Chronic wet cough for longer than 4 weeks is a hallmark of chronic suppurative lung diseases (CSLD), including protracted bacterial bronchitis (PBB), and bronchiectasis in children. Severe lower respiratory infection early in life is a major risk factor of PBB and paediatric bronchiectasis. In these conditions, failure to clear an underlying endobronchial infection is hypothesised to drive ongoing inflammation and progressive tissue damage that culminates in irreversible bronchiectasis. Historically, the microbiology of paediatric chronic wet cough has been defined by culture-based studies focused on the detection and eradication of specific bacterial pathogens. Various \'omics technologies now allow for a more nuanced investigation of respiratory pathobiology and are enabling development of endotype-based models of care. Recent years have seen substantial advances in defining respiratory endotypes among adults with CSLD; however, less is understood about diseases affecting children. In this review, we explore the current understanding of the airway microbiome among children with chronic wet cough related to the PBB-bronchiectasis diagnostic continuum. We explore concepts emerging from the gut-lung axis and multi-omic studies that are expected to influence PBB and bronchiectasis endotyping efforts. We also consider how our evolving understanding of the airway microbiome is translating to new approaches in chronic wet cough diagnostics and treatments.

Bronchiectasis is a pathologic state of conducting airways manifested radiographically by evidence of bronchial dilation and clinically by chronic productive cough. Considered an \"orphan disease\" for long, it remains a major contributor to morbidity and mortality in both developed and underdeveloped countries. With the advances in the medical field accompanied by widespread access to vaccines and antibiotics, improved health services and better access to nutrition, the incidences of bronchiectasis have markedly decreased, particularly in developed countries. This review summarizes the current knowledge pertaining to the clinical definition, etiology, clinical approach and management related to pediatric bronchiectasis.

Antimicrobial resistance is leading to increased mortality, posing risk to those with chronic suppurative lung disease (CSLD). One therapeutic option may be to target treatment-resistant bacteria using viruses (bacteriophages [phages]). Currently, patients receiving phage therapy on compassionate grounds may not be receiving optimal treatment as there is no defined approach for phage use. This review aims to explore administration route, regimen, and need for supplementary antibiotics in phage therapy to treat bacterial infection in CSLD. Twelve articles totaling 18 participants included details of numerous phage administration routes with varying regimens. All articles reported an initial reduction of bacterial load or an improvement in patient symptoms, highlighting the potential of phage therapy in CSLD. Fifteen out of 18 used supplementary antibiotics. Standardized protocols informed by high-quality research are necessary to ensure safe and effective phage therapy. In the interim, systematic recording of information within case reports may be useful.

Spinal Muscular Atrophy (SMA) is a severe neuromuscular disorder. Despite increased survival due to novel therapies, morbidity from respiratory complications still persists. We aim to describe these patients\' sputum cultures as an expression of chronic infectious airway disease.
Retrospective review of medical records of all children with SMA followed at the multidisciplinary respiratory neuromuscular clinic at Schneider Childrens\' Medical Center of Israel over a 16-year period. Sputum cultures were obtained during routine visits or pulmonary exacerbations.
Sixty-one SMA patients, aged 1 month to 21 years, were included in this cohort. Of these, sputum cultures were collected from 41 patients. Overall, 288 sputum cultures were obtained, and 98 (34%) were negative for bacterial growth. For the first culture taken from each patient, 12 out of 41 (29%) were sterile. The most common bacteria were pseudomonas aeruginosa (PSA) (38%) and staphylococcus aureus (19.6%). PSA was found in SMA type I patients more frequently than in type II patients (15/26 = 58% vs 4/13 = 31%, p < 0.001). PSA infection was positively associated with noninvasive ventilation, recurrent atelectasis, recurrent pneumonias, swallowing difficulties, but no significant association was found with cough assist machine usage. The incidence of positive cultures did not differ between those treated with Onasemnogene abeparvovec or Nusinersen compared to those without treatment, but the age of first PSA isolation was slightly older with Nusinersen treatment (p = 0.01).
Airway bacterial colonization is common in SMA type I patients and is not decreased by Onasemnogene abeparvovec or Nusinersen treatment.

Children with chronic wet cough and without cystic fibrosis (non-CF) may suffer from chronic suppurative lung disease (CSLD) or bronchiectasis. Pseudomonas aeruginosa (Pa) can be one of the offending microbes in these children. The present study aimed to describe the clinical course of children with the above two conditions who were infected with Pa. Data of 54 children with CSLD/bronchiectasis who were diagnosed and attended in our department were retrospectively analysed through a Cox proportional hazard model, with age, presence of bronchiectasis, use of inhaled colistin, azithromycin, inhaled hypertonic saline as the covariates. In 42 of the 54 patients, there was no identifiable cause or underlying chronic disorder. Microbiological clearance was defined as the absence of daily wet cough for four months along with four negative cultures taken during the last four consecutive follow-up visits. Multivariate analysis was performed with a Cox proportional hazard model with time to microbiological clearance as the outcome. Results are described as Hazard Ratios (HR) with 95% Confidence Intervals (95%CI). Nebulised antibiotics and the presence of bronchiectasis were statistically significant predictors of remission (HR: 3.99; 95%CI: 1.12-14.14; p = 0.032, and HR: 0.24; 95%CI: 0.08-0.71; p = 0.010). In conclusion, the rate of microbiological clearance increases with the use of inhaled colistin and decreases when there is established bronchiectasis.

Aspergillus fumigatus (Af) infection is associated with poor lung health in chronic suppurative lung diseases but often goes undetected. We hypothesised that inhibition of Af growth by Pseudomonas aeruginosa (Pa) increases the frequency of false-negative Af culture in co-infected people. Using a substantial group of cystic fibrosis (CF) airway samples, we assessed the relationship between Af and bacterial pathogens, additionally comparing fungal culture with next-generation sequencing.
Frequency of co-culture was assessed for 44,554 sputum/BAL cultures, from 1,367 CF patients between the years 2010-2020. In a subgroup, Internal Transcribed Spacer-2 (ITS2) fungal sequencing was used to determine sequencing-positive, culture-negative (S+/C-) rates.
Pa+ samples were nearly 40% less likely (P<0.0001) than Pa- samples to culture Af, an effect that was also seen with some other Gram-negative isolates. This impact varied with Pa density and appeared to be moderated by Staphylococcus aureus co-infection. Sequencing identified Af-S+/C- for 40.1% of tested sputa. Samples with Pa had higher rates of Af-S+/C- (49.3%) than those without (35.7%; RR 1.38 [1.02-1.93], P<0.05). Af-S+/C- rate was not changed by other common bacterial infections. Pa did not affect the S+/C- rates of Candida, Exophiala or Scedosporium.
Pa/ Af co-positive cultures are less common than expected in CF. Our findings suggest an Af-positive culture is less likely in the presence of Pa. Interpretation of negative cultures should be cautious, particularly in Pa-positive samples, and a companion molecular diagnostic could be useful. Further work investigating mechanisms, alternative detection techniques and other chronic suppurative lung diseases is needed.

BACKGROUND: Although the burden of bronchiectasis is recognized globally, pediatric data are limited, particularly on trends over the years. Also, no published data exists regarding whether vitamin D deficiency or insufficiency and human T-cell lymphotropic virus type 1 (HTLV-1) infection, both found to be related to severe bronchiectasis in First Nations adults, also are important in children with bronchiectasis.
OBJECTIVE: Among children with bronchiectasis, (1) have the clinical and BAL profiles changed between two 5-year periods (period 1, 2007-2011; period 2, 2012-2016) and (b) are vitamin D deficiency or insufficiency, HTLV-1 infection, or both associated with radiologic severity of bronchiectasis?
METHODS: We analyzed the data from children with bronchiectasis prospectively enrolled at Royal Darwin Hospital, Australia, at the first diagnosis; that is, no child was included in both periods. Data collected include demographics, BAL, routine investigation bloods, and high-resolution CT scan of the chest evaluated using the Bhalla and modified Bhalla scores.
RESULTS: The median age of the 299 children was 2.2 years (interquartile range, 1.5-3.7 years). One hundred sixty-eight (56%) were male and most were First Nations (92%). Overall, bronchiectasis was high over time, particularly among First Nations children. In the later period, numbers of non-First Nations children more than tripled, but did not reach statistical significance. In period 2 compared with period 1, fewer First Nations children demonstrated chronic cough (period 1, 61%; period 2, 47%; P = .03), and were younger, First Nations children were less likely to have received azithromycin (period 1, 42%; period 2, 21%; P < .001), and the BAL fluid of First Nations children showed lower Haemophilus influenzae and Moraxella catarrhalis infection. HTLV-1 infection was not detected, and vitamin D deficiency or insufficiency did not correlate with severity of bronchiectasis.
CONCLUSIONS: Bronchiectasis remains high particularly among First Nations children. Important changes in their profiles that arguably reflect improvements were present, but overall, the profiles remained similar. Although vitamin D deficiency was uncommon, its role in children with bronchiectasis requires further evaluation. HTLV-1 infection was nonexistent and is unlikely to play any role in First Nations children with bronchiectasis.

Acquiring sputum cultures from infants is considered challenging. We describe their yield in infants with cystic fibrosis (CF) and other chronic suppurative lung diseases (CSLDs).
Retrospective medical record review over a 4-year period, for infants aged 0-2 years with ≥2 airway bacterial cultures acquired by deep suction or induced sputum ≥4 weeks apart. Data included demographics, culture results, and clinical status.
A total of 98 infants (16 CF) were evaluated and 534 sputum cultures acquired, 201 in CF and 333 in CSLD. There were 12 (2-23), median (range) cultures/CF infant, and 3 (2-21)/CSLD infant. Age at first culture was 3.8 (1-19.5) months for CF and 10.4 (0.5-22) months for CSLD; p = .016. In total, 360 cultures (67%) were positive for any bacteria, with 170/234 (73%) positive during exacerbations, compared with 190/300 (63%) during routine visits; p = .05. More infants with CF than CSLD had cultures positive for Staphylococcus aureus (SA; 75% vs. 34%; p = .004) throughout the period. Pseudomonas aeruginosa (PA) was common in both CF and CSLD (56% and 44%, respectively; p = .42) and increased over time for CF but was high throughout for CSLD. The number of hospital days before PA acquisition was 6 (10.2) for CF and 28.8 (38.7) for CSLD (p = .003). No CF but 6/82 (7%) CSLD infants had chronic PA (p = .56).
Sputum cultures showed that infection, in particular PA, is common in CF and CSLD whereas SA is more common in CF. Prospective studies are warranted to elucidate the role of active surveillance in guiding antibiotic therapy.

Aims: To determine how respiratory pediatricians across Australia and New Zealand prescribe azithromycin for children with chronic wet cough, including recurrent protracted bacterial bronchitis, chronic suppurative lung disease (CSLD) and bronchiectasis. Methods: A prospective web-based questionnaire was emailed to members of the Pediatric Special Interest Group of the Thoracic Society of Australia and New Zealand (TSANZ) between April and May 2018. It comprised eight demographic and 15 clinically focused questions. Results: Of the 73 respiratory pediatricians listed across Australia and New Zealand, 29 (40%) responded and all prescribed azithromycin for chronic wet cough. Twelve (41%) indicated that they would consider prescribing a short-course (2-4 weeks) of azithromycin for children with a chronic wet cough. Although most respondents reported prescribing long-term (>4-weeks) azithromycin for either CSLD (n = 23, 79%) or bronchiectasis (n = 24, 83%), only nine (31%) respondents would commence treatment if in the previous 12-months these children experienced three non-hospitalized exacerbations and just 12 (41%) would do so if there had been two hospitalisations for severe exacerbations during the same period in accordance with the TSANZ national guidelines. A lower threshold for prescribing azithromycin was described for Indigenous children or if co-morbidities were present. None prescribed azithromycin for >24-months. Macrolide-resistance was reported in Streptococcus pneumoniae and Staphylococcus aureus. Conclusion: Although Australian and New Zealand respiratory pediatricians in this survey prescribed azithromycin for chronic wet cough most often in children with either CSLD or bronchiectasis, many did so outside the current national guidelines. Reasons for this need exploring.

The sole prospective longitudinal study of children with either chronic suppurative lung disease (CSLD) or bronchiectasis published in the current era was limited to a single center. We sought to extend this study by evaluating the longer-term clinical and lung function outcomes and their associated risk factors in Indigenous children of adolescents from Australia, Alaska, and New Zealand who participated in our previous CSLD or bronchiectasis studies during 2004-2010.
Between 2015 and 2018, we evaluated 131 out of 180 (72.8%) children of adolescents from the original studies at a single follow-up visit. We administered standardized questionnaires, reviewed medical records, undertook clinical examinations, performed spirometry, and scored available chest computed tomography scans.
Participants were seen at a mean age of 12.3 years (standard deviation: 2.6) and a median of 9.0 years (range: 5.0-13.0) after their original recruitment. With increasing age, rates of acute lower respiratory infections (ALRI) declined, while lung function was mostly within population norms (median forced expiry volume in one-second = 90% predicted, interquartile range [IQR]: 81-105; forced vital capacity [FVC] = 98% predicted, IQR: 85-114). However, 43 out of 111 (38.7%) reported chronic cough episodes. Their overall global rating judged by symptoms, including ALRI frequency, examination findings, and spirometry was well (20.3%), stable (43.9%), or improved (35.8%). Multivariable regression identified household tobacco exposure and age at first ALRI-episode as independent risk factors associated with lower FVC% predicted values.
Under our clinical care, the respiratory outcomes in late childhood or early adolescence are encouraging for these patient populations at high-risk of premature mortality. Prospective studies to further inform management throughout the life course into adulthood are now needed.