Reduced middle ear infection with non-typeable Haemophilus influenzae, but not Streptococcus pneumoniae, after transition to 10-valent pneumococcal non-typeable H. influenzae protein D conjugate vaccine.

BACKGROUND: In October 2009, 7-valent pneumococcal conjugate vaccine (PCV7: Prevenar(TM) Pfizer) was replaced in the Northern Territory childhood vaccination schedule by 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; Synflorix(™) GlaxoSmithKline Vaccines). This analysis aims to determine whether the reduced prevalence of suppurative otitis media measured in the PHiD-CV10 era was associated with changes in nasopharyngeal (NP) carriage and middle ear discharge (ED) microbiology in vaccinated Indigenous children. METHODS: Swabs of the NP and ED were collected in remote Indigenous communities between September 2008 and December 2012. Swabs were cultured using standardised methods for otitis media pathogens. Children less than 3 years of age and having received a primary course of 2 or more doses of one PCV formulation and not more than one dose of another PCV formulation were included in the primary analysis; children with non-mixed single formulation PCV schedules were also compared. RESULTS: NP swabs were obtained from 421 of 444 (95%) children in the PCV7 group and 443 of 451 (98%) children in the PHiD-CV10 group. Non-mixed PCV schedules were received by 333 (79%) and 315 (71%) children, respectively. Pneumococcal (Spn) NP carriage was 76% and 82%, and non-typeable Haemophilus influenzae (NTHi) carriage was 68% and 73%, respectively. ED was obtained from 60 children (85 perforations) in the PCV7 group and from 47 children (59 perforations) in the PHiD-CV10 group. Data from bilateral perforations were combined. Spn was cultured from 25% and 18%, respectively, and NTHi was cultured from 61% and 34% respectively (p = 0.008). CONCLUSIONS: The observed reduction in the prevalence of suppurative OM in this population was not associated with reduced NP carriage of OM pathogens. The prevalence of NTHi-infected ED was lower in PHiD-CV10 vaccinated children compared to PCV7 vaccinated children. Changes in clinical severity may be explained by the action of PHiD-CV10 on NTHi infection in the middle ear. Randomised controlled trials are needed to answer this question.

A PCR-high-resolution melt assay for rapid differentiation of nontypeable Haemophilus influenzae and Haemophilus haemolyticus.

We have developed a PCR-high-resolution melt (PCR-HRM) assay to discriminate nontypeable Haemophilus influenzae (NTHi) colonies from Haemophilus haemolyticus. This method is rapid and robust, with 96% sensitivity and 92% specificity compared to the hpd#3 assay. PCR-HRM is ideal for high-throughput screening for NTHi surveillance and clinical trials.

Dominance of Haemophilus influenzae in ear discharge from Indigenous Australian children with acute otitis media with tympanic membrane perforation.

BACKGROUND: Indigenous Australian children living in remote communities experience high rates of acute otitis media with tympanic membrane perforation (AOMwiP). Otitis media in this population is associated with dense nasopharyngeal colonization of three primary otopathogens; Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. Little is known about the relative abundance of these pathogens during infection. The objective of this study was to estimate the abundance and concordance of otopathogens in ear discharge and paired nasopharyngeal swabs from children with AOMwiP (discharge of not more than 6 weeks' duration and perforation size <2%). METHODS: Culture and quantitative PCR (qPCR) estimation of H. influenzae, S. pneumoniae, M. catarrhalis and total bacterial load were performed on paired nasopharyngeal and ear discharge swabs from 55 Indigenous children with AOMwiP aged 3.5 - 45.6 months and resident in remote communities. RESULTS: By culture, H. influenzae, S. pneumoniae, and M. catarrhalis were detected in 80%, 84% and 91% of nasopharyngeal swabs, and 49%, 33% and 4% of ear discharge swabs, respectively. Using qPCR, H. influenzae, S. pneumoniae, and M. catarrhalis were detected in 82%, 82%, and 93% of nasopharyngeal swabs, and 89%, 41% and 18% of ear discharge swabs, respectively. Relative abundance of H. influenzae in ear discharge swabs was 0-68% of the total bacterial load (median 2.8%); whereas S. pneumoniae and M. catarrhalis relative abundances were consistently <2% of the total bacterial load. S. pneumoniae and M. catarrhalis abundances were significantly lower in ear discharge compared with nasopharyngeal swabs (p = 0.001, p < 0.001); no significant difference was observed in H. influenzae mean abundance at the two sites. CONCLUSIONS: H. influenzae was the dominant otopathogen detected in ear discharge swabs collected from children with AOMwiP. High prevalence and abundance of S. pneumoniae and M. catarrhalis in the nasopharynx did not predict ear discharge prevalence and abundances of these pathogens. PCR was substantially more sensitive than culture for ear discharge, and a necessary adjunct to standard microbiology. Quantitative methods are required to understand species abundance in polymicrobial infections and may be needed to measure accurately the microbiological impact of interventions and to provide a better understanding of clinical failure in these children.

Respiratory bacterial pathogens in the nasopharynx and lower airways of Australian indigenous children with bronchiectasis.

OBJECTIVE: To test the hypothesis that bacterial density, strain diversity, and concordance of pathogens between upper and lower airways are higher in children with bronchiectasis than in those with non-bronchiectatic conditions. STUDY DESIGN: Nasopharyngeal (NP) swabs and bronchoalveolar lavage (BAL) fluid were cultured from 45 Indigenous children with bronchiectasis and 30 non-Indigenous children with non-bronchiectatic respiratory symptoms. Lower airway infection was defined as >10(4) colony-forming units of respiratory bacteria/mL of BAL fluid. Concordance was determined by phenotype or genotype. RESULTS: NP carriage of Streptococcus pneumoniae, nontypable Haemophilus influenzae (NTHi), and Moraxella catarrhalis, and lower airway infection by NTHi (47% vs 3%), were detected significantly more often in the children with bronchiectasis than in those without this condition. BAL specimens from the infected Indigenous children also showed greater strain diversity (71% vs 0%). Strain concordance in NP and BAL cultures was high in both infected subgroups. CONCLUSIONS: The high density and diversity of respiratory bacteria, along with strain concordance between upper and lower airways, found in Indigenous children with bronchiectasis suggest a possible pathogenic role of recurrent aspiration of NP secretions.

The bacteriology of lower respiratory infections in Papua New Guinean and Australian indigenous children.

Indigenous children in Australia and children in Papua New Guinea (PNG) share a high burden of respiratory disease. In PNG the focus has been on pneumonia as a major cause of mortality. While pneumonia incidence remains high in Australian Indigenous children, improved access to better health care has resulted in reduced mortality. However, severe and recurrent pneumonia are risk factors for chronic suppurative lung disease or bronchiectasis in Australian Indigenous children. Bronchiectasis is associated with significant morbidity, and early death in adulthood. This paper includes an outline of the disease manifestations of acute and chronic lower respiratory infections. The main bacterial pathogens involved in pneumonia, bronchiolitis, bronchitis and bronchiectasis have been determined. Capsular organisms such as Streptococcus pneumoniae and Haemophilus influenzae type b are more often implicated in acute infections, while chronic infections are frequently associated with nontypeable (noncapsular) H. influenzae. Moraxella catarrhalis is more often isolated from very young children. Possible reasons for the high burden of respiratory disease in Papua New Guinean children and Australian Indigenous (primarily Aboriginal) children include early and dense colonization with multiple species and strains of respiratory pathogens. There is a role for vaccines in preventing lower respiratory infection.

Lessons of the month: HLA-B27-associated syndrome and spontaneous intracranial hypotension resulting in behavioural variant frontotemporal dementia.

Spontaneous intracranial hypotension is uncommon and results from a cerebrospinal fluid (CSF) leak. We describe the case of a marathon runner who presented with postural headache attributable to CSF venous fistulation originating from a lower thoracic nerve root cyst. Subsequent investigations confirmed a unifying de novo diagnosis of human leukocyte antigen B27-associated syndrome. With unmitigated CSF loss over the following 3 months, the patient became bedbound and developed rapidly progressive behavioural variant frontotemporal dementia. Behavioural changes were somewhat reversible on restoration of CSF volume after surgical intervention.

Emerging pneumococcal carriage serotypes in a high-risk population receiving universal 7-valent pneumococcal conjugate vaccine and 23-valent polysaccharide vaccine since 2001.

BACKGROUND: In Australia in June 2001, a unique pneumococcal vaccine schedule commenced for Indigenous infants; seven-valent pneumococcal conjugate vaccine (7PCV) given at 2, 4, and 6 months of age and 23-valent pneumococcal polysaccharide vaccine (23PPV) at 18 months of age. This study presents carriage serotypes following this schedule. METHODS: We conducted cross sectional surveys of pneumococcal carriage in Aboriginal children 0 to 6 years of age living in remote Aboriginal communities (RACs) in 2003 and 2005. Nasal secretions were collected and processed according to published methods. RESULTS: 902 children (mean age 25 months) living in 29 communities in 2003 and 818 children (mean age 35 months) in 17 communities in 2005 were enrolled. 87% children in 2003 and 96% in 2005 had received two or more doses of 7PCV. From 2003 to 2005, pneumococcal carriage was reduced from 82% to 76% and reductions were apparent in all age groups; 7PCV-type carriage was reduced from 11% to 8%, and 23PPV-non-7PCV-type carriage from 31% to 25% respectively. Thus non-23PPV-type carriage increased from 57% to 67%. All these changes were statistically significant, as were changes for some specific serotypes. Shifts could not be attributed to vaccination alone. The top 10 of 40 serotypes identified were (in descending order) 16F, 19A, 11A, 6C, 23B, 19F, 6A, 35B, 6B, 10A and 35B. Carriage of penicillin non-susceptible (MIC > or = 0.12 microg/mL) strains (15% overall) was detected in serotypes (descending order) 19A, 19F, 6B, 16F, 11A, 9V, 23B, and in 4 additional serotypes. Carriage of azithromycin resistant (MIC > or = 2 microg/mL) strains (5% overall), was detected in serotypes (descending order) 23B, 17F, 9N, 6B, 6A, 11A, 23F, and in 10 additional serotypes including 6C. CONCLUSION: Pneumococcal carriage remains high (approximately80%) in this vaccinated population. Uptake of both pneumococcal vaccines increased, and carriage was reduced between 2003 and 2005. Predominant serotypes in combined years were 16F, 19A, 11A, 6C and 23B. Antimicrobial non-susceptibility was detected in these and 17 additional serotypes. Shifts in serotype-specific carriage suggest a need more research to clarify the association between pneumococcal vaccination and carriage at the serotype level.

Antimicrobial susceptibility and impact of macrolide antibiotics on Moraxella catarrhalis in the upper and lower airways of children with chronic endobronchial suppuration.

INTRODUCTION: Moraxella catarrhalis is an important but insufficiently studied respiratory pathogen. AIM: To determine antibiotic susceptibility and impact of recent antibiotics on M. catarrhalis from children with chronic endobronchial suppuration. METHODOLOGY: We cultured nasopharyngeal (NP) swabs and bronchoalveolar lavage (BAL) fluids collected from children who were prospectively enrolled in studies of chronic cough and had flexible bronchoscopy performed. Recent ß-lactam or macrolide antibiotic use was recorded. M. catarrhalis isolates stored at -80 °C were re-cultured and susceptibility determined to a range of antibiotics including the macrolide antibiotic erythromycin. RESULTS: Data from concurrently collected NP and BAL specimens were available from 547 children (median age 2.4 years) enrolled from 2007 to 2016. M. catarrhalis NP carriage was detected in 149 (27  %) children and lower airway infection (≥104 c.f.u. ml-1 BAL) in 67 (12  %) children. In total, 91  % of 222 M. catarrhalis isolates were ß-lactamase producers, and non-susceptibility was high to benzylpenicillin (98 %), cefaclor (39 %) and cotrimoxazole (38 %). Overall, >97  % isolates were susceptible to cefuroxime, chloramphenicol, erythromycin and tetracycline; three isolates were erythromycin-resistant (MIC >0.5 mg l-1). Recent macrolide antibiotics (n=152 children, 28 %) were associated with significantly reduced M. catarrhalis carriage and lower airway infection episodes compared to children who did not receive macrolides; odds ratios 0.19 (95  % CI 0.10-0.35) and 0.15 (0.04-0.41), respectively. CONCLUSION: Despite the frequent use of macrolides, few macrolide-resistant isolates were detected. This suggests a fitness cost associated with macrolide resistance in M. catarrhalis. Macrolide antibiotics remain an effective choice for treating M. catarrhalis lower airway infection in children with chronic endobronchial suppuration.

Do combined upper airway cultures identify lower airway infections in children with chronic cough?

BACKGROUND: Obtaining lower airway specimens is important for guiding therapy in chronic lung infection but is difficult in young children unable to expectorate. While culture-based studies have assessed the diagnostic accuracy of nasopharyngeal or oropharyngeal specimens for identifying lower airway infection, none have used both together. We compared respiratory bacterial pathogens cultured from nasopharyngeal and oropharyngeal swabs with bronchoalveolar lavage (BAL) cultures as the "gold standard" to better inform the diagnosis of lower airway infection in children with chronic wet cough. METHODS: Nasopharyngeal and oropharyngeal swabs and BAL fluid specimens were collected concurrently from consecutive children undergoing flexible bronchoscopy for chronic cough and cultured for bacterial pathogens. RESULTS: In cultures from 309 children (median age, 2.3 years) with chronic endobronchial suppuration, all main pathogens detected (Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis) were more prevalent in nasopharyngeal than oropharyngeal swabs (37%, 34%, and 23% vs 21%, 6.2%, and 3.2%, respectively). Positive and negative predictive values for lower airway infection by any of these three pathogens were 63% (95% confidence interval [95% CI] 55, 70) and 85% (95% CI, 78, 91) for nasopharyngeal swabs, 65% (95% CI, 54, 75), and 66% (95% CI, 59, 72) for oropharyngeal swabs, and 61% (95% CI, 54,68), and 88% (95% CI, 81, 93) for both swabs, respectively. CONCLUSIONS: Neither nasopharyngeal nor oropharyngeal swabs, alone or in combination, reliably predicted lower airway infection in children with chronic wet cough. Although upper airway specimens may be useful for bacterial carriage studies and monitoring antimicrobial resistance, their clinical utility in pediatric chronic lung disorders of endobronchial suppuration is limited.

A comparison of flocked nylon swabs and non-flocked rayon swabs for detection of respiratory bacteria in nasopharyngeal carriage in Australian Indigenous children.

This study compared flocked (nylon) swabs and (non-flocked) rayon swabs for the detection of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in nasopharyngeal samples from 20 enrolled Indigenous children under the age of 6 years living in remote Australian Aboriginal communities, and determined which swab the child or parent perceived to be more comfortable. There was no evidence of a significant difference between flocked and rayon swabs in the recovery of common respiratory bacteria. Rayon swabs detected presence of S. pneumoniae (90% cf. 74%, p = 0.375), H. influenzae (79% cf. 74%, p = 1.00) and M. catarrhalis (79% cf. 74%, p = 1.00) at higher rates than the flocked swabs. Analysis of semi-quantitative growth scores also showed no significant differences in either the ranked distributions or medians. Rayon swabs median semi-quantitative growth scores were higher for S. pneumoniae (4 [IQR 1-5] cf. 3 [IQR 0-6], p = 0.699), and H. influenzae (2 [IQR1-5] cf. 1 [IQR0-5], p = 0.946). Sixty percent of participants preferred samples to be taken with flocked swabs. This study demonstrates that microbiological outcomes are not compromised when using flocked or rayon swabs in respiratory bacterial carriage studies in this population. Therefore, cost, methodological consistency across studies, and participant preference can be considered when choosing swab type.

Povidone-iodine ear wash and oral cotrimoxazole for chronic suppurative otitis media in Australian aboriginal children: study protocol for factorial design randomised controlled trial.

BACKGROUND: Chronic suppurative otitis media (CSOM) is a significant health issue affecting Aboriginal Australians. Long-term hearing loss can cause communication problems, educational disadvantage, and social isolation. Current standard treatment for CSOM in our region is twice daily dry mopping of the pus from the ear canal followed by instillation of ciprofloxacin antibiotic ear drops for up to 16 weeks, or until the discharge resolves for a period of 3 days. The treatment is long, laborious and fails to resolve ear discharge in 70% of cases in remote communities. Bacterial pathogens also persist. Povidone-iodine ear wash is the preferred method of clearing ear discharge in Western Australia. However, evidence of its effectiveness is lacking. In systematic reviews, topical antibiotics (ciprofloxacin) have been shown to be more effective than oral antibiotics or topical antiseptics. Currently, it is unclear whether there are any benefits of combining these treatments. METHODS: This protocol describes a 2 × 2 factorial randomised controlled trial of two different interventions (povidone-iodine ear wash and oral cotrimoxazole), given as adjunctive therapy to standard treatment for CSOM. 280 children, between 2 months and 17 years of age, Indigenous or non-Indigenous, living in participating Northern Territory (NT) communities are randomised to standard treatment (dry mopping and ciprofloxacin drops) plus one of two topical treatments (dilute povidone-iodine ear wash or no wash) and one of two oral medication treatments (16 weeks of cotrimoxazole or placebo). DISCUSSION: Current treatment of CSOM in our region shows that eradication of bacterial pathogens from the middle ear space and dry ears is often not achieved. This trial will evaluate the efficacy of adjunctive treatments of antiseptic ear washes and oral antibiotics. Clinical, microbiological and hearing outcomes will be reported. TRIAL REGISTRATION: This trial (ACTRN12614000234617) was registered with ANZCTR on 05 April 2014.

Comparison of nasal swabs with nose blowing for community-based pneumococcal surveillance of healthy children.

The nasopharynx (NP) is the preferred site for detection of Streptococcus pneumoniae in young children, but NP sampling is not well tolerated. We compared nose blowing with paired nasal swabs. The sensitivity of nose blowing was 46% (95% confidence interval [CI] 38 to 56%), which increased to 94% (95% CI, 85 to 98%) for children with visible secretions.

Random colony selection versus colony morphology for detection of multiple pneumococcal serotypes in nasopharyngeal swabs.

Detection of multiple serotype carriage is important in understanding pneumococcal epidemiology. We compared random selection of 4 pneumococcal colonies per swab with selection by colony morphology. Multiple serotypes were detected in 20% of 98 swabs; 14% by morphology and 17% by random selection. Selection by morphology was more efficient per colony, but underestimated the true rate of multiple carriage.

Reduced nontypeable Haemophilus influenzae lower airway infection in children with chronic endobronchial suppuration vaccinated with the 10-valent pneumococcal H. influenzae protein D conjugate vaccine.

BACKGROUND: Nontypeable Haemophilus influenzae (NTHi), the most common bacterial lower airway infection in children with protracted bacterial bronchitis, is associated with progression to bronchiectasis. We determined whether vaccination with 10-valent pneumococcal NTHi protein-D conjugate vaccine (PHiD-CV) reduced NTHi lower airway infection compared to children not PHiD-CV-vaccinated. Our unique childhood vaccination schedule and prospective 9-year bronchoalveolar lavage (BAL) collection provided an exclusive opportunity to examine this hypothesis. METHODS: Paired BAL fluids and nasopharyngeal (NP) swabs were collected from 543 children (2007-2016) undergoing bronchoscopy for chronic cough. Children who received a primary course of ≥2 doses of one pneumococcal conjugate vaccine (PCV) and <2 doses of another PCV were included in each vaccine group. Logistic regression determined associations between NTHi lower airway infection (≥104 colony-forming units/mL BAL) and age, sex, Indigenous status, antibiotic exposure, and PHiD-CV vaccination. RESULTS: Of 262 PCV7-vaccinated, 53 PHiD-CV-vaccinated and 166 PCV13-vaccinated children (62 had mixed schedules, <2 PCV doses or missing vaccination data), NTHi lower airway infection was detected in 89 (34%), 9 (17%) and 47 (28%), respectively. On multivariate regression, significant independent factors associated with reduced NTHi lower airway infection were PHiD-CV vaccination (ORadjusted = 0.42, 95%CI 0.19-0.93), macrolide use (ORadjusted = 0.57, 95%CI 0.35-0.93) and increasing age (ORadjusted = 0.88, 95%CI 0.80-0.96). PHiD-CV vaccination had no impact on NTHi NP carriage. CONCLUSIONS: PHiD-CV-vaccinated children were significantly less likely to have NTHi lower airway infection than children not PHiD-CV-vaccinated. PHiD-CV is likely an effective intervention for reducing NTHi endobronchial infection in children at risk of chronic suppurative lung diseases.

Defining lower airway bacterial infection in children with chronic endobronchial disorders.

BACKGROUND: Differentiating lower airway bacterial infection from possible upper airway contamination in children with endobronchial disorders undergoing bronchoalveolar lavage (BAL) is important for guiding management. A diagnostic bacterial load threshold based on inflammatory markers has been determined to differentiate infection from upper airway contamination in infants with cystic fibrosis, but not for children with protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD), or bronchiectasis. METHODS: BAL samples from children undergoing bronchoscopy underwent quantitative bacterial culture, cytologic examination, and respiratory virus testing; a subset also had interleukin-8 examined. Geometric means (GMs) of total cell counts (TCCs) and neutrophil counts were plotted by respiratory pathogen bacterial load. Logistic regression determined associations between age, sex, Indigenous status, antibiotic exposure, virus detection and bacterial load, and elevated TCCs (>400 × 103 cells/mL) and airway neutrophilia (neutrophils >15% BAL leukocytes). RESULTS: From 2007 to 2016, 655 children with PBB, CSLD, or bronchiectasis were enrolled. In univariate analyses, Indigenous status and bacterial load ≥105 colony-forming units (CFU)/mL were positively associated with high TCCs. Viruses and bacterial load ≥104 CFU/mL were positively associated with neutrophilia; negative associations were seen for Indigenous status and macrolides. In children who had not received macrolide antibiotics, bacterial load was positively associated in multivariable analyses with high TCCs at ≥104 CFU/mL and with neutrophilia at ≥105 CFU/mL; GMs of TCCs and neutrophil counts were significantly elevated at 104 and 105 CFU/mL compared to negative cultures. CONCLUSIONS: Our findings support a BAL threshold ≥104 CFU/mL to define lower airway infection in children with chronic endobronchial disorders.

Impact of the 23-valent pneumococcal polysaccharide vaccination in pregnancy against infant acute lower respiratory infections in the Northern Territory of Australia.

BACKGROUND: Indigenous children in Australia's Northern Territory are densely colonised with the pneumococcus within weeks of birth antecedent to a high prevalence of acute lower respiratory infection (ALRI). We assessed the impact of the 23-valent pneumococcal polysaccharide vaccine (23vPPV) in pregnancy against infant ALRI in this setting. METHODS: In an open label, allocation concealed, outcome-assessor blinded, randomised controlled trial conducted in the Northern Territory of Australia, healthy Indigenous women aged 17-39 years were randomised to receive the 23vPPV during pregnancy (n = 75; 30-36 weeks gestation), at birth (n = 75), or at 7 months post-partum (n = 77). Randomisation was stratified by community of residence. In a secondary analysis, we compared the incidence of ALRI hospitalisations and ALRI clinic presentations (ascertained from electronic medical records) among infants of pregnancy vaccinees versus infants of mothers not vaccinated in pregnancy (controls) in the first year of life. RESULTS: ALRI hospitalisation incidence was 12.3 per 100 child-years among infants of pregnancy vaccinees compared with 15.8 per 100 child-years among controls (hazard ratio (HR) 0.77, 95%CI 0.29-2.03). ALRI hospitalisations were more common among remote compared to urban infants (27.7 versus 8.6 per 100 child-years). Stratification by dwelling highlighted a differential antenatal vaccine effect against ALRI hospitalisations (urban HR 2.45, 95%CI 0.60-9.99; remote HR 0.21, 95%CI 0.04-1.08). ALRI clinic presentation incidence was similar among infants of pregnancy vaccinees and controls. CONCLUSIONS: In this small study, antenatal 23vPPV vaccination was not associated with a reduced incidence of infant ALRI hospitalisations or ALRI clinic presentations during the first year of life. A potential differential effect between urban and remote settings warrants further investigation. TRIAL REGISTRATION: PneuMum; ClinicalTrials.gov NCT00714064.

Bronchiectasis in Children: Current Concepts in Immunology and Microbiology.

Bronchiectasis is a complex chronic respiratory condition traditionally characterized by chronic infection, airway inflammation, and progressive decline in lung function. Early diagnosis and intensive treatment protocols can stabilize or even improve the clinical prognosis of children with bronchiectasis. However, understanding the host immunologic mechanisms that contribute to recurrent infection and prolonged inflammation has been identified as an important area of research that would contribute substantially to effective prevention strategies for children at risk of bronchiectasis. This review will focus on the current understanding of the role of the host immune response and important pathogens in the pathogenesis of bronchiectasis (not associated with cystic fibrosis) in children.

Streptococcus pneumoniae and chronic endobronchial infections in childhood.

Streptococcus pneumoniae (pneumococcus) is the main cause of bacterial pneumonia worldwide and has been studied extensively in this context. However, its role in chronic endobronchial infections and accompanying lower airway neutrophilic infiltration has received little attention. Severe and recurrent pneumonia are risk factors for chronic suppurative lung disease (CSLD) and bronchiectasis; the latter causes considerable morbidity and, in some populations, premature death in children and adults. Protracted bacterial bronchitis (PBB) is another chronic endobronchial infection associated with substantial morbidity. In some children, PBB may progress to bronchiectasis. Although nontypeable Haemophilus influenzae is the main pathogen in PBB, CSLD and bronchiectasis, pneumococci are isolated commonly from the lower airways of children with these diagnoses. Here we review what is known currently about pneumococci in PBB, CSLD and bronchiectasis, including the importance of pneumococcal nasopharyngeal colonization and how persistence in the lower airways may contribute to the pathogenesis of these chronic pulmonary disorders. Antibiotic treatments, particularly long-term azithromycin therapy, are discussed together with antibiotic resistance and the impact of pneumococcal conjugate vaccines. Important areas requiring further investigation are identified, including immune responses associated with pneumococcal lower airway infection, alone and in combination with other respiratory pathogens, and microarray serotyping to improve detection of carriage and infection by multiple serotypes. Genome wide association studies of pneumococci from the upper and lower airways will help identify virulence and resistance determinants, including potential therapeutic targets and vaccine antigens to treat and prevent endobronchial infections. Much work is needed, but the benefits will be substantial.

Propensity of pneumococcal carriage serotypes to infect the lower airways of children with chronic endobronchial infections.

BACKGROUND: Chronic endobronchial infections in children are responsible for a high disease burden. Streptococcus pneumoniae is frequently isolated; however, few publications have described serotypes associated with non-invasive lower airway infection. METHODS: Paired nasopharyngeal (NP) swabs and bronchoalveolar lavage (BAL) fluids were collected from children undergoing bronchoscopy for chronic cough. NP swabs were also collected from asymptomatic children in otitis media surveillance studies (controls). Specimens were processed and lower airway infection defined (⩾104 colony forming units/mL BAL) as previously described. Serotype-specific odds ratios (ORs) were calculated (as described for invasive pneumococcal disease) to indicate propensity for infection. RESULTS: From 2007-2015, paired specimens were processed from 435 children with protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD) or bronchiectasis. S. pneumoniae lower airway infection was detected in 95 children: 27% with PBB and 20% with CSLD/bronchiectasis. Most (91%) children were vaccinated with ⩾2 doses of 7-valent, 10-valent or 13-valent pneumococcal conjugate vaccine. Paired NP and BAL serotype distributions were very similar; prevalent serotypes (>10 isolates) were 19A (9%), 19F, 6C, 35B, 15B, 16F, 15A, 15C, 23A, 23F and 11A. For 21 serotypes found in both NP and BAL specimens, ORs for infection were low; range 0.46 (serotype 23B) to 2.15 (serotype 6A). In the 2008-2013 surveillance studies, NP swabs were collected from 1565 asymptomatic children; 74% were pneumococcal carriers. For 21 of 22 serotypes found in both control NP swabs and BAL specimens, ORs for infection were similarly low; range 0.33 (serotype 23B) to 3.29 (serotype 22F); none was significantly different from 1. The exception was serotype 7B with OR 8.84 (95% CI 1.46, 38.1). CONCLUSIONS: Most NP carriage serotypes have a similar propensity to cause lower airway infection in children with suppurative lung diseases. Further development of pneumococcal vaccines is needed to prevent non-invasive disease caused by commonly carried serotypes.