Recurrent pulmonary tuberculosis in a child with primary ciliary dyskinesia: a rare association

Objective: To evaluate the value of nasal nitric oxide (nNO) measurement as a diagnostic tool for Chinese patients with primary ciliary dyskinesia (PCD). Methods: This study is a retrospective study. The patients were recruited from those who were admitted to the respiratory Department of Respiratory Medicine, Children's Hospital of Fudan University from March 2018 to September 2022. Children with PCD were included as the PCD group, and children with situs inversus or ambiguus, cystic fibrosis (CF), bronchiectasis, chronic suppurative lung disease and asthma were included as the PCD symptom-similar group. Children who visited the Department of Child health Care and urology in the same hospital from December 2022 to January 2023 were selected as nNO normal control group. nNO was measured during plateau exhalation against resistance in three groups. Mann-Whitney U test was used to analyze the nNO data. The receiver operating characteristic of nNO value for the diagnosis of PCD was plotted and, the area under the curve and Youden index was calculated to find the best cut-off value. Results: nNO was measured in 40 patients with PCD group, 75 PCD symptom-similar group (including 23 cases of situs inversus or ambiguus, 8 cases of CF, 26 cases of bronchiectasis or chronic suppurative lung disease, 18 cases of asthma), and 55 nNO normal controls group. The age of the three groups was respectively 9.7 (6.7,13.4), 9.3 (7.0,13.0) and 9.9 (7.3,13.0) years old. nNO values were significantly lower in children with PCD than in PCD symptom-similar group and nNO normal controls (12 (9,19) vs. 182 (121,222), 209 (165,261) nl/min, U=143.00, 2.00, both P<0.001). In the PCD symptom-similar group, situs inversus or ambiguus, CF, bronchiectasis or chronic suppurative lung disease and asthma were significantly higher than children with PCD (185 (123,218), 97 (52, 132), 154 (31, 202), 266 (202,414) vs. 12 (9,19) nl/min,U=1.00, 9.00, 133.00, 0, all P<0.001). A cut-off value of 84 nl/min could provide the best sensitivity (0.98) and specificity (0.92) with an area under the curve of 0.97 (95%CI 0.95-1.00, P<0.001). Conclusions: nNO value can draw a distinction between patients with PCD and others. A cut-off value of 84 nl/min is recommended for children with PCD.

Chronic suppurative lung disease (CSLD) describes a range of lung diseases characterised by chronic productive cough, compromised airway clearance and poor long-term health. Evidence is still sparse regarding the best...

Pediatricians Are Not Just Small Internists

Establishing the underlying cause in a child with chronic suppurative lung disease (CSLD) allows for targeted treatment and screening for associated complications. One cause of CSLD is primary ciliary dyskinesia (PCD). Testing for PCD requires specialist expertise which is not widely available. Computed tomography (CT) scans are commonly performed when assessing CSLD. Identifying PCD-specific signs on CT would help clinicians in deciding when to refer for specialist testing. One potential PCD-specific sign we have observed is fissure adjacent partial lobe atelectasis (FAPLA). We aimed to assess if FAPLA is commonly found in CT of PCD patients. Fifty-eight CT scans from 42 adult and child PCD patients were analysed. The presence and distribution of FAPLA were noted, and its association to sputum culture and other signs commonly seen in CSLD (bronchiectasis, bronchial wall thickening, air trapping and mucus plugging). FAPLA was found in 13 of 40 participants in their earliest CT scan. The prevalence of FAPLA was similar in children and adults. FAPLA involved the right middle lobe in all 13 cases and was systematically associated with ≥1 other structural change. There was no association between FAPLA and bacterial isolation from sputum. FAPLA was found in 32.5% PCD scans, without difference between children and adults in terms of frequency. Future work will determine if it is a PCD-specific sign by assessing whether it is also found in other CSLD processes and analysing more scans from children with PCD to determine how early this sign develops.

RationaleThe airway microbiota is important in chronic suppurative lung diseases, such as primary ciliary dyskinesia (PCD) and cystic fibrosis (CF). This comparison has not previously been described but is important...

We describe the clinical, bronchoscopic, bronchoalveolar lavage (BAL) and radiographic characteristics of children whose chronic wet cough did not resolve with oral antibiotics and which led to their hospitalisation for intravenous antibiotics and airway clearance therapy. Between 2010 and 2014, medical chart review identified 22 such children. Their median cough duration was 26weeks (interquartile range (IQR) 13-52). All received oral antibiotics immediately before their hospitalisation (median 4weeks; IQR 4-6.5). On chest examination, seven (31%) children had auscultatory crackles. At bronchoscopy, 9 (41%) had tracheomalacia, 18 (86%) demonstrated airway neutrophilia (>15%) and 12 (57%) grew Haemophilus influenzae from their BAL fluid. They received intravenous antibiotics (mostly cefotaxime or ceftriaxone) and airway clearance therapy as inpatients (median 12.5days (IQR 10.8-14). All were cough-free at follow-up. The children's BAL characteristics are similar to those with protracted bacterial bronchitis and bronchiectasis, but their poor clinical response to oral antibiotics and non-specific chest CT findings differentiated them from these other two disorders. The findings are consistent with chronic suppurative lung disease. Intravenous antibiotics and airway clearance therapy should therefore be considered in children whose wet cough persists despite 4weeks of oral antibiotics and where other causes of chronic wet cough are absent. What is known on this topic? • Chronic wet cough not resolving with appropriate antibiotics increases the likelihood of bronchiectasis. • Children with chronic suppurative lung disease (CSLD) have clinical features of bronchiectasis, but lack the radiographic evidence for this diagnosis. • Children with CSLD have airway neutrophilia and predominantly Haemophilus influenzae in lower airway cultures, similar to children with protracted bacterial bronchitis and bronchiectasis. • Chronic wet cough in CSLD, unresponsive to oral antibiotics, resolves with intravenous antibiotics and airway clearance therapy.

Chronic wet cough in children and further exploration of protracted bacterial bronchitis

Non-typeable Haemophilus influenzae (NTHi) is commonly associated with chronic suppurative lung disease in children. We have previously shown that children with chronic suppurative lung disease have a reduced capacity to produce IFN-γ in response to NTHi compared with healthy control children. The aim of this study was to determine if deficient NTHi-specific IFN-γ production is associated with heightened systemic or airway inflammation. We measured a panel of cytokines (IFN-γ, IL-1β, IL-6, IL-8, IL-12 p70), antimicrobial proteins (LL-37, IP-10) as well as cellular and clinical factors associated with airway and systemic inflammation in 70 children with chronic suppurative lung disease. IFN-γ was measured in peripheral blood mononuclear cells challenged in vitro with live NTHi. Regression analysis was used to assess the association between the systemic and airway inflammation and the capacity to produce IFN-γ. On multivariate regression, NTHi-specific IFN-γ production was significantly negatively associated with the BAL concentrations of the inflammatory cytokines IL-6 (β=-0.316; 95%CI -0.49, -0.14; p=0.001) and IL-1β (β=-0.023; 95%CI -0.04, -0.01; p=0.001). This association was independent of bacterial or viral infection, BAL cellularity and the severity of bronchiectasis (using modified Bhalla score on chest CT scans). We found limited evidence of systemic inflammation in children with chronic suppurative lung disease. In summary, increased local airway inflammation is associated with a poorer systemic cell-mediated immune response to NTHi in children with chronic suppurative lung disease. These data support the emerging body of evidence that impaired cell-mediated immune responses and dysregulated airway inflammation may be linked and contribute to the pathobiology of chronic suppurative lung disease.

Primary ciliary dyskinesia (PCD) is characterised by chronic suppurative lung disease, rhino-sinusitis, hearing impairment and sub-fertility. We have developed the first multidimensional measure to assess health-related quality of life (HRQoL) in adults with PCD (QOL–PCD).Following a literature review and expert panel meeting, open-ended interviews with patients investigated the impact of PCD on HRQoL in the UK and North America (n=21). Transcripts were content analysed to derive saturation matrices. Items were rated for relevance by patients (n=49). Saturation matrices, relevance scores, literature review, evaluation of existing measures, and expert opinion contributed to development of a preliminary questionnaire. The questionnaire was refined following cognitive interviews (n=18).Open-ended interviews identified a spectrum of issues unique to adults with PCD. Saturation matrices confirmed comprehensive coverage of content. QOL–PCD includes 48 items covering the following seven domains: Physical Functioning, Emotional Functioning, Treatment Burden, Respiratory and Sinus Symptoms, Ears and Hearing, Social Functioning, and Vitality and Health Perceptions. Cognitive testing confirmed that content was comprehensive and the items were well-understood by respondents.Content validity and cognitive testing supported the items and structure. QOL–PCD has been translated into other languages and is awaiting psychometric testing.

Chronic suppurative lung disease (CSLD) is characterized by the presence of a chronic wet or productive cough and recurrent lower respiratory infections. The aim of this study was to identify features of innate, cell-mediated and humoral immunity that may increase susceptibility to respiratory infections in children with CSLD. Because non-typeable Haemophilus influenzae (NTHi) is commonly isolated from the airways in CSLD, we examined immune responses to this organism in 80 age-stratified children with CSLD and compared their responses with 51 healthy control children. Cytokines involved in the generation and control of inflammation (IFN-γ, IL-13, IL-5, IL-10 at 72 hours and TNFα, IL-6, IL-10 at 24 hours) were measured in peripheral blood mononuclear cells challenged in vitro with live NTHi. We also measured circulating IgG subclass antibodies (IgG1 and IgG4) to two H. influenzae outer membrane proteins, P4 and P6. The most notable finding was that PBMC from children with CSLD produced significantly less IFN-γ in response to NTHi than healthy control children whereas mitogen-induced IFN-γ production was similar in both groups. Overall there were minor differences in innate and humoral immune responses between CSLD and control children. This study demonstrates that children with chronic suppurative lung disease have an altered systemic cell-mediated immune response to NTHi in vitro. This deficient IFN-γ response may contribute to increased susceptibility to NTHi infections and the pathogenesis of CSLD in children.

Bronchiectasis, Chronic Suppurative Lung Disease and Protracted Bacterial Bronchitis

Improving immunity to Haemophilus influenzae in children with chronic suppurative lung disease

IntroductionBronchiectasis unrelated to cystic fibrosis (CF) remains an under-researched area and is often labelled a “neglected disease”. Yet, worldwide it is more common than CF and causes substantial morbidity and mortality in both children and adults.To reduce morbidity and premature mortality from bronchiectasis in adults, interventions should begin in childhood. Diagnosing bronchiectasis early and providing effective treatment, including treating exacerbations, can prevent significant morbidity. Although the importance of recognising and treating exacerbations effectively is well-accepted, there have been no prior randomised trials for managing exacerbations of bronchiectasis in children. The studies in my PhD address several important clinical and research gaps relating to children with bronchiectasis, including its early identification and antibiotic treatment of exacerbations.AimsThe overarching aim of my thesis is to improve knowledge of bronchiectasis, the pre-bronchiectasis state and management of bronchiectasis exacerbations in children.The specific main objectives were to:1. Identify whether children with a poor response to at least 4-weeks of oral antibiotics predict an increased risk of finding bronchiectasis on a multi-detector computed-tomography (MDCT) scan of the chest.2. Describe the clinical characteristics, investigations and treatment outcomes for children with chronic suppurative lung disease (CSLD) without radiographic evidence of bronchiectasis.3. Determine in children with bronchiectasis the effect of oral azithromycin and oral amoxicillin-clavulanate (each compared to placebo) on symptom resolution after 14-days treatment of non-severe (non-hospitalised) acute respiratory exacerbations.4. Asses in children with bronchiectasis whether oral azithromycin was non-inferior (within a 20% margin) to oral amoxicillin-clavulanate at achieving symptom resolution after21-days treatment of non-severe (non-hospitalised) acute respiratory exacerbations.5. Estimate the cost of hospitalised bronchiectasis exacerbations.6. Undertake a systematic review using Cochrane methodology to assess the effects of inhaled long-acting beta-2-agonists (LABA) combined with inhaled corticosteroids (ICS) in children and adults with bronchiectasis during (a) acute exacerbations and (b) stable state.An overview of the major findings for each objective is detailed below:Objective-1 was addressed by studying 144 children undergoing chest CT scans for a chronic wet cough. Among the 105 children with persistent cough despite at least 4-weeks of antibiotics, 88 (83.8%) had bronchiectasis. In contrast, of the 24 children whose cough resolved after 4-weeks of antibiotics, only six (25.0%) received this diagnosis (adjusted OR 20.9; 95%CI 5.36 to 81.8).1 The study addressing objective-2 is the first to describe children with CSLD. These 22 children lacked features of bronchiectasis on CT scans but had a wet cough unresponsive to oral antibiotics, which resolved with intravenous antibiotics and airway clearance therapy. Children with CSLD had broncho-alveolar lavage (BAL) characteristics similar to protracted bacterial bronchitis and bronchiectasis, but their poor clinical response to oral-antibiotics and non-specific chest-CT findings differentiated them from the other two disorders respectively.2 Objective-3 was accomplished by a multicentre three-arm, double-dummy, randomised controlled trial (RCT) involving 197 children. Compared to placebo, the relative risk of resolution by day-14 for amoxicillin-clavulanate was 1.50 (95%CI 1.08-2.09) and for azithromycin 1.41 (95%CI 1.01-1.97). However, azithromycin was associated with increased carriage of antibiotic-resistant bacteria.3Objective-4 was achieved by a multicentre double-dummy, double-blind, placebo-containing RCT comprising 179 children. By day-21, 61/73 (84%) exacerbations had resolved in the azithromycin group versus 73/87 (84%) in the amoxicillin-clavulanate group. The risk difference showed non-inferiority (–0.3%, 95%CI –11.8-11.1). Exacerbations were significantly shorter in the amoxicillin-clavulanate than the azithromycin group (median 10-days [IQR 6–15] versus 14-days [8–16]; p=0.014). Thus, azithromycin provides another option for treating exacerbations but must be balanced with the risk of treatment failure (within a 20% margin), longer exacerbation duration, and the risk of inducing macrolide-resistance.4For objective-5, a prospective study of hospitalisation costs for 100 children was undertaken. The cost of one hospital admission for bronchiectasis exacerbation was A$30,182 (SD 13998) with an average length-of-stay of 12.3 (SD 4.6) days. In planning this study, the absence of a Disease-Related-Group (DRG) classification for treating bronchiectasis exacerbations in Australia was evident. Thus, a public submission to the Australian Consortium for Classification Development for a bronchiectasis DRG was made and subsequently, hospitalisation for bronchiectasis was assigned a code from July 1, 2018.Objective-6 led to a systematic review showing no high-quality evidence exists for combined ICS and LABA therapy in paediatric bronchiectasis.5ConclusionsThe studies arising from this thesis provide new knowledge in relation to:1. Identifying children with a wet cough who need further investigation for bronchiectasis.2. Describing the clinical, bronchoscopic, BAL and treatment outcome findings for children with CSLD.3. Proving for the first time, evidence for antibiotic efficacy compared to placebo for treating non-severe bronchiectasis exacerbations.4. Establishing that azithromycin is non-inferior (within 20% margin) to amoxicillin-clavulanate for treating non-severe bronchiectasis exacerbations.5. Providing data for the hospitalisation costs for bronchiectasis exacerbations in Australia.6. Identifying the current lack of high-quality evidence for combined ICS and LABA in children and adults with bronchiectasis.

Whole-Exome Capture and Sequencing Identifies HEATR2 Mutation as a Cause of Primary Ciliary Dyskinesia

What Is in a Name?: The Dilemma of “Prebronchiectasis”