Scandinavian Journal of Infectious Diseases, 2014; 46: 486–492

ORIGINAL ARTICLE

Relationships between the varied ciliated respiratory epithelium abnormalities and severity of Mycoplasma pneumoniae pneumonia

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WUJUN JIANG1, LULU QIAN2, HUI LIANG2, MAN TIAN2, FENG LIU2 & DEYU ZHAO2 From the 1Department of Respiratory Medicine, Children’s Hospital Affiliated to Soochow University, Suzhou, and 2Department of Respiratory Medicine, the Affiliated Nanjing Children’s Hospital of Nanjing Medical University, Nanjing, China

Abstract Background: The pathogenesis of Mycoplasma pneumoniae infection involves cytoadherence of M. pneumoniae to the ciliated respiratory epithelium (CRE), followed by CRE injury caused by the M. pneumoniae. However, whether CRE abnormalities are related to the severity of M. pneumoniae pneumonia (MP) remains to be determined. Methods: Thirty-eight patients with MP and 8 controls who underwent fiber-optic bronchoscopy with bronchial biopsy were included in this study. Patients with MP were divided into 2 groups: a mild disease group (12 patients) and a severe disease group (26 patients). The clinical features, laboratory findings, chest radiographic findings, and CRE abnormalities were characterized. Results: Patients with severe pneumonia had a higher epithelial integrity score than those with mild pneumonia (5.1 ⫾ 0.76 vs 3.8 ⫾ 0.75; p ⬍ 0.01). Patients with severe CRE abnormalities had a longer duration of fever (p ⬍ 0.01), higher C-reactive protein (p ⬍ 0.01), and lower proportion of blood lymphocytes (p ⬍ 0.05) compared to those with mild abnormalities. Patients with a positive bacteria culture had a higher epithelial integrity score compared to those with a negative culture (6.0 ⫾ 0.44 vs 4.8 ⫾ 0.71; p ⬍ 0.01). Conclusions: CRE abnormalities are closely related to the severity of MP. These findings extend our current knowledge of MP.

Keywords: Ciliated respiratory epithelium, Mycoplasma pneumoniae pneumonia, children

Introduction Mycoplasma pneumoniae is an important causative organism of respiratory infections in children. M. pneumoniae infection is typically mild and selflimited. There are, however, several reports suggesting that severe M. pneumoniae infection leads to longstanding pulmonary sequelae such as bronchiectasis [1,2] and bronchiolitis obliterans [3,4]. The pathogenesis of M. pneumoniae in respiratory infection is still not thoroughly understood. It is generally acknowledged that the initial event in the pathogenic process involves cytoadherence of M. pneumoniae to the ciliated respiratory epithelium (CRE), followed by CRE injury caused by M. pneumoniae [5,6]. A study in children showed severe M. pneumoniae pneumonia (MP) to be associated with low lymphocyte counts, a long period of fever, and high CRP levels [7]. Also, lymphopenia has been demonstrated

in adult patients with severe MP [8,9]. Bacterial load has also been shown to be associated with the severity of MP disease [10]. However, whether CRE abnormalities are in line with the severity of MP appears to be less well known. The aim of this study was to identify any association between CRE abnormalities and the severity of MP. The clinical features, laboratory findings, chest radiographic findings, and CRE abnormalities were characterized in children with MP.

Patients and methods Study population The study participants included 38 patients with MP and 8 controls; all underwent fiber-optic bronchoscopy with bronchial biopsy at the Affiliated Nanjing

Correspondence: D. Zhao, Department of Respiratory Medicine, the Affiliated Nanjing Children’s Hospital of Nanjing Medical University, No. 72 Guangzhou Road, Nanjing 210008, China. Tel/Fax: ⫹86 25 83117367. E-mail: [email protected] (Received 3 November 2013 ; accepted 29 December 2013) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2014.885658

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Epithelium abnormalities in Mycoplasma infection Children’s Hospital of Nanjing Medical University between 2009 and 2012. The MP group consisted of 38 consecutive patients (18 boys and 20 girls; median age 7.5 y, range 4.0– 13.0 y) who had a clinical condition requiring hospitalization. The diagnosis of MP was based on symptoms and signs (fever, dyspnea, cough, rales, etc.), radiologic findings, and a 4-fold or greater increase in the titer of anti-Mycoplasma antibodies in acute and convalescent sera [11]. The titration of anti-Mycoplasma antibodies in serum was performed using the indirect particle agglutination test (Serodia-Myco II, Fujirebio, Japan). A real-time polymerase chain reaction (PCR) assay using nasopharyngeal aspirates was applied for the early detection of MP infection [12]. Nasopharyngeal aspirates were obtained within 24 h of admission. A quantitative diagnostic kit (DaAn Gene Co., Ltd, Guangzhou, China) for M. pneumoniae DNA was used to measure the load of M. pneumoniae. Flexible bronchoscopy was indicated when radiographic findings showed lobar/segmental consolidation or atelectasis after appropriate antibiotic treatment for 1 week. Those with the following conditions were excluded: immunocompromised disease, hospitalization within 12 weeks before diagnosis, underlying pulmonary disease including asthma, bronchiectasis, tuberculosis, and primary ciliary dyskinesia, and treatment with corticoids or immunosuppressants for other diseases. We divided the 38 patients into 2 groups according to the severity of pneumonia, as described previously [13]; 12 patients were in the mild disease group and 26 in the severe disease group. The severe disease group was defined by the presence of 2 or more of the following features: respiratory rate higher than the World Health Organization classification for age, apnea, increased work of breathing (e.g. retractions, dyspnea, nasal flaring, grunting), PaO2/FiO2 ratio ⬍ 250, multilobar infiltrates, altered mental status, hypotension, presence of effusion, comorbid conditions (e.g. immunosuppression or immunodeficiency), and unexplained metabolic acidosis. A control group comprised 8 patients with suspected foreign body aspiration. Foreign body aspiration was excluded after bronchoscopy.Their leukocyte count and C-reactive protein (CRP) concentration were within the normal range. A computed tomography (CT) scan of the chest showed no infiltration. Patients and their parents were informed of the exact nature and the goal of any of the investigations performed and gave their informed consent. Flexible bronchoscopy with bronchoalveolar lavage and biopsy All patients received nothing by mouth for at least 8 h prior to the procedure. Premedications included

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diazepam 0.2 mg/kg and atropine 0.02 mg/kg, given intramuscularly 30 min prior to the procedure. The procedures were carried out with a bronchofiberscope (Olympus BF-P260F or Pentax FB-10V, depending on age; by transnasal approach) under intravenous anesthesia with propofol. Under direct vision, the vocal cords were furthered anesthetized with 1% lidocaine through the bronchoscope suction and biopsy channel. Heart rate and transcutaneous oxygen saturation were monitored throughout the procedure, and monitoring was continued for 4 h. Bronchoalveolar lavage (BAL) was performed in an area most prominently affected on the chest radiographs by gently wedging the tip of the bronchoscope in a segmental or subsegmental bronchus. Two 1-ml/kg aliquots of sterile, non-bacteriostatic saline at room temperature were instilled through the instrumentation channel. Each aliquot was immediately aspirated into a sterile specimen container using a wall suction pressure of 100 to 150 mmHg. BAL fluid aspirated after each instillation was pooled together into a single specimen. Standard biopsy forceps that accompany the bronchoscope were passed peripherally in the closed position until mild resistance was met. A bronchial biopsy was performed in the same area as the BAL. All bronchial biopsies were performed by a single experienced bronchoscopist (HL). The bronchoscopist was unaware of the patient’s clinical condition. Processing and analysis of the BAL fluid Pooled BAL fluid was separated into 2 aliquots. One aliquot was submitted to the microbiology department for bacterial culture. The other was taken to the pathology department for analysis of the cellular fractions. Differentials were obtained from CytoSpin (Shandon, Pittsburgh, PA, USA) slide preparations, using a May–Grünwald–Giemsa stain and by calculating a percentage of 400 cells. Processing and analysis of the CRE abnormalities On the day of collection, tissue submitted for ultrastructural evaluation was fixed in 5% glutaraldehyde. After 48 h, post-fixation was performed using 1% osmium tetroxide and 0.1 M cacodylate at pH 7.2 to 7.4. Sections of 40–60 nm were collected on 200 mesh thin-bar copper grids and stained in uranyl acetate and lead citrate. The sections were then examined by transmission electron microscopy. The ciliated epithelium was assessed in a blinded fashion for both epithelial and ciliary ultrastructural changes. Dynein arms were considered to be absent when the structure was missing from at least 6 of the 9 peripheral doublets. To facilitate the definition of axonemal

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abnormalities, the central structures (central microtubules and central sheath) were termed the ‘central complexes’, as described previously. Abnormalities of peripheral microtubules included absence of doublet(s) and supernumerary microtubule(s). Ciliary ultrastructural results were expressed as a percentage of abnormal cilia among the total number of cilia analyzed. As some cilia in control specimens can exhibit ultrastructural defects, a cut-off value of 15% abnormal cilia is usually considered to be abnormal. Disruption and damage to the tissue for each patient was scored for the following parameters: (1) loss of cilia from ciliated cells: 0 (fully ciliated), 1 (minor), 2 (major), 3 (total loss of cilia); (2) cytoplasmic blebbing: 0 (absent), 1 (minor), 2 (major); (3) mitochondrial damage: 0 (absent), 1 (present); (4) absence of dynein arms: 0 (absent), 1 (present); (5) central complex defects: 0 (absent), 1 (present); (6) abnormalities of peripheral microtubules: 0 (absent), 1 (present). To give an overall evaluation of CRE abnormalities, an epithelial integrity score was given to the epithelium, which incorporated ciliary loss, cytoplasmic blebbing and mitochondrial damage, and ciliary ultrastructural changes. The epithelial integrity score was grouped into 2 categories, mild (1–4) and severe (ⱖ 5) CRE abnormalities. All CRE abnormalities were evaluated independently by 2 pathologists who had no knowledge of the patient’s clinical condition. Differences in interpretation were resolved by joint assessment and consensus between the 2 examiners.

Statistical analysis The statistical analysis was performed using GraphPad Prism 5 and SPSS for Windows version v. 13.0 software. Non-parametric data were described as the median with the interquartile range (IQR). Groups were initially compared using the Kruskal–Wallis test. A p-value of ⬍ 0.05 was considered statistically significant.

Results All the patients received erythromycin and a third-generation cephalosporin after admission. Thirty-three patients (7 in the mild group and 26 in the severe group) received corticosteroids because of fever persisting for 48 h after admission. Four patients in the severe group received intravenous immunoglobulin. Thoracentesis was performed in 6 patients in the severe group. Pleural fluid culture was performed in the 6 patients. Flexible bronchoscopy was performed 1 week after admission. Flexible bronchoscopy with biopsy was relatively well-tolerated by all patients. Minor procedureassociated complications occurred on 3 occasions, including transient hypoxia (n ⫽ 2) and minor epistaxis (n ⫽ 5). These complications did not preclude the completion of the procedure. Two children had a transitory hoarse cough after the procedure, which resolved spontaneously within 24 h.

Table I Baseline characteristics of the patients.a

Characteristic Age, y Sex, male/female, n Macrolide usage before diagnosis Duration of fever, days Chest CT findings Multilobar infiltrates Presence of effusion Blood leukocytes, ⫻ 103/μl Neutrophil, % Lymphocyte, % CRP, mg/dl Elevated ALT, ⬎ 40 U/l Positive PCR findings in nasopharyngeal aspirates Positive bacteria culture from pleural fluid or BAL fluid Streptococcus pneumoniae Haemophilus influenzae Staphylococcus aureus Escherichia coli Epithelial integrity score

Mild group (n ⫽ 12)

Severe group (n ⫽ 26)

Control group (n ⫽ 8)

7.8 (7.0–8.7) 6/6 5 (41.6%) 8 (7–9)

7.3 (4.4–9.2) 12/14 15 (57.7%) 14.5 (9.8–20.0)b

8.3 (7.3–11.2) 5/3 – –

0 (16.7%) (5.3–13.0) (58.5–73.7) (24.0–34.2) (8.0–41.8) (16.7%) (100%) (16.7%) 2 – – – 3.8 (0.75)

26 15 8.0 83.0 11.3 87.0 12 26 8

2 7.3 61.7 28 12.0 2 12 2

(100%)b (57.7%) (6.4–12.9) (71.1–87.4)b (9.6–22.5)b (18.3–129.8)b (46.2%) (100%) (30.8%) 3 2 1 2 5.1 (0.76)b

– – 6.8. (5.0–9.1) 60.2 (54.1–69.4) 32.1 (26.2–35.6) 2.1 (0.1–5.3) 0 0 – – – – – 0

CT, computed tomography; CRP, C-reactive protein; ALT, alanine aminotransferase; PCR, polymerase chain reaction; BAL, bronchoalveolar lavage; IQR, interquartile range; SD, standard deviation. aData expressed as n (%), median (IQR), or mean (SD). bp ⬍ 0.05 compared to the mild group.

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Figure 1. (A) Ciliated respiratory epithelium from a healthy control showing normal mitochondria (arrow); epithelial integrity score ⫽ 0. (B) Mild ciliated respiratory epithelium (CRE) abnormalities showing minor loss of cilia, minor cytoplasmic bleb (black arrow), and abnormal mitochondria (white arrow); epithelial integrity score ⫽ 3. (C) Mild CRE abnormalities showing minor loss of cilia, major cytoplasmic bleb, and abnormal mitochondria; epithelial integrity score ⫽ 4. (D) Severe CRE abnormalities showing major loss of cilia, major cytoplasmic bleb (black arrow), and abnormal mitochondria (white arrow); epithelial integrity score ⫽ 5. (E) Severe CRE abnormalities with hypoplasia of epithelial cells, ciliated cells with total loss of cilia, cytoplasmic blebbing, and disruption of tight junctions with separation of cells; epithelial integrity score ⫽ 6. Internal scale bar ⫽ 2 μm.

Table I shows the baseline characteristics of subjects with MP. There were no significant differences in age, sex, or blood leukocyte counts. Patients with severe pneumonia showed a longer duration of fever (p ⬍ 0.01), lower lymphocyte differential (p ⫽ 0.02), and higher C-reactive protein (CRP) level (p ⫽ 0.01). BAL fluid differentials may be important, but insufficient data were available for an analysis of this factor because it could not be assessed in 12 patients (4 in the mild group and 8 in the severe group). Patients with severe pneumonia had higher epithelial integrity scores compared to those with mild pneumonia (5.1 ⫾ 0.76 vs 3.8 ⫾ 0.75; p ⬍ 0.01). All 8 patients in the control group had normal CRE (epithelial integrity score ⫽ 0). Representative images of CRE abnormalities and ciliary ultrastructural abnormalities are shown in Figures 1 and 2.

We also examined the correlation between CRE abnormalities and fever duration, CRP, proportion of blood lymphocytes, and alanine aminotransferase (ALT) in patients with MP. We found a longer duration of fever in patients with severe CRE abnormalities versus mild abnormalities (p ⬍ 0.01; Figure 3A). The CRP level was higher in patients with severe CRE abnormalities than in patients with mild abnormalities (p ⬍ 0.01; Figure 3B). The proportion of blood lymphocytes was lower in patients with severe CRE abnormalities than in those with mild abnormalities (p ⬍ 0.05; Figure 3C). Although we did not find a significant difference in ALT levels between patients with mild and severe abnormalities, there was a trend towards higher ALT in patients with severe abnormalities (p ⫽ 0.10; Figure 3D). Ten patients (2 in the mild group and 8 in the severe group) showed bacteria in culture from

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Figure 2. Various main ultrastructural defects of respiratory cilia. (A) Normal ciliary ultrastructure: cross-section of cilia showing ‘9 ⫹ 2’ microtubule doublet. (B) Abnormalities of peripheral microtubules; note the presence of microtubules with missing structures (black arrow) and free microtubular doublets (white arrow). (C) The presence of compound cilia (arrow). Internal scale bar ⫽ 0.2 μm.

pleural fluid or BAL fluid, indicating a bacterial co-infection. Patients with positive bacteria cultures had higher epithelial integrity scores than those with negative cultures (6.0 ⫾ 0.44 vs 4.8 ⫾ 0.71; p ⬍ 0.01). In order to eliminate the effect of CRE abnormalities caused by bacteria, we further compared

CRE abnormalities in patients without a bacterial co-infection (10 in the mild group and 18 in the severe group). Also, patients with severe pneumonia had higher epithelial integrity scores than those with mild pneumonia (4.9 ⫾ 0.75 vs 3.7 ⫾ 0.73; p ⬍ 0.01).

Figure 3. (A) Duration of fever, (B) C-reactive protein (CRP) level, (D) proportion of lymphocytes, and (E) alanine aminotransferase (ALT) levels of patients with mild and severe ciliated respiratory epithelium (CRE) abnormalities.

Epithelium abnormalities in Mycoplasma infection The duration of follow-up was 1–48 months for all of the patients. Residual pulmonary disease, such as bronchiectasis (3 patients) and bronchiolitis obliterans (1 patient) was observed in 4 children. All 4 patients had severe CRE abnormalities.

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Discussion In our study, we found that patients with severe lung injury (severe MP group) had more severe CRE abnormalities than patients with mild lung injury (mild MP group). This finding suggests that the extent of CRE abnormality might be associated with the severity of MP. Previous studies have found that severe M. pneumoniae infections exhibit a longer duration of fever, higher CRP level, and lower lymphocyte level [7,14]. We also found that severe CRE abnormalities were associated with a longer duration of fever, higher CRP, and lower lymphocytes. These findings also suggest that the severity of CRE abnormality is in line with severity of MP. We did not assess the pathological findings of these patients. According to previous studies, however, the pathology of human MP shows peribronchial lymphoplasmocytic cell infiltration and intraluminal exudates that may obstruct bronchioles [15–17]. We found severe MP to be associated with severe CRE abnormalities. Severe CRE abnormalities will impair mucociliary clearance and lead to an impaired capability to sweep viscid secretions out of the lungs. The coexistence of a peribronchial inflammatory cell infiltration and impaired mucociliary clearance may lead to small airway occlusion. These pathological changes correspond to large infiltrates on radiographic findings, reflecting the severity of the disease. Our study also explains some of the clinical features of MP, such as persistent hacking cough and delayed radiographic resolution. Patients with ciliary abnormalities have to rely on cough as their main mechanism of mucus clearance. The cough will persist until the ciliated epithelium has healed. Wong et al. reported that ciliary loss and epithelial abnormalities persist on average for 13–17 weeks following acute bronchiolitis in infancy [18]. Whether CRE abnormalities persist for the same length of time and are correlated with the duration of cough has not been investigated. Our previous study reported that 10 out of 22 patients with the radiographic finding of a large infiltration had a resolution time of more than 12 weeks [19]. Severe CRE abnormalities reduce the immune function of the airways and disrupt the mucociliary clearance, causing mucous plug and bronchial casts that are responsible for the development of atelectasis or persistent pneumonia.

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Also, severe CRE abnormalities and a markedly reduced mucociliary clearance will predispose these patients to secondary bacterial infection, and, indeed, MP complicated with a secondary bacterial infection has been reported [20,21]. The coexistence of impaired mucociliary clearance and infection may lead to the development of bronchiectasis. As a matter of fact, such a coexistence has been reported in a number of patients, especially in those with severe MP [1,2]. In this study, 3 patients with severe ciliary abnormalities had evidence of bronchiectasis. The current study has several limitations. Our controls were not healthy children. Although these controls were not completely appropriate, we did not think it reasonable to perform biopsies in normal healthy children. Ciliary function was not assessed. The CRE of our study was derived from the central airways, and it is not certain whether these abnormalities extend into the small airways. It would be of great interest to investigate ciliary function and epithelial structure in both the central and peripheral airways of patients with MP. Whether our findings are specific to MP or indeed a feature of other infectious diseases such as Streptococcus pneumoniae pneumonia needs to be investigated. Actually, in our clinical setting, patients with S. pneumoniae pneumonia or other bacterial pneumonia have usually shown good resolution on chest radiographs after appropriate antibiotic therapy, and bronchoscopy has not been needed. Between 2009 and 2012, only 3 patients with S. pneumoniae pneumonia underwent bronchoscopy and biopsy; the median epithelial integrity score was 1 (IQR 1–2). The number of patients was too small to study as a control group. In summary, our study provides evidence that CRE abnormalities are closely related to the severity of MP. These findings extend our current knowledge of MP.

Acknowledgements We are indebted to Dr Zhengrong Xia and Wene Zhao for their assistance in the pathological interpretation of CRE abnormalities, and to the patients and their families. Declaration of interest: The authors declare no conflicts of interest.

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[13] Bradley JS, Byington CL, Shah SS, Alverson B, Carter ER, Harrison C, et al. Executive summary: the management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis 2011;53: 617–30. [14] Defilippi A, Silvestri M, Tacchella A, Giacchino R, Melioli G, Di Marco E, et al. Epidemiology and clinical features of Mycoplasma pneumoniae infection in children. Respir Med 2008;102:1762–8. [15] Clyde WA Jr. Clinical overview of typical Mycoplasma pneumoniae infections. Clin Infect Dis 1993;17(Suppl 1): S32–6. [16] Kim CK, Chung CY, Kim JS, Kim WS, Park Y, Koh YY. Late abnormal findings on high-resolution computed tomography after Mycoplasma pneumonia. Pediatrics 2000;105:372–8. [17] Rollins S, Colby T, Clayton F. Open lung biopsy in Mycoplasma pneumoniae pneumonia. Arch Pathol Lab Med 1986;110:34–41. [18] Wong JY, Rutman A, O’Callaghan C. Recovery of the ciliated epithelium following acute bronchiolitis in infancy. Thorax 2005;60:582–7. [19] Liang H, Jiang W, Han Q, Liu F, Zhao D. Ciliary ultrastructural abnormalities in Mycoplasma pneumoniae pneumonia in 22 pediatric patients. Eur J Pediatr 2012;171:559–63. [20] Staugas R, Martin AJ. Secondary bacterial infections in children with proved Mycoplasma pneumoniae. Thorax 1985;40:546–8. [21] Stadel BV, Foy HM, Nuckolls JW, Kenny GE. Mycoplasma pneumoniae infection followed by Haemophilus influenzae pneumonia and bacteremia. Am Rev Respir Dis 1975; 112:131–3.

Relationships between the varied ciliated respiratory epithelium abnormalities and severity of Mycoplasma pneumoniae pneumonia.

The pathogenesis of Mycoplasma pneumoniae infection involves cytoadherence of M. pneumoniae to the ciliated respiratory epithelium (CRE), followed by ...
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