- Email: [email protected]
Microbiology of early CF lung disease
PAEDIATRIC RESPIRATORY REVIEWS (2004) 5(Suppl A), S367–S369
Microbiology of early CF lung disease Lisa Saiman° Columbia University, New York, USA
Summary Recent bronchoscopy studies using assays to measure inflammation and molecular typing techniques have facilitated an increased understanding of the early events that occur within the lungs of young children with cystic fibrosis and provided additional insights into the natural history of lung disease in children. In 2000, the US CF National Patient Registry data showed that among 1000 infants <2 years of age, the first bacterial pathogens detected are Haemophilus influenzae, Staphylococcus aureus, and Pseudomonas aeruginosa and the prevalence of these pathogens in these young infants are 19%, 42%, and 29%, respectively. In addition, 7% harbour Stenotrophomonas maltophilia and <1% harbour Burkholderia cepacia complex. Several investigators have performed bronchoscopy studies on young infants to further examine the natural history of lung disease. In one such study of 40 CF infants, 65%, 63% and 70% of children at 1, 2, and 3 years of age harboured at least one CF pathogen. H. influenzae was most common (38%) in infants at 1 year of age, and S. aureus was most common in 2 (37%) and 3 (36%) year olds. P. aeruginosa increased from 18% at 1 year of age to 33% at 3 years of age and was usually present in high numbers, i.e., 105 CFU/ml of BAL fluid. Investigators have studied the microbiology of young CF infants using specimens derived from the upper airway (deep throat) compared with the lower airway (broncheoalveolar lavage specimens) to determine if the upper airway is predictive of pathogens in the lower airway. In general, these studies have shown that a negative oropharyngeal culture indicated that isolation of P. aeruginosa from the lower airway was unlikely, but a positive culture did not predict lower airway infection. Similar findings were noted for H. influenzae and S. aureus. © 2004 Elsevier Science Ltd.
INTRODUCTION The lung disease of CF is characterised by a vicious cycle of inflammation and infection and the primary cause of morbidity and mortality in CF is caused by progressive obstructive lung disease caused by P. aeruginosa and a neutrophil-dominated inflammatory response. Recent bronchoscopy studies using assays to measure inflammation and molecular typing techniques have facilitated an increased understanding of the early events that occur within the lungs of young children and provided additional insights into the natural history of lung disease in children. It is critical to understand early lung disease to address potential treatment and prevention strategies. * Correspondence to: Lisa Saiman. E-mail: [email protected] Correspondence address: Columbia University, 650 West 168th St., New York, NY 10032, USA (No reprints) 1526-0542/$ – see front matter
EPIDEMIOLOGY: US CFF NATIONAL PATIENT REGISTRY The US CFF maintains an annual CF patient registry. Each year >115 accredited CF care centres provide demographic and clinical data including the results of respiratory tract cultures. For the past decade, the median age at CF diagnosis remains 6 months in the USA. Thus, in the registry for 2000, there were approximately 1000 children <2 years of age. As predicted, the first bacterial pathogens detected are Haemophilus influenzae, Staphylococcus aureus, and Pseudomonas aeruginosa and the prevalence of these pathogens in these young infants are 19%, 42%, and 29%, respectively.1 In addition, 7% harbour Stenotrophomonas maltophilia and <1% harbour Burkholderia cepacia complex. These cultures reflect throat, sputum and bronchoscopy cultures. © 2004 Elsevier Science Ltd. All rights reserved.
S368
L. SAIMAN
INFECTIOUS AGENTS DETECTED FROM CORRELATION OF UPPER AIRWAY AND INFANT BRONCHOCOPY STUDIES LOWER AIRWAY MICROBIOLOGY Several investigators have performed bronchoscopy studies on young infants to further examine the natural history of lung disease. Such studies are important to examine possible lung pathology in asymptomatic infants and to understand the relationship between infection and inflammation. Abman et al. followed 42 children diagnosed with CF after newborn screening and found that by one year of age 17%, 29%, and 6% of infants harboured H. influenza, S. aureus, and/or P. aeruginosa.2 Over the course of the study, 11/42 (26%) of children harboured P. aeruginosa of whom 2 had P. aeruginosa as the first pathogen detected; 3/11 first isolates were mucoid strains. Khan et al. studied 16 infants with CF <12 months and found 7/16 (44%) were infected with S. aureus, one of whom was co-infected with H. influenzae.3 None had P. aeruginosa. Armstrong et al. performed bronchoscopy on 46 newly diagnosed CF infants <6 months of age and 39% (18/46) had lower respiratory tract infection; S. aureus (n = 12) and viral pathogens (n = 6) were most common.4 None had P. aeruginosa. Viral pathogens included: RSV, rhinovirus, adenovirus, and parainfluenza virus type 3. In a longitudinal study of these children, 9/44 (20%) acquired P. aeruginosa and these children had the highest number of neutrophils, and the highest concentrations of IL-8 and neutrophil elastase. Most importantly, if infection was eradicated, signs of airway inflammation decreased, suggesting that infection was responsible for initiating and maintaining airway inflammation. Rosenfeld et al. performed a 3-year longitudinal study of 40 CF infants and found that 65%, 63% and 70% of children at 1, 2, and 3 years of age harboured at least one CF pathogen.5 H. influenzae was most common (38%) in infants at 1 year of age, and S. aureus was most common in 2 (37%) and 3 (36%) year olds. P. aeruginosa increased from 18% at 1 year of age to 33% at 3 years of age and was usually present in high numbers, i.e., 105 CFU/ml of BAL fluid. Thus, several studies of early microbiology from young infants with CF have had very similar findings. However, some of the differences may be methodological, e.g., the age of the study participants, the methods used to perform lavage, the assays used. For example, Gutierrez et al. showed heterogeneity in the bacteriologic findings between lobes of children undergoing bronchoscopy; when counts from the right middle lobe and lingula were compared, counts from the right middle lobe were higher.6
It is obvious that bronchoscopy carries some risk. Thus, investigators have studied the microbiology of young CF infants using specimens derived from the upper airway (deep throat) as well as the lower airway (broncheoalveolar lavage specimens) to determine if the upper airway is predictive of pathogens in the lower airway. Ramsey et al. examined 26 non-expectorating patients and found that the specificity of oropharyngeal cultures to be >90% for both S. aureus and P. aeruginosa found in the lower airway, but the sensitivity was extremely poor for P. aeruginosa (46%) and somewhat better for S. aureus (77%).7 Armstrong noted that the sensitivity, specificity, positive and negative predictive value of cultures from oropharynx compared with the lower respiratory tract were 82%, 83%, 41% and 97%, respectively, for all CF respiratory tract pathogens.8 Thus, these studies reached somewhat different conclusions about our ability to conclude that if a pathogen is detected in the upper airway, it is likely to be found in the lower airway. In efforts to resolve these discrepancies, Rosenfeld et al. examined study participants from three separate research protocols to compare oropharyngeal vs. BAL specimens in children <5 years of age.9 In all, 141 children were studied and 52% of all BAL yielded either S. aureus, H. influenzae, and/or P. aeruginosa. Results were compared for children 18 months of age (mean 8 months) vs children >18 months of age (mean 26 months). In both age groups, the specificity and negative predictive value of oropharyngeal cultures were high, but the sensitivity and positive predictive value were low (44%). Thus, a negative oropharyngeal culture indicated that isolation of P. aeruginosa from the lower airway was unlikely, but a positive culture did not predict lower airway infection. Similar findings were noted for H. influenzae and S. aureus.
MOLECULAR TYPING OF EARLY ISOLATES OF PSEUDOMONAS AERUGINOSA Molecular typing can be very useful to examine the epidemiology of pathogens in an individual patient and to examine patient-to-patient spread. In 1991, Abman et al. studied serial isolates of P. aeruginosa from young infants (mean age at follow-up 27 months) using Southern blot with probes from the Exotoxin A structural gene.2 Of the 8 infants who had 2 isolates to compare, 7/8
MICROBIOLOGY OF EARLY CF LUNG DISEASE were infected with a single, persistent clone. No patients shared a clone. Munck et al. examined 19 patients (mean age 5 years) who were treated with IV antibiotic therapy and aerosolised colistin after initial detection of P. aeruginosa by RAPD to determine if initially colonising strains were the same as strains isolated from the same patient later.10 Initial and subsequent isolates were unique in 14/19 (74%) of patients. However, 5/19 (26%) had the same RAPD and PFGE type isolated before and after therapy including one patient without detectable P. aeruginosa for 25 months, suggesting a persistent environmental source or undetectable infection. All patients harboured unique clones suggesting that patient-to-patient transmission had not occurred. In contrast, Nixon et al. followed 56 children identified by newborn screening for CF and found that 24/56 (43%) of subjects became infected by P. aeruginosa by 7 years of age.11 Four of 7 were infected by the same multi-drug resistant mucoid strain, suggesting that patient-topatient transmission had occurred.
RISK FACTORS FOR ACQUISITION OF PSEUDOMONAS AERUGINOSA Kosorok et al. used the Wisconsin newborn screening study for CF to determine risk factors for acquisition of P. aeruginosa.12 In a step-wise multi-regression model, infants who were treated with aerosolised medications and were cared for at Center B prior to June 1, 1990 were at higher risk of becoming infected with P. aeruginosa, while increased maternal education proved to be protective.
S369
REFERENCES 1. CF Foundation National Patient Registry, Bethesda Maryland, 2000. 2. Abman SH, Ogle JW, Harbeck RJ, et al. Early bacteriologic, immunologic, and clinical courses of young infants with cystic fibrosis identified by neonatal screening. J Pediatr 1991; 119: 211−217. 3. Khan TZ, Wagener JS, Bost T, et al. Early pulmonary inflammation in infants with cystic fibrosis. Am J Resp Crit Care Med 1995; 151: 1075−1082. 4. Armstrong DS, Grimwood K, Carlin JB, et al. Lower airway inflammation in infants and young children with cystic fibrosis. Am J Respir Crit Care Med 1997; 156: 1197−1204. 5. Rosenfeld M, Gibson RL, McNamara S, et al. Early pulmonary infection, inflammation, and clinical outcomes in infants with cystic fibrosis. Pediatr Pulmonol 2001; 32: 356−366. 6. Gutierrez JP, Grimwood K, Armstrong DS, et al. Interlobar differences in bronchoalveolar lavage fluid from children with cystic fibrosis. Eur Respis J 2001; 17: 281−286. 7. Ramsey BW, Wentz KR, Smith AL, et al. Predictive value of oropharyngeal cultures for identifying lower airway bacteria in cystic fibrosis patients. Am Rev Respir Dis 1991; 144: 331−337. 8. Armstrong DS, Grimwood K, Carlin JB, et al. Bronchoalveolar lavage or oropharyngeal cultures to identify lower respiratory pathogens in infants with cystic fibrosis. Pediatr Pulmonol 1996; 21: 267−275. 9. Rosenfeld M, Emerson J, Accurso F, et al. Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis. Pediatr Pulmonol 1999; 28: 321−328. 10. Munck A, Bonacorsi S, Mariani-Kurkdjian P, et al. Genotypic characterization of Pseudomonas aeruginosa strains isolated from patients with cystic fibrosis after initial and subsequent colonization. Pediatr Pulmonol 2001; 32: 288−292. 11. Nixon GM, Armstrong DS, Cazino R, et al. Clinical outcome after early Pseudomonas aeruginosa infection in cystic fibrosis. J Pediatr 2001; 138: 699−704. 12. Kosorok MR, Jalaluddin M, Farrell PM, et al. Comprehensive analysis of risk factors for acquisition of Pseudomonas aeruginosa in young children with cystic fibrosis. Pediatr Pulmonol 1998; 26: 81−88.
Microbiology of early CF lung disease Lisa Saiman° Columbia University, New York, USA
Summary Recent bronchoscopy studies using assays to measure inflammation and molecular typing techniques have facilitated an increased understanding of the early events that occur within the lungs of young children with cystic fibrosis and provided additional insights into the natural history of lung disease in children. In 2000, the US CF National Patient Registry data showed that among 1000 infants <2 years of age, the first bacterial pathogens detected are Haemophilus influenzae, Staphylococcus aureus, and Pseudomonas aeruginosa and the prevalence of these pathogens in these young infants are 19%, 42%, and 29%, respectively. In addition, 7% harbour Stenotrophomonas maltophilia and <1% harbour Burkholderia cepacia complex. Several investigators have performed bronchoscopy studies on young infants to further examine the natural history of lung disease. In one such study of 40 CF infants, 65%, 63% and 70% of children at 1, 2, and 3 years of age harboured at least one CF pathogen. H. influenzae was most common (38%) in infants at 1 year of age, and S. aureus was most common in 2 (37%) and 3 (36%) year olds. P. aeruginosa increased from 18% at 1 year of age to 33% at 3 years of age and was usually present in high numbers, i.e., 105 CFU/ml of BAL fluid. Investigators have studied the microbiology of young CF infants using specimens derived from the upper airway (deep throat) compared with the lower airway (broncheoalveolar lavage specimens) to determine if the upper airway is predictive of pathogens in the lower airway. In general, these studies have shown that a negative oropharyngeal culture indicated that isolation of P. aeruginosa from the lower airway was unlikely, but a positive culture did not predict lower airway infection. Similar findings were noted for H. influenzae and S. aureus. © 2004 Elsevier Science Ltd.
INTRODUCTION The lung disease of CF is characterised by a vicious cycle of inflammation and infection and the primary cause of morbidity and mortality in CF is caused by progressive obstructive lung disease caused by P. aeruginosa and a neutrophil-dominated inflammatory response. Recent bronchoscopy studies using assays to measure inflammation and molecular typing techniques have facilitated an increased understanding of the early events that occur within the lungs of young children and provided additional insights into the natural history of lung disease in children. It is critical to understand early lung disease to address potential treatment and prevention strategies. * Correspondence to: Lisa Saiman. E-mail: [email protected] Correspondence address: Columbia University, 650 West 168th St., New York, NY 10032, USA (No reprints) 1526-0542/$ – see front matter
EPIDEMIOLOGY: US CFF NATIONAL PATIENT REGISTRY The US CFF maintains an annual CF patient registry. Each year >115 accredited CF care centres provide demographic and clinical data including the results of respiratory tract cultures. For the past decade, the median age at CF diagnosis remains 6 months in the USA. Thus, in the registry for 2000, there were approximately 1000 children <2 years of age. As predicted, the first bacterial pathogens detected are Haemophilus influenzae, Staphylococcus aureus, and Pseudomonas aeruginosa and the prevalence of these pathogens in these young infants are 19%, 42%, and 29%, respectively.1 In addition, 7% harbour Stenotrophomonas maltophilia and <1% harbour Burkholderia cepacia complex. These cultures reflect throat, sputum and bronchoscopy cultures. © 2004 Elsevier Science Ltd. All rights reserved.
S368
L. SAIMAN
INFECTIOUS AGENTS DETECTED FROM CORRELATION OF UPPER AIRWAY AND INFANT BRONCHOCOPY STUDIES LOWER AIRWAY MICROBIOLOGY Several investigators have performed bronchoscopy studies on young infants to further examine the natural history of lung disease. Such studies are important to examine possible lung pathology in asymptomatic infants and to understand the relationship between infection and inflammation. Abman et al. followed 42 children diagnosed with CF after newborn screening and found that by one year of age 17%, 29%, and 6% of infants harboured H. influenza, S. aureus, and/or P. aeruginosa.2 Over the course of the study, 11/42 (26%) of children harboured P. aeruginosa of whom 2 had P. aeruginosa as the first pathogen detected; 3/11 first isolates were mucoid strains. Khan et al. studied 16 infants with CF <12 months and found 7/16 (44%) were infected with S. aureus, one of whom was co-infected with H. influenzae.3 None had P. aeruginosa. Armstrong et al. performed bronchoscopy on 46 newly diagnosed CF infants <6 months of age and 39% (18/46) had lower respiratory tract infection; S. aureus (n = 12) and viral pathogens (n = 6) were most common.4 None had P. aeruginosa. Viral pathogens included: RSV, rhinovirus, adenovirus, and parainfluenza virus type 3. In a longitudinal study of these children, 9/44 (20%) acquired P. aeruginosa and these children had the highest number of neutrophils, and the highest concentrations of IL-8 and neutrophil elastase. Most importantly, if infection was eradicated, signs of airway inflammation decreased, suggesting that infection was responsible for initiating and maintaining airway inflammation. Rosenfeld et al. performed a 3-year longitudinal study of 40 CF infants and found that 65%, 63% and 70% of children at 1, 2, and 3 years of age harboured at least one CF pathogen.5 H. influenzae was most common (38%) in infants at 1 year of age, and S. aureus was most common in 2 (37%) and 3 (36%) year olds. P. aeruginosa increased from 18% at 1 year of age to 33% at 3 years of age and was usually present in high numbers, i.e., 105 CFU/ml of BAL fluid. Thus, several studies of early microbiology from young infants with CF have had very similar findings. However, some of the differences may be methodological, e.g., the age of the study participants, the methods used to perform lavage, the assays used. For example, Gutierrez et al. showed heterogeneity in the bacteriologic findings between lobes of children undergoing bronchoscopy; when counts from the right middle lobe and lingula were compared, counts from the right middle lobe were higher.6
It is obvious that bronchoscopy carries some risk. Thus, investigators have studied the microbiology of young CF infants using specimens derived from the upper airway (deep throat) as well as the lower airway (broncheoalveolar lavage specimens) to determine if the upper airway is predictive of pathogens in the lower airway. Ramsey et al. examined 26 non-expectorating patients and found that the specificity of oropharyngeal cultures to be >90% for both S. aureus and P. aeruginosa found in the lower airway, but the sensitivity was extremely poor for P. aeruginosa (46%) and somewhat better for S. aureus (77%).7 Armstrong noted that the sensitivity, specificity, positive and negative predictive value of cultures from oropharynx compared with the lower respiratory tract were 82%, 83%, 41% and 97%, respectively, for all CF respiratory tract pathogens.8 Thus, these studies reached somewhat different conclusions about our ability to conclude that if a pathogen is detected in the upper airway, it is likely to be found in the lower airway. In efforts to resolve these discrepancies, Rosenfeld et al. examined study participants from three separate research protocols to compare oropharyngeal vs. BAL specimens in children <5 years of age.9 In all, 141 children were studied and 52% of all BAL yielded either S. aureus, H. influenzae, and/or P. aeruginosa. Results were compared for children 18 months of age (mean 8 months) vs children >18 months of age (mean 26 months). In both age groups, the specificity and negative predictive value of oropharyngeal cultures were high, but the sensitivity and positive predictive value were low (44%). Thus, a negative oropharyngeal culture indicated that isolation of P. aeruginosa from the lower airway was unlikely, but a positive culture did not predict lower airway infection. Similar findings were noted for H. influenzae and S. aureus.
MOLECULAR TYPING OF EARLY ISOLATES OF PSEUDOMONAS AERUGINOSA Molecular typing can be very useful to examine the epidemiology of pathogens in an individual patient and to examine patient-to-patient spread. In 1991, Abman et al. studied serial isolates of P. aeruginosa from young infants (mean age at follow-up 27 months) using Southern blot with probes from the Exotoxin A structural gene.2 Of the 8 infants who had 2 isolates to compare, 7/8
MICROBIOLOGY OF EARLY CF LUNG DISEASE were infected with a single, persistent clone. No patients shared a clone. Munck et al. examined 19 patients (mean age 5 years) who were treated with IV antibiotic therapy and aerosolised colistin after initial detection of P. aeruginosa by RAPD to determine if initially colonising strains were the same as strains isolated from the same patient later.10 Initial and subsequent isolates were unique in 14/19 (74%) of patients. However, 5/19 (26%) had the same RAPD and PFGE type isolated before and after therapy including one patient without detectable P. aeruginosa for 25 months, suggesting a persistent environmental source or undetectable infection. All patients harboured unique clones suggesting that patient-to-patient transmission had not occurred. In contrast, Nixon et al. followed 56 children identified by newborn screening for CF and found that 24/56 (43%) of subjects became infected by P. aeruginosa by 7 years of age.11 Four of 7 were infected by the same multi-drug resistant mucoid strain, suggesting that patient-topatient transmission had occurred.
RISK FACTORS FOR ACQUISITION OF PSEUDOMONAS AERUGINOSA Kosorok et al. used the Wisconsin newborn screening study for CF to determine risk factors for acquisition of P. aeruginosa.12 In a step-wise multi-regression model, infants who were treated with aerosolised medications and were cared for at Center B prior to June 1, 1990 were at higher risk of becoming infected with P. aeruginosa, while increased maternal education proved to be protective.
S369
REFERENCES 1. CF Foundation National Patient Registry, Bethesda Maryland, 2000. 2. Abman SH, Ogle JW, Harbeck RJ, et al. Early bacteriologic, immunologic, and clinical courses of young infants with cystic fibrosis identified by neonatal screening. J Pediatr 1991; 119: 211−217. 3. Khan TZ, Wagener JS, Bost T, et al. Early pulmonary inflammation in infants with cystic fibrosis. Am J Resp Crit Care Med 1995; 151: 1075−1082. 4. Armstrong DS, Grimwood K, Carlin JB, et al. Lower airway inflammation in infants and young children with cystic fibrosis. Am J Respir Crit Care Med 1997; 156: 1197−1204. 5. Rosenfeld M, Gibson RL, McNamara S, et al. Early pulmonary infection, inflammation, and clinical outcomes in infants with cystic fibrosis. Pediatr Pulmonol 2001; 32: 356−366. 6. Gutierrez JP, Grimwood K, Armstrong DS, et al. Interlobar differences in bronchoalveolar lavage fluid from children with cystic fibrosis. Eur Respis J 2001; 17: 281−286. 7. Ramsey BW, Wentz KR, Smith AL, et al. Predictive value of oropharyngeal cultures for identifying lower airway bacteria in cystic fibrosis patients. Am Rev Respir Dis 1991; 144: 331−337. 8. Armstrong DS, Grimwood K, Carlin JB, et al. Bronchoalveolar lavage or oropharyngeal cultures to identify lower respiratory pathogens in infants with cystic fibrosis. Pediatr Pulmonol 1996; 21: 267−275. 9. Rosenfeld M, Emerson J, Accurso F, et al. Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis. Pediatr Pulmonol 1999; 28: 321−328. 10. Munck A, Bonacorsi S, Mariani-Kurkdjian P, et al. Genotypic characterization of Pseudomonas aeruginosa strains isolated from patients with cystic fibrosis after initial and subsequent colonization. Pediatr Pulmonol 2001; 32: 288−292. 11. Nixon GM, Armstrong DS, Cazino R, et al. Clinical outcome after early Pseudomonas aeruginosa infection in cystic fibrosis. J Pediatr 2001; 138: 699−704. 12. Kosorok MR, Jalaluddin M, Farrell PM, et al. Comprehensive analysis of risk factors for acquisition of Pseudomonas aeruginosa in young children with cystic fibrosis. Pediatr Pulmonol 1998; 26: 81−88.