalis 1 Mixed-pathogen  MP + RSV 6  MP + InFA 3  MP + InFB 2  HRV + SP 1  HRV + KP 1  MP + PA 1  RSV + HBoV 3  Enterococcus + MP 2  MP + Escherichia coli 3  MP + HBoV 3  MP + SP 9  Gram-positive coccus + MP 9  MP + HI 2  RSV + HI 2  MP + CP 3  Neisseria bacteria + MP 1  MP + SA 2  MP + Stenotrophomonas maltophilia 1  SP + HI 1  MP + RSV + SP 2  MP + RSV + HI 1  MP + PinfIII + Enterobacter aerogenes 1 Table 3 Pathogens identified from patients with no airway malacia Pathogen Cases (n) Single-pathogen  MP 153  SP 10  RSV 5  ADV 3  HBoV 2  PIV III 1  InFA 2  CP 1  PA 3  Enterobacter aerogenes 2  Haemophilus influenzae 3  Gram-positive coccus 1  Moraxella catarrhalis 1 Mixed-pathogen  MP + RSV 6  MP + InFA 3  MP + InFB 2  HRV + SP 1  HRV + KP 1  MP + PA 1  RSV + HBoV 3  Enterococcus + MP 2  MP + Escherichia coli 3  MP + HBoV 3  MP + SP 9  Gram-positive coccus + MP 9  MP + HI 2  RSV + HI 2  MP + CP 3  Neisseria bacteria + MP 1  MP + SA 2  MP + Stenotrophomonas maltophilia 1  SP + HI 1  MP + RSV + SP 2  MP + RSV + HI 1  MP + PinfIII + Enterobacter aerogenes 1 Pathogen Cases (n) Single-pathogen  MP 153  SP 10  RSV 5  ADV 3  HBoV 2  PIV III 1  InFA 2  CP 1  PA 3  Enterobacter aerogenes 2  Haemophilus influenzae 3  Gram-positive coccus 1  Moraxella catarrhalis 1 Mixed-pathogen  MP + RSV 6  MP + InFA 3  MP + InFB 2  HRV + SP 1  HRV + KP 1  MP + PA 1  RSV + HBoV 3  Enterococcus + MP 2  MP + Escherichia coli 3  MP + HBoV 3  MP + SP 9  Gram-positive coccus + MP 9  MP + HI 2  RSV + HI 2  MP + CP 3  Neisseria bacteria + MP 1  MP + SA 2  MP + Stenotrophomonas maltophilia 1  SP + HI 1  MP + RSV + SP 2  MP + RSV + HI 1  MP + PinfIII + Enterobacter aerogenes 1 Comparison of clinical features of CAP patients with and without airway malacia Airway malacia patients were younger than those without malacia (10.5 vs. 50 months, p < .001). The proportion of males with airway malacia was higher than that of females (73.7% vs. 26.7%, p = 0.005). Wheezing, cyanosis and admission to pediatric intensive care unit (PICU) were more common in children with airway malacia (68.3% vs. 30.9%, p < 0.001; 8.3% vs. 0.8%, p = 0.002; 11.7% vs. 3.5%, p = 0.013). The average hospital stay was longer in children with airway malacia (10 days vs. 8.0 days, p = 0.004). MP (81.4%) was the most common single pathogen in CAP patients without airway malacia while virus (56.3%) was the most common pathogen with airway malacia (Table 4). Table 4 Demographic and clinical features of community-acquired pneumonia with or without airway malacia Characteristics No airway deformity (n = 368), n (%) Airway deformity (n = 60) n (%) X2/Z test p Mean age (months) 50.0 (21.0–85.0) 10.5 (4.75–24.25) Z = 7.372 <0.001 Sex  Male 199 (54.1) 44 (73.3)  Female 169 (45.9) 16 (26.7) X2 = 7.796 0.005 Symptom  Cough 357 (97) 59 (98.3) 1.0  Wheezing 114 (30.9) 41 (68.3) X2 = 31.164 <0.001  Fever 252 (68.5) 24 (40) X2 = 18.269 <0.001  Dyspnea 26 (7.1) 8 (13.3) X2 = 2.27 0.132  Cyanosis 3 (0.8) 5 (8.3) 0.002 Physical examination  Lung wheezing rales 114 (30.9) 41 (68.3) X2 = 31.164 <0.001  Lung moisture rales 11 (39.2) 12 (9.3) X2 = 29.359 <0.001 Lab tests WBC (×109) 9.0445 (6.59–13.02) 10.83 (8.0795–15.65) Z = 2.769 0.006 CRP (mg/l) 1.04 (0.2–9.02) 1.03 (0.135–2.915) Z = 1.194 0.233 PICU admission 13 (3.5) 7 (11.7) 0.013 Hospital stay (days) 8.0 (6.0–11.0) 10.0 (7.0–16.0) Z = 2.912 0.004 Cellularity of BALF  Neutrophil (%) 40.0 (15.0–74.0) 39.0 (19.5–67.5) Z = 0.433 0.665  Lymphocyte (%) 3.0 (2.0–7.0) 4.0 (2.0–7.0) Z = 2.157 0.031  Macrophage (%) 51.0 (19.0–81.0) 55.0 (21.5–73.0) Z = 0.23 0.818  Eosinophil (%) 0.0 (0.0–1.0) 0 (0–1.0) Z = 0.151 0.88 Positive pathogen of BALF 249 (67.7) 44 (73.3) X2 = 0.768 0.381  One pathogen 188 (75.5) 32 (72.7) X2 = 0.104 0.747   Mycoplasma pneumoniae 153 (81.4) 6 (18.8) X2 = 10.138 <0.001   Bacteria 21 (11.2) 8 (25) 0.057   Virus 13 (6.9) 18 (56.3) X2 = 25.436 <0.001   Chlamydia pneumoniae 1 (0.5) 0 (0) 1.0  Two pathogens 57 (22.9) 10 (22.7) X2 = 0.054 0.816   MP + CP 3 (5.3) 0 (0) 1.0   MP + virus 15 (26.3) 6 (60) 0.097   MP + bacteria 32 (54.4) 2 (20) 0.292   Virus + bacteria 2 (3.5) 2 (20) 0.096   Two viruses 4 (7) 0 (0) 1.0   Two bacteria 1 (3.5) 0 (0) 1.0  Three pathogens 4 (3.6) 2 (4.5) 0.2   MP + virus + bacteria 3 (75) 2 (100) 0.146   MP + virus + virus 1 (25) 0 (0) 1.0 Characteristics No airway deformity (n = 368), n (%) Airway deformity (n = 60) n (%) X2/Z test p Mean age (months) 50.0 (21.0–85.0) 10.5 (4.75–24.25) Z = 7.372 <0.001 Sex  Male 199 (54.1) 44 (73.3)  Female 169 (45.9) 16 (26.7) X2 = 7.796 0.005 Symptom  Cough 357 (97) 59 (98.3) 1.0  Wheezing 114 (30.9) 41 (68.3) X2 = 31.164 <0.001  Fever 252 (68.5) 24 (40) X2 = 18.269 <0.001  Dyspnea 26 (7.1) 8 (13.3) X2 = 2.27 0.132  Cyanosis 3 (0.8) 5 (8.3) 0.002 Physical examination  Lung wheezing rales 114 (30.9) 41 (68.3) X2 = 31.164 <0.001  Lung moisture rales 11 (39.2) 12 (9.3) X2 = 29.359 <0.001 Lab tests WBC (×109) 9.0445 (6.59–13.02) 10.83 (8.0795–15.65) Z = 2.769 0.006 CRP (mg/l) 1.04 (0.2–9.02) 1.03 (0.135–2.915) Z = 1.194 0.233 PICU admission 13 (3.5) 7 (11.7) 0.013 Hospital stay (days) 8.0 (6.0–11.0) 10.0 (7.0–16.0) Z = 2.912 0.004 Cellularity of BALF  Neutrophil (%) 40.0 (15.0–74.0) 39.0 (19.5–67.5) Z = 0.433 0.665  Lymphocyte (%) 3.0 (2.0–7.0) 4.0 (2.0–7.0) Z = 2.157 0.031  Macrophage (%) 51.0 (19.0–81.0) 55.0 (21.5–73.0) Z = 0.23 0.818  Eosinophil (%) 0.0 (0.0–1.0) 0 (0–1.0) Z = 0.151 0.88 Positive pathogen of BALF 249 (67.7) 44 (73.3) X2 = 0.768 0.381  One pathogen 188 (75.5) 32 (72.7) X2 = 0.104 0.747   Mycoplasma pneumoniae 153 (81.4) 6 (18.8) X2 = 10.138 <0.001   Bacteria 21 (11.2) 8 (25) 0.057   Virus 13 (6.9) 18 (56.3) X2 = 25.436 <0.001   Chlamydia pneumoniae 1 (0.5) 0 (0) 1.0  Two pathogens 57 (22.9) 10 (22.7) X2 = 0.054 0.816   MP + CP 3 (5.3) 0 (0) 1.0   MP + virus 15 (26.3) 6 (60) 0.097   MP + bacteria 32 (54.4) 2 (20) 0.292   Virus + bacteria 2 (3.5) 2 (20) 0.096   Two viruses 4 (7) 0 (0) 1.0   Two bacteria 1 (3.5) 0 (0) 1.0  Three pathogens 4 (3.6) 2 (4.5) 0.2   MP + virus + bacteria 3 (75) 2 (100) 0.146   MP + virus + virus 1 (25) 0 (0) 1.0 Note: Red: Fisher’s exact test; M (P25–P75): Mann–Whitney U-test. Table 4 Demographic and clinical features of community-acquired pneumonia with or without airway malacia Characteristics No airway deformity (n = 368), n (%) Airway deformity (n = 60) n (%) X2/Z test p Mean age (months) 50.0 (21.0–85.0) 10.5 (4.75–24.25) Z = 7.372 <0.001 Sex  Male 199 (54.1) 44 (73.3)  Female 169 (45.9) 16 (26.7) X2 = 7.796 0.005 Symptom  Cough 357 (97) 59 (98.3) 1.0  Wheezing 114 (30.9) 41 (68.3) X2 = 31.164 <0.001  Fever 252 (68.5) 24 (40) X2 = 18.269 <0.001  Dyspnea 26 (7.1) 8 (13.3) X2 = 2.27 0.132  Cyanosis 3 (0.8) 5 (8.3) 0.002 Physical examination  Lung wheezing rales 114 (30.9) 41 (68.3) X2 = 31.164 <0.001  Lung moisture rales 11 (39.2) 12 (9.3) X2 = 29.359 <0.001 Lab tests WBC (×109) 9.0445 (6.59–13.02) 10.83 (8.0795–15.65) Z = 2.769 0.006 CRP (mg/l) 1.04 (0.2–9.02) 1.03 (0.135–2.915) Z = 1.194 0.233 PICU admission 13 (3.5) 7 (11.7) 0.013 Hospital stay (days) 8.0 (6.0–11.0) 10.0 (7.0–16.0) Z = 2.912 0.004 Cellularity of BALF  Neutrophil (%) 40.0 (15.0–74.0) 39.0 (19.5–67.5) Z = 0.433 0.665  Lymphocyte (%) 3.0 (2.0–7.0) 4.0 (2.0–7.0) Z = 2.157 0.031  Macrophage (%) 51.0 (19.0–81.0) 55.0 (21.5–73.0) Z = 0.23 0.818  Eosinophil (%) 0.0 (0.0–1.0) 0 (0–1.0) Z = 0.151 0.88 Positive pathogen of BALF 249 (67.7) 44 (73.3) X2 = 0.768 0.381  One pathogen 188 (75.5) 32 (72.7) X2 = 0.104 0.747   Mycoplasma pneumoniae 153 (81.4) 6 (18.8) X2 = 10.138 <0.001   Bacteria 21 (11.2) 8 (25) 0.057   Virus 13 (6.9) 18 (56.3) X2 = 25.436 <0.001   Chlamydia pneumoniae 1 (0.5) 0 (0) 1.0  Two pathogens 57 (22.9) 10 (22.7) X2 = 0.054 0.816   MP + CP 3 (5.3) 0 (0) 1.0   MP + virus 15 (26.3) 6 (60) 0.097   MP + bacteria 32 (54.4) 2 (20) 0.292   Virus + bacteria 2 (3.5) 2 (20) 0.096   Two viruses 4 (7) 0 (0) 1.0   Two bacteria 1 (3.5) 0 (0) 1.0  Three pathogens 4 (3.6) 2 (4.5) 0.2   MP + virus + bacteria 3 (75) 2 (100) 0.146   MP + virus + virus 1 (25) 0 (0) 1.0 Characteristics No airway deformity (n = 368), n (%) Airway deformity (n = 60) n (%) X2/Z test p Mean age (months) 50.0 (21.0–85.0) 10.5 (4.75–24.25) Z = 7.372 <0.001 Sex  Male 199 (54.1) 44 (73.3)  Female 169 (45.9) 16 (26.7) X2 = 7.796 0.005 Symptom  Cough 357 (97) 59 (98.3) 1.0  Wheezing 114 (30.9) 41 (68.3) X2 = 31.164 <0.001  Fever 252 (68.5) 24 (40) X2 = 18.269 <0.001  Dyspnea 26 (7.1) 8 (13.3) X2 = 2.27 0.132  Cyanosis 3 (0.8) 5 (8.3) 0.002 Physical examination  Lung wheezing rales 114 (30.9) 41 (68.3) X2 = 31.164 <0.001  Lung moisture rales 11 (39.2) 12 (9.3) X2 = 29.359 <0.001 Lab tests WBC (×109) 9.0445 (6.59–13.02) 10.83 (8.0795–15.65) Z = 2.769 0.006 CRP (mg/l) 1.04 (0.2–9.02) 1.03 (0.135–2.915) Z = 1.194 0.233 PICU admission 13 (3.5) 7 (11.7) 0.013 Hospital stay (days) 8.0 (6.0–11.0) 10.0 (7.0–16.0) Z = 2.912 0.004 Cellularity of BALF  Neutrophil (%) 40.0 (15.0–74.0) 39.0 (19.5–67.5) Z = 0.433 0.665  Lymphocyte (%) 3.0 (2.0–7.0) 4.0 (2.0–7.0) Z = 2.157 0.031  Macrophage (%) 51.0 (19.0–81.0) 55.0 (21.5–73.0) Z = 0.23 0.818  Eosinophil (%) 0.0 (0.0–1.0) 0 (0–1.0) Z = 0.151 0.88 Positive pathogen of BALF 249 (67.7) 44 (73.3) X2 = 0.768 0.381  One pathogen 188 (75.5) 32 (72.7) X2 = 0.104 0.747   Mycoplasma pneumoniae 153 (81.4) 6 (18.8) X2 = 10.138 <0.001   Bacteria 21 (11.2) 8 (25) 0.057   Virus 13 (6.9) 18 (56.3) X2 = 25.436 <0.001   Chlamydia pneumoniae 1 (0.5) 0 (0) 1.0  Two pathogens 57 (22.9) 10 (22.7) X2 = 0.054 0.816   MP + CP 3 (5.3) 0 (0) 1.0   MP + virus 15 (26.3) 6 (60) 0.097   MP + bacteria 32 (54.4) 2 (20) 0.292   Virus + bacteria 2 (3.5) 2 (20) 0.096   Two viruses 4 (7) 0 (0) 1.0   Two bacteria 1 (3.5) 0 (0) 1.0  Three pathogens 4 (3.6) 2 (4.5) 0.2   MP + virus + bacteria 3 (75) 2 (100) 0.146   MP + virus + virus 1 (25) 0 (0) 1.0 Note: Red: Fisher’s exact test; M (P25–P75): Mann–Whitney U-test. Comparison of clinical features of single- and mixed-pathogen infection in CAP patients without airway malacia Of those CAP patients without airway malacia, the proportion of males with mixed-pathogen infections was higher than that of females. CRP was higher in those with mixed-pathogen infections without airway malacia than in those with single-pathogen infections (Table 5). Table 5 Demographic and clinical features of single-pathogen and mixed-pathogen infections in community-acquired pneumonia without airway malacia Characteristics Single-pathogen infection (n = 188), n (%) Mixed-pathogen infection (n = 61) n (%) X2/Z test p Mean age (months) 49.5 (23.0–80.75) 53.0 (19.0–83.25) Z = 0.535 0.593 Sex  Male 93 (54.1) 44 (73.3)  Female 95 (45.9) 17 (26.7) X2 = 9.558 0.002 Symptom  Cough 183 (97.3) 59 (96.7) 0.681  Wheezing 60 (31.9) 21 (34.4) X2 = 0.132 0.716  Fever 127 (67.6) 46 (75.4) X2 = 1.341 0.247  Dyspnea 7 (3.7) 6 (9.8) 0.092  Cyanosis 3 (1.6) 0 (0) 1.0 Physical examination  Lung wheezing rales 58 (30.9) 21 (34.4) X2 = 0.272 0.602  Lung moisture rales 115 (61.2) 33 (54.1) X2 = 0.955 0.328 Lab tests WBC (×109) 8.93 (6.555–13.09) 8.86 (6.77–15.28) Z = 0.422 0.673 CRP (mg/l) 0.41 (0.1–1.65) 3.7045 (0.275–12.515) Z = 3.49 0.001 PICU admission 6 (3.2) 3 (4.9) 0.693 Hospital stay (days) 9.0 (7.0–12.0) 8.0 (6.0–10.0) Z = 1.6 0.11 Characteristics Single-pathogen infection (n = 188), n (%) Mixed-pathogen infection (n = 61) n (%) X2/Z test p Mean age (months) 49.5 (23.0–80.75) 53.0 (19.0–83.25) Z = 0.535 0.593 Sex  Male 93 (54.1) 44 (73.3)  Female 95 (45.9) 17 (26.7) X2 = 9.558 0.002 Symptom  Cough 183 (97.3) 59 (96.7) 0.681  Wheezing 60 (31.9) 21 (34.4) X2 = 0.132 0.716  Fever 127 (67.6) 46 (75.4) X2 = 1.341 0.247  Dyspnea 7 (3.7) 6 (9.8) 0.092  Cyanosis 3 (1.6) 0 (0) 1.0 Physical examination  Lung wheezing rales 58 (30.9) 21 (34.4) X2 = 0.272 0.602  Lung moisture rales 115 (61.2) 33 (54.1) X2 = 0.955 0.328 Lab tests WBC (×109) 8.93 (6.555–13.09) 8.86 (6.77–15.28) Z = 0.422 0.673 CRP (mg/l) 0.41 (0.1–1.65) 3.7045 (0.275–12.515) Z = 3.49 0.001 PICU admission 6 (3.2) 3 (4.9) 0.693 Hospital stay (days) 9.0 (7.0–12.0) 8.0 (6.0–10.0) Z = 1.6 0.11 Note: Red: Fisher’s exact test. Table 5 Demographic and clinical features of single-pathogen and mixed-pathogen infections in community-acquired pneumonia without airway malacia Characteristics Single-pathogen infection (n = 188), n (%) Mixed-pathogen infection (n = 61) n (%) X2/Z test p Mean age (months) 49.5 (23.0–80.75) 53.0 (19.0–83.25) Z = 0.535 0.593 Sex  Male 93 (54.1) 44 (73.3)  Female 95 (45.9) 17 (26.7) X2 = 9.558 0.002 Symptom  Cough 183 (97.3) 59 (96.7) 0.681  Wheezing 60 (31.9) 21 (34.4) X2 = 0.132 0.716  Fever 127 (67.6) 46 (75.4) X2 = 1.341 0.247  Dyspnea 7 (3.7) 6 (9.8) 0.092  Cyanosis 3 (1.6) 0 (0) 1.0 Physical examination  Lung wheezing rales 58 (30.9) 21 (34.4) X2 = 0.272 0.602  Lung moisture rales 115 (61.2) 33 (54.1) X2 = 0.955 0.328 Lab tests WBC (×109) 8.93 (6.555–13.09) 8.86 (6.77–15.28) Z = 0.422 0.673 CRP (mg/l) 0.41 (0.1–1.65) 3.7045 (0.275–12.515) Z = 3.49 0.001 PICU admission 6 (3.2) 3 (4.9) 0.693 Hospital stay (days) 9.0 (7.0–12.0) 8.0 (6.0–10.0) Z = 1.6 0.11 Characteristics Single-pathogen infection (n = 188), n (%) Mixed-pathogen infection (n = 61) n (%) X2/Z test p Mean age (months) 49.5 (23.0–80.75) 53.0 (19.0–83.25) Z = 0.535 0.593 Sex  Male 93 (54.1) 44 (73.3)  Female 95 (45.9) 17 (26.7) X2 = 9.558 0.002 Symptom  Cough 183 (97.3) 59 (96.7) 0.681  Wheezing 60 (31.9) 21 (34.4) X2 = 0.132 0.716  Fever 127 (67.6) 46 (75.4) X2 = 1.341 0.247  Dyspnea 7 (3.7) 6 (9.8) 0.092  Cyanosis 3 (1.6) 0 (0) 1.0 Physical examination  Lung wheezing rales 58 (30.9) 21 (34.4) X2 = 0.272 0.602  Lung moisture rales 115 (61.2) 33 (54.1) X2 = 0.955 0.328 Lab tests WBC (×109) 8.93 (6.555–13.09) 8.86 (6.77–15.28) Z = 0.422 0.673 CRP (mg/l) 0.41 (0.1–1.65) 3.7045 (0.275–12.515) Z = 3.49 0.001 PICU admission 6 (3.2) 3 (4.9) 0.693 Hospital stay (days) 9.0 (7.0–12.0) 8.0 (6.0–10.0) Z = 1.6 0.11 Note: Red: Fisher’s exact test. Comparison of clinical features of single- and mixed-pathogen infections in CAP with airway malacia There was no significant difference in clinical characteristics, such as age, fever, wheezing, dyspnea, cyanosis, admission to PICU and hospital stay, between patients with single-pathogen infections and those with mixed-pathogen infections in CAP with airway malacia (Table 6). Table 6 Demographic and clinical features of single-pathogen and mixed-pathogen infections in CAP patients with airway malacia Characteristics Single-pathogen infection (n = 32), n (%) Mixed-pathogen infection (n = 12), n (%) X2/Z test p Mean age (months) 10.5 (4.0–23.0) 7.5 (4.5–14.5) Z = 0.158 0.874 Sex  Male 24 (75) 9 (75)  Female 8 (25) 3 (25) 1.0 Symptom  Cough 31 (96.8) 12 (100) 1.0  Wheezing 20 (62.5) 10 (83.3) 0.282  Fever 12 (37.5) 4 (41.7) 1.0  Dyspnea 6 (18.8) 2 (16.7) 1.0  Cyanosis 3 (9.4) 2 (16.7) 0.603 Physical examination  Lung wheezing rales 18 (56.3) 8 (66.7) 0.733  Lung moisture rales 23 (71.8) 11 (91.7) 0.241 Lab tests WBC (×109) 10.05 (7.96–13.51) 13.07 (9.04–18.44) Z = 1.814 0.07 CRP (mg/l) 1.84 (0.115–3.2775) 1.94 (0.275–6.1675) Z = 0.514 0.607 PICU admission 5 (15.6) 2 (16.7) 1.0 Hospital stay (days) 9.0 (7.25–15.0) 12.5 (8.5–17.0) Z = 1.23 0.219 Characteristics Single-pathogen infection (n = 32), n (%) Mixed-pathogen infection (n = 12), n (%) X2/Z test p Mean age (months) 10.5 (4.0–23.0) 7.5 (4.5–14.5) Z = 0.158 0.874 Sex  Male 24 (75) 9 (75)  Female 8 (25) 3 (25) 1.0 Symptom  Cough 31 (96.8) 12 (100) 1.0  Wheezing 20 (62.5) 10 (83.3) 0.282  Fever 12 (37.5) 4 (41.7) 1.0  Dyspnea 6 (18.8) 2 (16.7) 1.0  Cyanosis 3 (9.4) 2 (16.7) 0.603 Physical examination  Lung wheezing rales 18 (56.3) 8 (66.7) 0.733  Lung moisture rales 23 (71.8) 11 (91.7) 0.241 Lab tests WBC (×109) 10.05 (7.96–13.51) 13.07 (9.04–18.44) Z = 1.814 0.07 CRP (mg/l) 1.84 (0.115–3.2775) 1.94 (0.275–6.1675) Z = 0.514 0.607 PICU admission 5 (15.6) 2 (16.7) 1.0 Hospital stay (days) 9.0 (7.25–15.0) 12.5 (8.5–17.0) Z = 1.23 0.219 Note: Red: Fisher’s exact test. Table 6 Demographic and clinical features of single-pathogen and mixed-pathogen infections in CAP patients with airway malacia Characteristics Single-pathogen infection (n = 32), n (%) Mixed-pathogen infection (n = 12), n (%) X2/Z test p Mean age (months) 10.5 (4.0–23.0) 7.5 (4.5–14.5) Z = 0.158 0.874 Sex  Male 24 (75) 9 (75)  Female 8 (25) 3 (25) 1.0 Symptom  Cough 31 (96.8) 12 (100) 1.0  Wheezing 20 (62.5) 10 (83.3) 0.282  Fever 12 (37.5) 4 (41.7) 1.0  Dyspnea 6 (18.8) 2 (16.7) 1.0  Cyanosis 3 (9.4) 2 (16.7) 0.603 Physical examination  Lung wheezing rales 18 (56.3) 8 (66.7) 0.733  Lung moisture rales 23 (71.8) 11 (91.7) 0.241 Lab tests WBC (×109) 10.05 (7.96–13.51) 13.07 (9.04–18.44) Z = 1.814 0.07 CRP (mg/l) 1.84 (0.115–3.2775) 1.94 (0.275–6.1675) Z = 0.514 0.607 PICU admission 5 (15.6) 2 (16.7) 1.0 Hospital stay (days) 9.0 (7.25–15.0) 12.5 (8.5–17.0) Z = 1.23 0.219 Characteristics Single-pathogen infection (n = 32), n (%) Mixed-pathogen infection (n = 12), n (%) X2/Z test p Mean age (months) 10.5 (4.0–23.0) 7.5 (4.5–14.5) Z = 0.158 0.874 Sex  Male 24 (75) 9 (75)  Female 8 (25) 3 (25) 1.0 Symptom  Cough 31 (96.8) 12 (100) 1.0  Wheezing 20 (62.5) 10 (83.3) 0.282  Fever 12 (37.5) 4 (41.7) 1.0  Dyspnea 6 (18.8) 2 (16.7) 1.0  Cyanosis 3 (9.4) 2 (16.7) 0.603 Physical examination  Lung wheezing rales 18 (56.3) 8 (66.7) 0.733  Lung moisture rales 23 (71.8) 11 (91.7) 0.241 Lab tests WBC (×109) 10.05 (7.96–13.51) 13.07 (9.04–18.44) Z = 1.814 0.07 CRP (mg/l) 1.84 (0.115–3.2775) 1.94 (0.275–6.1675) Z = 0.514 0.607 PICU admission 5 (15.6) 2 (16.7) 1.0 Hospital stay (days) 9.0 (7.25–15.0) 12.5 (8.5–17.0) Z = 1.23 0.219 Note: Red: Fisher’s exact test. Associations between severity of airway malacia and PICU stay and duration of hospitalization No statistically significant associations between severity of airway malacia and PICU admission and duration of hospitalization were observed in the airway malacia group (Table 7). Table 7 Associations between severity of airway malacia and admission to the PICU and duration of hospitalization Characteristics Mild malacia (n = 43) Moderate malacia (n = 14) Severe malacia (n = 3) Kruskal–Wallis/Fisher p PICU admission 6 (13.9) 0 (0) 1 (33.3) 2.064 >0.05 Duration of hospitalization 12.23 ± 6.34 9.5 ± 5.56 12.0 ± 11.36 3.565 >0.05 Characteristics Mild malacia (n = 43) Moderate malacia (n = 14) Severe malacia (n = 3) Kruskal–Wallis/Fisher p PICU admission 6 (13.9) 0 (0) 1 (33.3) 2.064 >0.05 Duration of hospitalization 12.23 ± 6.34 9.5 ± 5.56 12.0 ± 11.36 3.565 >0.05 Table 7 Associations between severity of airway malacia and admission to the PICU and duration of hospitalization Characteristics Mild malacia (n = 43) Moderate malacia (n = 14) Severe malacia (n = 3) Kruskal–Wallis/Fisher p PICU admission 6 (13.9) 0 (0) 1 (33.3) 2.064 >0.05 Duration of hospitalization 12.23 ± 6.34 9.5 ± 5.56 12.0 ± 11.36 3.565 >0.05 Characteristics Mild malacia (n = 43) Moderate malacia (n = 14) Severe malacia (n = 3) Kruskal–Wallis/Fisher p PICU admission 6 (13.9) 0 (0) 1 (33.3) 2.064 >0.05 Duration of hospitalization 12.23 ± 6.34 9.5 ± 5.56 12.0 ± 11.36 3.565 >0.05 DISCUSSION Current management of lower respiratory tract infections in children with airway malacia, which includes liberal use of antibiotics and physiotherapy, is not evidence based [9]; therefore, determining the correct pathogen is particularly important for determining the correct treatment. This is the first study examining the etiology of pneumonia with airway malacia in China. Of the 60 protracted and recurrent CAP cases with airway malacia, with a positive pathogen detection rate of 73.3%, we found RSV to be the most common pathogen, followed by SP and MP. However, in CAP patients without airway malacia, MP was the most common pathogen, the results of which are different from those of previous reports of 10–40% [10, 11]. In addition, RSV and MP incidences were higher than those in previous reports [12, 13]. De Baets et al. [6] studied 124 children with persistent respiratory symptoms and fiberoptic bronchoscopy with BAL were performed; they found that 47% of cases had structural abnormality of the central airways, 56% of BAL samples tested positive for bacterial culture with Moraxella catarrhalis (51%), HI (28%), SP (13%), Staphylococcus aureus (10%). The pathogen detection rate was higher than that in our study, and the pathogen was different. In those patients with tracheobronchomalacia, which lack specific clinical symptoms, Pan et al. [14] studied 459 cases of children with airway malacia and found chronic cough and wheezing to be the main clinical manifestations, accompanied by difficulty in breathing, fever and sputum production. In the present study, we found that wheezing and cyanosis were common in patients with airway malacia. Patients with airway malacia had higher rates of admission to PICU and longer hospital stays, suggesting that airway malacia aggravated the disease. However, no significant associations between severity of airway malacia and PICU admission and duration of hospitalization were observed. Our study was consistent with Masters et al. [15], who reported that children with malacia have an increased disease severity and a tendency for delayed recovery. Whether mixed-pathogen infection increases the severity of pneumonia remains controversial. Some studies showed that viruses and bacteria in a mixed-pathogen infection prolongs hospitalization and increases the risk of admission to PICU [16–19]. However, other studies have shown no significant difference between average hospital stay, hospitalization rates and mortality when comparing mixed-pathogen infections with single-pathogen infections in patients with pneumonia [20–22]. In our study, we found the CRP level was higher in the mixed-pathogen infection group. The rate of admission to PICU and the length of hospital stay showed no obvious differences between the two groups, indicating that mixed-pathogen infections have no relationship to protracted and recurrent CAP patient mortality. CONCLUSIONS This study found that airway malacia is the underlying cause predisposing to persistence or recurrence of pneumonia in children; co-existing airway malacia did aggravate the disease. RSV was the most common pathogen, and mixed-pathogen infection accounted for 20% of infections. Thus, when treating children with protract and recurrent pneumonia who do not respond to antibiotics treatment, clinicians should consider airway malacia as a possible precipitant and perform a bronchoscopy. Study Limitations This study had some limitations. First, it was a retrospective study. Second, it was a single-center study. Third, there was no study of potential fungal pathogens. Finally, there was a certain selection bias because patients who refused bronchoscopy were not included in the study. ACKNOWLEDGEMENTS This work was supported by a grant from the National Natural Science Foundation of China (No. 81573167). Funding This work was supported by National Natural Science Foundation of China (81573167), Science and Technology Projects of Jiangsu Province (2017657) and Science and Technology Projects of Suzhou (SYS201436). References 1 Lodha R , Kabra SK. Recurrent/persistent pneumonia . Indian Pediatr 2000 ; 37 : 1085 – 92 . 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Braz J Infect Dis 2007 ; 11 : 507 – 14 . Google Scholar CrossRef Search ADS PubMed 11 Eun BW , Kim NH , Choi EH , et al. Mycoplasma pneumoniae in Korean children: the epidmiology of pneumonia over an 18-year period [J] . J Infect 2008 ; 56 : 326 – 31 . Google Scholar CrossRef Search ADS PubMed 12 Bezerra PG , Britto MC , Correia JB , et al. Viral and atypical bacterial detection in acute respiratory infection in children under five years[J] . PLoS One 2011 ; 6 : e18928 . Google Scholar CrossRef Search ADS PubMed 13 Feikin DR , Njenga MK , Bigogo G , et al. Etiology and Incidence of viral and bacterial acute respiratory illness among older children and adults in rural western Kenya, 2007-2010 . PLoS One 2012 ; 7 : e43656 . Google Scholar CrossRef Search ADS PubMed 14 Pan W , Peng D , Luo J , et al. Clinical features of airway malacia a retrospective analysis of 459 patients . Int J Clin Exp Med ; 7 : 3005 – 12 . PubMed 15 Masters IB , Zimmerman PV , Pandeya N , et al. Quantified tracheobronchomalacia disorders and their clinical profiles in children . Chest 2008 ; 133 : 461 – 7 . Google Scholar CrossRef Search ADS PubMed 16 Kurz H , Gopfrich H , Huber K , et al. Spectrum of pathogens of in-patient children and youths with community acquired pneumonia: a 3 year survey of a community hospital in Vienna, Austria . Wien Klin Wochenschr 2013 ; 125 : 674 – 9 . Google Scholar CrossRef Search ADS PubMed 17 Ghani AS , Morrow BM , Hardie DR , et al. An investigation into the prevalence and outcome of patients admitted to a pediatric intensive care unit with viral respiratory tract infections in Cape Town, South Africa . Pediatr Crit Care Med 2012 ; 13 : e275 – 81 . Google Scholar CrossRef Search ADS PubMed 18 Resch B , Gusenleitner W , Mueller WD. Risk of concurrent bacterial infection in preterm infants hospitalized due to respiratory syncytial virus infection . Acta Paediatr 2007 ; 96 : 495 – 8 . 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Google Scholar CrossRef Search ADS PubMed © The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Tropical PediatricsOxford University Press

Published: Aug 1, 2018

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