Background: Pediatric lung transplantation is a life-saving procedure for children with end-stage lung disease. As immunosuppression and treatment have improved, so too have survival outcomes; however, pediatric lung transplant recipients still face challenges, including acute rejection, infection, and long-term issues such as chronic lung allograft dysfunction (CLAD). Methods: This review details early complications following pediatric lung transplantation and provides an explorative investigation of the mechanisms underlying acute allograft dysfunction, and current prevention and treatment strategies. Focus is then given to CLAD with an overview of the subtypes of CLAD, review of recognized risk factors, challenges around diagnostics, current treatment strategies, and importantly future research goals to aid in the better identification and characterization of CLAD. Conclusions: As our understanding of acute and CLAD has evolved over time so have prevention and treatment strategies, including the assessment and treatment of risk factors such as infection and aspiration. The diagnosis of CLAD, however, remains extremely challenging with limited treatment options. Future research should focus on the prevention of CLAD.

Children with advanced lung diseases are eligible to be considered as potential candidates for lung transplantation around the world. The timing of referral, evaluation, determination of candidacy, and listing of candidates poses challenges and ethical dilemmas for pediatric care providers. To address these challenges, the International Society for Heart and Lung Transplantation appointed an international panel of expert members to review the literature, to consider recent advances in the management of advanced pediatric lung diseases, and to generate the first consensus guidelines on the referral criteria and selection of pediatric lung transplant (LTx) candidates. This consensus document is meant to assist pediatric care providers throughout the world caring for children with advanced lung diseases to identify potential candidates for LTx, to optimize the timing of the referral of these patients to LTx centers, and to provide transplant centers with a framework for the evaluation and selection of children as candidates.

BACKGROUND:Previous research showed that lung function abnormalities are common in infants with cystic fibrosis (IwCF) but real-world data are missing. METHODS:This single-center retrospective study analyzed infant lung function results from IwCF born in 2012-2018. The tests were conducted at Great Ormond Street Hospital, London, as part of routine care at 3 months, 1 year, and 2 years of age. Z-scores for SF6 Lung Clearance Index (zLCI), plethysmographic FRC (zFRCpleth) and FEV0.5 were derived. Microbiology and antibiotics prescription from 3 months before lung function assessments, up to the closest medical review following the lung function encounter, were analyzed, along with changes in management advised by the physician. RESULTS:A total of 126 lung function encounters (n = 43 at 3 months, 46 at 1 year, 37 at 2 years) from 60 IwCF were included. LCI was abnormal (zLCI > 1.96) in 31% (12/39) of 3-month-olds (mean± zLCI 1.21 ± 1.08), 28% (12/43) of 1-year-olds and 19% (7/36) of 2-year-olds (mean± zLCI 1.13 ± 1.10). Among 74 cases with recent positive microbiology or abnormal chest findings at medical review, 100% (31/31) of those with abnormal lung function and 86% (37/43) of those with normal lung function (p = 0.04) had a recent antibiotic prescription or a change in clinical management. Conversely, in encounters with abnormal lung function but normal clinical findings, management changes occurred in only 12% (2/16) of cases. CONCLUSION:In this real-word cohort of IwCF, clinical management was mainly influenced by clinical findings and only marginally by abnormal lung function (elevated FRC or LCI).

Highly effective modulator therapy (HEMT) has been available for adults and young adults aged 12 years and over with cystic fibrosis for approximately 5 years, with real-world evidence (RWE) emerging that confirms the significant impacts of these novel medications in older patient groups. As licensing has been extended to younger children (2 years and above in some jurisdictions), we summarize the clinical experience of these medications in pre-school and school-aged children and compare how changes in the objective markers of the disease can be elucidated in younger children. We also discuss the different incidences and severity of side effect profiles, the efforts to mediate these in younger children, and the particular challenges in introducing novel medications into pediatrics. We speculate on the use of HEMT in younger infants and its potential use in prenatal care.

A common eligibility criterion in respiratory clinical trials is a per cent-predicted forced expiratory volume in 1 second (ppFEV1) between 40% and 90%, using the ethnicity-dependent Global Lung Function Initiative (GLI)-2012 spirometry reference equations. International societies now endorse the newer 'race-neutral' GLI-Global equations. We quantify the impact on trial eligibility of switching from GLI-2012 to GLI-Global for the UK Cystic Fibrosis Registry (n=8182). In a future trial with a maximum eligibility threshold of ppFEV1=90%, the changes in ppFEV1 would lead to over 700 people becoming newly ineligible. Urgent review of fixed ppFEV1 thresholds is required, with an initial recommendation to widen the range to 30-95% ppFEV1 when GLI-Global is implemented to ensure equitable access for people of all ethnicities. There is also a wider need to review the use of fixed ppFEV1 spirometry limits for trial eligibility.

Chronic human norovirus (HuNoV) infections in immunocompromised patients result in severe disease, yet approved antivirals are lacking. RNA-dependent RNA polymerase (RdRp) inhibitors inducing viral mutagenesis display broad-spectrum in vitro antiviral activity, but clinical efficacy in HuNoV infections is anecdotal and the potential emergence of drug-resistant variants is concerning. Upon favipiravir (and nitazoxanide) treatment of four immunocompromised patients with life-threatening HuNoV infections, viral whole-genome sequencing showed accumulation of favipiravir-induced mutations which coincided with clinical improvement although treatment failed to clear HuNoV. Infection of zebrafish larvae demonstrated drug-associated loss of viral infectivity and favipiravir treatment showed efficacy despite occurrence of RdRp variants potentially causing favipiravir resistance. This indicates that within-host resistance evolution did not reverse loss of viral fitness caused by genome-wide accumulation of sequence changes. This off-label approach supports the use of mutagenic antivirals for treating prolonged RNA viral infections and further informs the debate surrounding their impact on virus evolution.

Cystic fibrosis (CF) is a multisystem, genetic disease with a significantly reduced life expectancy. Despite substantial progress in therapies in the last 10-15 years, there is still no cure. There are dozens of drugs in the development pipeline and multiple clinical trials are being conducted across the globe. The UK Cystic Fibrosis Trust’s (CFT) Clinical Trials Accelerator Platform (CTAP) is a national initiative bringing together 25 UK based CF centres to support the CF community in accessing and participating in CF clinical trials. CTAP enables more CF centres to run a broader portfolio of trials and increases the range of CF studies available for UK patients.There are four large specialist CF centres based in London, all within a small geographical region as well as two smaller centres which deliver CF care. At the launch of CTAP, these centres formed a sub-network in a consortium-style collaboration. The purpose of the network was to ensure equity of access to trials for patients across the UK’s capital, and to share experience and knowledge. Four years into the programme we have reviewed our practices through working group meetings and an online survey. We sought to identify strengths and areas for improvement. We share our findings here, as we believe they are relevant to others delivering research in regions outside of London and in other chronic diseases.

Background & Aims: Cystic Fibrosis (CF) liver disease progresses to liver failure requiring transplantation in about 3 % of patients, 0.7 % of CF patients are post liver transplant. The prognosis of CF has improved with the introduction of elexacaftor/tezacaftor/ivacaftor (ETI). Due to the paucity of data and concerns regarding interactions with immunosuppressive drug regimens, there is no general consensus on use of ETI post liver transplantation. The aim of this review is to report the safety and efficacy of ETI in CF patients who underwent liver transplantation. Methods: A systematic review was conducted through MEDLINE/Pubmed and EMBASE databases. Englishwritten articles reporting clinical data on liver transplanted CF patients treated with ETI were included. Article quality was evaluated using the Critical Appraisal Checklist for Case Reports. Results: Twenty cases were retrieved from 6 reports. Temporary discontinuation and/or dose reduction due to elevated transaminases was required in 5 cases. ETI restarted on a reduced dose was tolerated in 3 out of 5 patients, 1 patient tolerated full dose. Tacrolimus dose change was required in 14 cases, in 1 case ETI was discontinued due to tacrolimus toxicity. Improvement in percentage predicted FEV1 was noted in 15/19 patients (median +17 %, range 8 %-38 %). Conclusions: In the majority of liver transplanted patients ETI is well tolerated, although adverse events and liver function abnormalities may occur. Close monitoring of liver function and tacrolimus level is warranted. Significant improvement in lung function after ETI initiation is confirmed, highlighting the importance of accessing this medication for this group of patients.

Lung transplantation is a recognized therapy for end-stage respiratory failure in children and young people. It is only available in selected countries and is limited by access to suitable organs. Data on disparities in access and outcomes for children undergoing lung transplantation are limited. It is clear from data from studies in adults, and from studies in other solid organ transplants in children, that systemic inequities exist in this field. While data relating specifically to pediatric lung transplantation are relatively sparse, professionals should be aware of the risk that healthcare systems may result in disparities in access and outcomes following lung transplantation in children.

Objectives: Children and young people with CF taking elexacaftor/tezacaftor/ivacaftor (ETI), have shown increases in weight and BMI, however these markers do not distinguish between gain in fat mass (FM) or fat-free mass (FFM). FFM has a stronger association with FEV1 than BMI [1Calella P et al.Nutrition. 2018; 55–56: 131-139Crossref PubMed Scopus (42) Google Scholar]. No studies have reported the impact of ETI on body composition (BC) in paediatric populations. We sought to assess anthropometry and BC in 6–11 year olds after starting ETI. Methods: We measured anthropometry and BC from January to December 2022 at clinic visits, using bio-electrical impedance (BIA), in addition to spirometry, performed before starting ETI. Repeat measurements were taken within first 6 months of starting ETI. Results were converted to z-scores where reference data available, and descriptive statistics analysed using paired t-test. Results: 48 children (23 male) had baseline measurements (mean ± sd age 9.2 years ± 1.8), including all modulator-naïve (MN) patients (19/48), and those previously prescribed other modulators, with repeat measurements in 40 (16 MN) at mean± sd 194 days ± 46. At baseline weight z-scores were lower in MN patients. There was no significant difference in anthropometric markers between baseline and follow-up in either group. Raw skeletal muscle mass (SMM) values increased significantly, whereas FM did not. FEV1 increased significantly in both groups. Conclusions: Our data suggests this age group do not have significant increases in BMI on starting ETI. Improved nutritional status appears evident with increased SMM rather than FM. These data are limited by a lack of controls and clinically available reference values. Diet and exercise advice should focus on promotion of SMM for improved FEV1, whilst achieving or maintaining optimal BMI. Further work is recommended to establish frequency of BC monitoring using BIA. Table(abstract: EPS5.07).Mean (SD)Weight z-scoreHeight z-scoreBMI z-scoreSMM (kg)FM (kg)FEV1 z-scoreBaseline MN n = 19−0.69 ± 1.18−0.51 ± 1.26−0.38 ± 1.0111.71 ± 3.724.47 ± 3.90−0.42 ± 1.09Baseline other n = 290.00 ± 0.83−0.07 ± 1.140.03 ± 0.9113.00 ± 3.044.44 ± 2.02−0.49 ± 0.99Repeat MN n = 16−0.60 ± 1.20−0.60 ± 1.14−0.37 ± 1.0612.73**p <0.001. ± 4.295.43 ± 4.81−0.14*p <0.05 ± 1.08Repeat other n = 240.08 ± 0.83−0.19 ± 1.100.10 ± 1.0314.43**p <0.001. ± 3.794.68 ± 2.16−0.22*p <0.05 ± 0.88* p <0.05** p <0.001. Open table in a new tab

Purpose Serological responses to Covid-19 vaccines in adults post solid organ transplant are impaired [1]. We sought to measure antibodies to SARS-CoV-2 in adolescents post lung, heart, kidney-liver and kidney transplant following the vaccine rollout to 12-17 year-olds in the UK. Methods We measured anti-spike, receptor binding domain and nucleocapsid IgG in adolescents attending our centre for routine drug monitoring after Pfizer/BioNTech BNT 162b2 was made available in autumn 2021, and collected information on prior infection from electronic records and via patient/parent recall. Results Samples were obtained from 42 participants, with paired samples pre and post vaccine in 14 patients. 52% had serological evidence of past exposure at baseline (fig 1). Receptor binding domain IgG was positive in all subjects at follow up, with spike IgG positive in 13/14 (p<0.001, fig 2). Individuals who had received vaccine and been infected had higher levels of spike IgG than those who had been infected and unvaccinated (p<0.05). Conclusion All subjects demonstrated antibody responses to vaccine, and vaccine increases antibody levels in adolescents who have also had a SARS-CoV-2 infection in comparison to the unvaccinated. These data support an age-related relationship to antibody responses in post solid organ transplant recipients and support efforts to increase vaccine uptake in this at-risk group.

Introduction: At our centre, infant lung function (ILF) is routinely performed in children with cystic fibrosis (CF). Research question: do ILF results affect clinical management? Methods: Mono-centre retrospective cohort analysis of subjects with CF born between 2014 and 2018. Z-scores for SF6 Lung Clearance Index (zLCI), plethysmographic FRC (zFRCpleth) and zFEV0.5 were derived. The closest clinical encounter following each ILF data point was reviewed to evaluate whether there were changes in clinical management and why. Results: Following 95 ILF tests there were 10 changes in management, but only one of these was for abnormal ILF results alone. In the other 9 cases there were also increased symptoms and/or abnormal microbiology. See table for full results Conclusion: This analysis did not demonstrate change in clinical management following ILF results alone. Prospective studies involving weighting of different factors are required to assess the utility of ILF.

Rationale The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. Objectives To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods Children were randomized to receive either ELX/TEZ/IVA (n = 60) or placebo (n = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children <30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ⩾30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). Measurements and Main Results The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index2.5 of 2.29 units (95% confidence interval [CI], 1.97–2.60) compared with 0.02 units (95% CI, −0.29 to 0.34) in children given placebo (between-group treatment difference, −2.26 units; 95% CI, −2.71 to −1.81; P < 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, −51.2 mmol/L; 95% CI, −55.3 to −47.1) and in the other endpoints of percent predicted FEV1 (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9–15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0–10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity. Conclusions In this first randomized, controlled study of a cystic fibrosis transmembrane conductance regulator modulator conducted in children 6 through 11 years of age with F/MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and cystic fibrosis transmembrane conductance regulator function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings.

S72 Table 1Table of lung function results expressed as mean and 95% CI = Confidence IntervalDemographic N= Mean (95% CI) Age (years) N= 30 11.73 (10.70, 12.77) Sex, Female% N=14 (48%) Height (cm) N=30 152.24 (145.62, 158.86) FeNO (ppb) N=26 16.28 (9.01, 23.55) FEV1%pred (%) N=29 103.85 (98.04, 109.66) FEV1 z-score N= 29 0.32 (0.00, 1.00) FVC%pred (%) N= 29 103.3 (98.25, 108.35) FVC z-score N= 29 0.25 (-0.15, 0.66) FEV1:FVC Ratio%pred (%) N= 29 98.84 (96.69, 100.99) FEV1:FVC Ratio z-score N=29 -0.09 (-0.41, 0.23) TLCO%pred N=23 86.69 (80.00, 93.39) TLCO z-score N=23 -1.04 (-1.70, -0.37) KCO%pred N=23 97.22 (91.34, 103.01) KCO z-score N=23 -0.22 (-0.65, 0.21) VA%pred N=23 88.87 (84.09, 93.65) VA z-score N=23 -1.01 (-1.44, -0.58) FRCpleth%pred (%) N=15 88.00 (80.99, 95.01) FRCpleth z-score N=15 -0.77 (-1.26, -0.28) TLC%pred (%) N=15 98.2 (92.17, 104.23) TLC z-score N=15 -0.15 (-0.66, 0.36) RV%pred (%) N=15 83.47 (71.34, 95.60) RV z-score N=15 -0.43 (-0.88, 0.02) ConclusionSimilar to other systemic inflammatory syndromes (Staphylococcal toxic shock, Kawasaki disease), and unlike Covid-19 in adults, it appears that children’s lungs are at low risk of long term damage by PIMS-TS. This data is preliminary and we have not assessed exercise tolerance, or outcomes in those with presentations that did not require initial respiratory support. Assessments are ongoing in this cohort and in children presenting following infection with new variants of concern.ReferencePenner, et al. 6-month multidisciplinary follow-up and outcomes of patients with paediatric inflammatory multisystem syndrome (PIMS-TS) at a UK tertiary paediatric hospital: a retrospective cohort study. Lancet Child Adolesc Health 2021;5(7):473–482.

© BMJ Publishing Group Limited 2021. No commercial reuse. See rights and permissions. Published by BMJ. DESCRIPTION A 6yearold previously healthy boy presented with a 5day history of fever, malaise and pharyngitis. His parents brought him to the emergency department due to a new onset of cough and difficulty in breathing. He was fully immunised with no recent travel history or infectious contacts. At presentation his respiratory rate and oxygen saturation were normal. Chest examination revealed reduced air entry over the right upper zone. His chest radiograph (day 7 of illness, figure 1) showed right upper lobe subsegmental consolidation and right paratracheal lymphadenopathy. He was discharged with oral coamoxiclav, however represented after 48 hours with worsening symptoms. On admission he was feverish (38.5°C), hypoxic (saturation 91% breathing room air) and tachypnoeic (respiratory rate 28 breaths/min). Examination demonstrated signs of respiratory distress with bronchial breathing over the right upper zone, pharyngeal congestion, anterior cervical lymphadenopathy but no hepatosplenomegaly. Investigations showed a normal white cell count (5.78×10/L), neutrophil count (3.28×10/L), lymphocyte count (1.58×10/L) and a mildly raised Creactive protein (10 mg/dL). A repeat chest radiograph (day 10 of illness, figure 2) demonstrated right upper lobe collapse and consolidation within the left lower lobe. He was referred to a specialist paediatric respiratory team on day 12 of his illness due to persistent fever and respiratory symptoms. Right upper lobe collapse secondary to extrinsic bronchial obstruction due to lymph node enlargement should prompt exclusion of tuberculosis (TB). However, the clinical presentation is more suggestive of an atypical infection which has not improved with empirical treatment for a presumed typical communityacquired pneumonia (CAP). Investigations for TB including Mantoux test, QuantiferonTB and three early morning gastric aspirates were negative. Nasopharyngeal aspirate for respiratory virus detection by reverse transcription PCR was also negative. As the cough was nonproductive, sputum cultures were not sent. Multiplex PCR assay was positive for Mycoplasma pneumoniae from an oropharyngeal swab. This patient showed significant clinical and radiological response to intravenous coamoxiclav and oral azithromycin after 5 days. Followup (8 weeks) chest radiograph showed complete aeration within the right upper lobe. M. pneumoniae pathogenicity arises from specialised terminal organelles composed of integral membrane proteins (eg, P30) that mediate attachment and gliding motility along the respiratory epithelium. Mycoplasma lacks a peptidoglycan cell wall, differentiating it from other bacteria and conferring intrinsic resistance to betalactam antibiotics that inhibit cell wall synthesis. Macrolides exhibit activity against Mycoplasma by binding to the 50S ribosomal subunit inhibiting protein synthesis at the chain elongation step. M. pneumoniae in children hospitalised with CAP is associated with variable radiographic abnormalities. 4 In a prospective study of 2254 US children (<18 years) hospitalised with CAP, 8% were M. pneumoniae PCRpositive. Hilar lymphadenopathy was more common in M. pneumoniae PCRpositive than negative children (10% vs 6%; p=0.02). There were no reports of lobar or segmental collapse. The most frequent radiographic abnormalities included consolidation (59%), single lobar infiltrate (32%) and pleural effusion (26%). Our case highlights an ‘atypical’ radiographic presentation of M. pneumoniae responsive to both the antimicrobial and antiinflammatory effects of a macrolide agent. Figure 1 Chest radiograph (day 7 of illness). There is right upper lobe subsegmental consolidation and right paratracheal lymphadenopathy; the lungs are also hyperinflated. Figure 2 Chest radiograph (day 10 of illness). There is a dense right upper lobe collapse; consolidation is present within the left lower lobe and right middle lobe.