Background Hematopoietic Stem Cell Transplant (HSCT) is an established treatment for malignant and non-malignant conditions and pulmonary disease is a leading cause of late term morbidity and mortality. Accurate and early detection of pulmonary complications is a critical step in improving long term outcomes. Existing guidelines for surveillance of pulmonary complications post-HSCT contain conflicting recommendations. Objective To determine the breadth of current practice in monitoring for pulmonary complications of pediatric HSCT. Study Design An institutional review board approved, online, anonymous multiple-choice survey was distributed to HSCT and pulmonary physicians from the United States of America and Australasia using the REDcap platform. The survey was developed by members of the American Thoracic Society Working Group on Complications of Childhood Cancer, and was designed to assess patient management and service design. Results A total of 40 (34.8%) responses were received. The majority (62.5%) were pulmonologists, and 82.5% were from the United States of America. In all, 67.5% reported having a protocol for monitoring pulmonary complications and 50.0% reported adhering “well” or “very well” to protocols. Pulmonary function tests (PFTs) most commonly involved spirometry and diffusion capacity for carbon monoxide. The frequency of PFTs varied depending on time post-HSCT and presence of complications. In all, 55.0% reported a set threshold for a clinically significant change in PFT. Conclusions These results illustrate current variation in surveillance for pulmonary complications of pediatric HSCT. The results of this survey will inform development of future guidelines for monitoring of pulmonary complications after pediatric HSCT.

Background There are limited data in paediatric populations evaluating whether chronic cardiorespiratory conditions are associated with increased risk of COVID-19. We aimed to compare the rates of chronic cardiac and respiratory disease in children testing positive (SARS-CoV-2[+]) compared to those testing negative (SARS-CoV-2[-]) at our institution. Method Prospective cohort with nested case-control study of all children tested by PCR for SARS-CoV-2 by nasopharyngeal/oropharyngeal sampling between March and October 2020. Children were identified prospectively via laboratory notification with age and sex-matching of SARS-CoV-2[+] to SARS-CoV-2[-] (1:2). Clinical data were extracted from the electronic medical record. Results In total, 179 SARS-CoV-2[+] children (44% female, median age 3.5 yrs, range 0.1 to 19.0 yrs) were matched to 391 SARS-CoV-2[-] children (42% female, median age 3.7 yrs, range 0.1 to 18.3 yrs). The commonest co-morbidities showed similar frequencies in the SARS-CoV-2[+] and [-] groups: asthma (n = 9, 5% vs n = 17, 4.4%, p = 0.71), congenital heart disease (n = 6, 3.4% vs n = 7, 1.8%, p = 0.25) and obstructive sleep apnoea (n = 4, 2.2% vs n = 10, 2.3%, p = 0.82). In the SARS-CoV-2 group, the prevalence of symptomatic disease was similar amongst children with and without cardiorespiratory comorbidities (n = 12, 75% vs n = 103, 57%, p = 0.35) who tested positive. A high proportion of children hospitalised with SARS-CoV-2 infection had cardiac comorbidities (23.8%). Conclusions In this single site dataset, rates of pre-existing cardiorespiratory disease were similar in SARS-CoV-2[+] and SARS-CoV-2[-] children. High rates of comorbid cardiac disease were observed amongst hospitalised children with COVID-19, warranting further research to inform public health measures and vaccine prioritisation.

Bronchoalveolar Lavage in Children: Still the Gold StandardShivanthan Shanthikumar1,2,3 and Sarath C Ranganathan1,2,3Respiratory and Sleep Medicine, Royal Children’s Hospital, Melbourne, AustraliaRespiratory Diseases, Murdoch Children’s Research Institute, Melbourne, AustraliaDepartment of Paediatrics, University of Melbourne, Melbourne, AustraliaCorresponding Author; Dr Shivanthan Shanthikumar; Respiratory Medicine, Royal Children’s Hospital, 50 Flemington Road, Parkville, VIC, 3052, Australia; [email protected]; The authors have no conflicts of interest to declareDear Editor,We read with great interest the recent article by Craven et al , entitled “High levels of inherent variability in microbiological assessment of bronchoalveolar lavage samples from children with persistent bacterial bronchitis and healthy controls .”1 In a small study of 18 children, funded by GlaxoSmithKline, the authors demonstrate variability in the results of bronchoalveolar lavage (BAL) collected from controls and children with protracted bacterial bronchitis (PBB). Specifically, they show that when the BAL was divided and sent to two laboratories the results were discordant in terms of both the organisms isolated and their relative abundance. From these data the authors draw conclusions which include questioning “assumptions about this procedure being the gold standard .” Whilst these data are of interest, there are significant limitations to their value especially when considering existing literature.One of the key findings of the study is the discordant results between laboratories. A lack of detail regarding the methods used at each site is a major limitation. It is recognised that laboratory processes can affect the yield of samples collected from patients with chronic airway infection, and the need for a consistent approach has led to disease specific consensus guidelines on this topic.2 The discordant results seen in the study could result from different laboratory handling of specimens, and hence the findings of this study could purely be explained by a difference in practice between two centres, not least of which was the transport of samples to the second laboratory in STGG. Molecular studies have identified that even media considered sterile can contain numerous organisms albeit in low densities.3 We note that it was laboratory 2 where additional bacteria were cultured from the BAL.Hare et al analysed BAL samples from 655 children collected and analysed at two different sites compared with 18 samples in the study of Craven et al .4 They compared bacterial pathogen load (control, negative, 102 colony forming units per ml (CFU/ml), 103 CFU/ml, 104 CFU/ml, 105 CFU/ml) and inflammatory markers to determine an appropriate definition for infection. They found that a bacterial pathogen load of ≥104 CFU/ml was associated with increased markers of inflammation and hence an appropriate threshold for defining infection. This was in keeping with previous studies.4 Whilst the authors contend the current paper does not support the use of ≥104 CFU/ml, given it only includes 13 children with PBB an explanation of the findings of Hareet al in their considerably larger study and other studies needs explanation.Another key finding of the study was the limited correlation between semiquantitative and quantitative methods of measuring bacterial pathogen load. Whilst there has not been direct comparison of different methods of determining bacterial pathogen load in PBB and other paediatric suppurative disorders, a large amount of data speaks to the validity of using a semiquantitative or qualitative approach. For instance, the previously discussed Hare et al study utilised a semiquantitative approach, and was able to clearly identify a threshold for lower airway infection that was associated with inflammation. In addition, the qualitative approach used by AREST CF (the long running study of CF patients cited in the article) to define infection is supported by the fact that this definition is associated with important clinical outcomes. For example, in a recent AREST-CF study analysing 1161 BAL from 265 children with CF, the presence of early life infection using the AREST-CF definition, was associated with future risk of structural lung disease severity.5Further, we have used molecular studies to assess the microbiome in CF and shown considerable agreement between pathogen-dominated microbiota and routine laboratory bacterial culture even though these samples were assessed by two different techniques, in two laboratories in different continents and analysed two decades apart in time.6Despite the data that contradicts the findings of their study, and while not discussed by the authors themselves, we do contend that use of both quantitative and semi-quantitative microbiologic cultures are likely problematic given that bacterial density is influenced by the dilution from the 0.9% saline used to lavage the target lobe. Dilution further depends on the volume of return retrieved on suctioning. The consensus has been that standardising for this dilution is not required but data supporting this are few.In summary, there are significant issues that limit the value of the key findings of the study by Craven et al . A large amount of published data in PBB and cystic fibrosis support the use of BAL as a biological specimen associated with important clinical outcomes. These studies have been conducted in multiple centres, over many years, and included many children. While the findings of Craven et alhighlight there can be inconsistencies in results, this potentially speaks to the methods used by the laboratories involved in handing the small number of samples. When these findings are compared to the large amount of evidence already generated, they should prompt evaluation of local practices and not just a reconsideration of whether BAL is the gold standard method of sampling the lower airway of children with suppurative lung disease. While we believe that BAL remains the gold standard for the detection of lower respiratory infection we do not believe it is a perfect test and its use and many limitations need to be considered and minimised.Therefore, we agree with the authors that interpretation of microbial culture results utilizing BAL samples can be challenging. However, we disagree that assumptions about this procedure being the “gold standard” fail to take into account its many limitations as despite these BAL remains the best test to detect endobronchial infection that is associated with lower respiratory inflammation especially in CF.

Identification of Pediatric Bronchiolitis Obliterans Syndrome Post Hematopoietic Stem Cell Transplantation; Surveillance Is the KeyShivanthan Shanthikumar1,2,3, Liam Welsh1, 2, Nicole Westrupp1,2, Theresa Cole3,4, Katherine B Frayman1,2,3, Colin F Robertson1,2,3, Sarath C Ranganathan1,2,3Respiratory and Sleep Medicine, Royal Children’s Hospital, Melbourne, AustraliaRespiratory Diseases, Murdoch Children’s Research Institute, Melbourne, AustraliaDepartment of Paediatrics, University of Melbourne, Melbourne, AustraliaAllergy and Immunology, Royal Children’s Hospital, Melbourne, AustraliaCorresponding Author; Dr Shivanthan Shanthikumar; Respiratory Medicine, Royal Children’s Hospital, 50 Flemington Road, Parkville, VIC, 3052, Australia; [email protected]; The authors have no conflicts of interest to declareDear Editor,We read with great interest the article by Walther et al1 regarding long term outcomes of bronchiolitis obliterans syndrome (BOS) in children following haematopoietic stem cell transplantation (HSCT). The authors are to be commended on their study as it is an important contribution to a field where there is a relative paucity of evidence. Given the increasing numbers of HSCT being performed and improved outcomes, timely identification and management of pulmonary complications such as BOS is vital.In particular, the study used multibreath washout to calculate lung clearance index, a more sensitive test for BOS than traditional spirometry.2 In addition, the identification of three trajectories for children diagnosed with BOS; rapid persistent decline, persistent obstructive disease with secondary restriction, and resolution, is an important and novel description. This more nuanced understanding of the natural history of BOS in this setting will be an important consideration when designing therapeutic intervention trials. Given there are now ample data showing that around 4.8-6.5% children post HSCT will develop BOS, with significant associated morbidity and mortality, well designed intervention trials should be strongly considered.There are however limitations of Walther et al’s study that warrant more detailed discussion, as they limit the applicability of this single centre retrospective chart review to wider clinical practice. The manuscript does not adequately describe the institution’s clinical practice regarding evaluation for BOS post-HSCT, although the authors acknowledge a “lack of a standardised follow up protocol for lung function. ” This is not in keeping with current international practice. International guidelines3-5 consistently recommend scheduled lung function surveillance. In addition, in a recent survey of HSCT physicians and pediatric pulmonologists from North America and Australasia, 71.4% reported that a protocol for monitoring lung function post HSCT existed at their hospital and 53.6% reported adhering “well” or “very well” to surveillance protocols.6 A retrospective review of a centre with a screening program in place showed 75.2% of patients had a lung function test 12 months post HSCT.7 These data indicate that the majority of HSCT centres have a screening protocol in place, and within the limitations of self-reported and single centre data, protocols are adhered too. A potential explanation for the lack of a protocol in the study is that the review period started in 2000, which predates the guidelines. However, if the results are to influence contemporary practice, clinicians must be able to relate the reported findings to current standards of care. In the absence of a standardised follow up protocol, it would be useful if the authors reported the proportion of the 526 eligible patients who underwent lung function assessment, and what triggered a referral for testing (i.e. clinical symptoms, graft vs. host disease (GVHD) in another organ). If a high proportion of patients underwent testing then their findings will be more comparable to current international practice, however if only a small proportion underwent testing this is a significant limitation.The prevalence of BOS in the current study is lower than that reported in the wider literature. We suspect their prevalence is underestimated. The overall GVHD rate (45%) is higher than might be expected for a cohort that includes nearly 50% matched sibling donors.8, although GVHD grading is not reported. Given the high GVHD rate in this cohort it would be expected that the prevalence of BOS should also be higher or at least in keeping with the literature. The lack of a standardised protocol for screening lung function would likely lead to an underestimation of the prevalence of BOS. It is well established that the early phases of BOS are often asymptomatic and diagnosed based on lung function abnormality.9 All 14 BOS cases in this study were symptomatic, suggesting that asymptomatic early cases of BOS cases may have been missed due to lung function not being performed. In particular, this would underestimate BOS cases which follow the resolution trajectory as well as potentially the persistent obstruction trajectory. It also would affect two of the key conclusions of the paper; that BOS incidence is low and that BOS is associated with high mortality.In summary, the article by Walther et al is a useful contribution to what is an area of growing clinical importance. Strengths of the study include the use of the most sensitive test of small airway function (multibreath washout with calculation of the lung clearance index) and description of three trajectories post BOS diagnosis. However, the lack of a formal surveillance program and likely resultant underestimation of BOS cases is a significant limitation that should be acknowledged before efforts are made to prevent or attenuate lung function decline in BOS