Editorial: Respiratory outcomes post Nusinersen in Spinal Muscular Atrophy Type 11 Kate Gonski1,2 Dominic A. FitzgeraldDepartment of Respiratory Medicine, The Children’s Hospital at Westmead, Sydney, NSW, Australia 2145Discipline of Child & Adolescent Health, Sydney Medical School, Faculty of Health Sciences, University of Sydney, NSW, Australia 2145Corresponding author:Dominic A. Fitzgerald MBBS PhD FRACPClinical Professor Child & Adolescent HealthDepartment of Respiratory MedicineThe Children’s Hospital at WestmeadLocked Bag 4001Westmead, NSWAustralia, 2145.1458 words15 referencesTime to wake up and smell the roses as the real world respiratory experiences have arrived for Spinal Muscular Atrophy type 1 (SMA1)! Nusinersen, the first drug to be approved for treatment of SMA1, has changed the natural history of the disease and has now been commercially available in many countries for up to four years(1). SMA 1, the most common cause of infant death attributed to respiratory insufficiency, results from a degeneration of alpha motor neurons in the spinal cord and brainstem resulting in progressive skeletal muscle weakness of the limbs, respiratory and bulbar muscles (2). Most patients with SMA1 will have respiratory complications in the first year of life requiring therapy to support airway clearance and ventilation (2). The pan-ethnic incidence is 1 in 11,000 births (3). Milder phenotypes occur as SMA types 2 and 3 in childhood with a much better prognosis (4) and countries may offer nusinersen for these patients also.In this issue, Lavie and colleagues (5) offer insights into clinicalrespiratory outcomes from 3 years of prospective data collection in their cohort of 20 SMA1 patients treated before and after 2 years of nusinersen in Israel. Their work builds on the scientific evidence of efficacy of nusinersen primarily for motor outcomes over the last decade. A phase 3 randomised, double-blinded, sham controlled clinical trial in patients with SMA 1 showed that those treated with nusinersen had a significant motor milestone response with a higher likelihood of event-free survival(6). This group did not show a difference in the frequency of serious respiratory adverse events between the groups, thereby leaving unanswered questions about the effect of the medication on respiratory morbidity. Over the past few years, the translatability of outcomes from randomized controlled studies to current real-world outcomes has been questioned (7-9).A letter to the editor by LoMauro et al. involving children with SMA1 described a milder subset of children with SMA 1 [Described as type SMA 1c: onset between 3 and 6 months] treated with nusinersen who had an improvement in accessory muscle use and reduced daily hours of ventilation when compared to a natural history cohort (7). This was not reported in the more severe SMA 1a and 1b groups. Sansone et al. (8) published an observational, longitudinal cohort study looking at respiratory support requirements at baseline, 6 months and 10 months after nusinersen treatments in 118 children with SMA1. Semi-structured qualitative interviews from caregivers were collected at each interval. They showed that 77% of the cohort’s respiratory requirements remained stable and more than 80% of children treated before 2 years survived in contrast to the lower survival reported in natural history studies. The limitation of this study is that they used modality and number of hours of ventilation as the surrogate for respiratory function which can be influenced significantly by respiratory care, management and patient compliance. Chen et al. (9) also published follow-up data (single-centre) in SMA 1 children treated with nusinersen in order to further understand the comprehensive real-world outcomes of this new treatment. While this study was limited by its small sample size of 9, it highlighted that children with SMA1 treated with nusinersen continued to develop considerable respiratory comorbidities. Although a large amount of data has been collected over the past 5 years, there remain gaps in the understanding of many aspects of the use of nusinersen in SMA beyond modest increases in peripheral muscle strength and in particular whether these improvements will translate into reduced respiratory morbidity and less respiratory failure with dependence upon non-invasive ventilation (NIV) (10).The paper by Lavie et al. (5) contributes to our understanding with its focus on ‘real-world’ variables including starting or ongoing need for assisted ventilation, the use of mechanical insufflation-exsufflation, respiratory complications, and treatment cessation due to respiratory reasons, or death in around 15% of cases attributed to pulmonary aspiration. In essence, it is a source of modest encouragement for clinicians as the majority of children demonstrated stability of respiratory support over the first two years of treatment with nusinersen which is in itself much better than the natural history of the condition with progressive decline and death in 90% by the age of 2 years. However, there are some gaps in knowledge in this paper which will require further studies. It is unclear exactly why children started ventilation specifically, who went to tracheostomy and why others went to NIV and what their initial ventilator pressures were. Management algorithms have been available to outline this in neuromuscular diseases . Further, it is unclear how many children had polysomnograms and what the results were in terms of apnoea indices, measures of hypoventilation, alterations in oxygenation and extent of transcutaneous CO2 abnormalities, other than that they were consistent with the standards of care for the treatment of children with SMA published in 2007 . Further guidelines have since emerged in the nusinersen era . Certainly, the positive impact of the use of NIV on respiratory outcomes, including hospitalisations, albeit in the broader neuromuscular population, has been established . As would be hoped, a reduction in admissions was seen in the present study in SMA1. Nonetheless, as all clinicians appreciate, what is prescribed and what is used for the treatment of anything in “the real world” varies widely. Think of asthma preventers or any therapies in cystic fibrosis including expensive correctors. In a prospective study on real world respiratory outcomes, the absence of information on adherence with average daily hours of support from memory cards inside the NIV devices is a short-coming of the study of Lavie et al. (5). This is something which, with serial assessment of polysomnography parameters, should be addressed in future studies in SMA1 treated patients to ascertain the true rather than potentially perceived benefit of NIV.Lavie et al. (5) provide insight into the everyday clinical respiratory burden of patients with SMA1 treated with nusinersen while highlighting further areas of research. Specifically, they rightly suggest a beneficial effect with the earliest initiation of nusinersen due to the possibility that nusinersen may have an effect on preserving respiratory function if started at a younger age. This mirrors data in the larger RCT where earlier treatment was associated with better motor outcomes. Logically, this could be readily achieved with emerging increase in new born screening programs including SMA genes in countries such as Australia and Belgium . This would also enable quantification of the number of copies of SMN2 genes present, missing in 30% of cases in the series of Lavie et al. (5). This stratification of genotype may be more important than ever in the nusinersen era as we improve our ability to predict outcomes beyond age of presentation [Types 1a, 1b and 1c] . The argument for newborn screening for SMA, with earlier diagnosis and improved outcomes for such an expensive therapy seems persuasive.This article explores patient outcomes in a real-world setting and found that the need for assisted ventilation did not worsen as would be with the natural progression of SMA1. However, they showed no improvement either. Therefore, nusinersen is a small step forward with the promise of much more to come from gene therapy and potentially combinations of therapies. Longer term studies with international prospective data registries are warranted and should be funded by international neuromuscular societies at arm’s length from pharmaceutical companies. It is as important to document respiratory outcomes rather than just predominantly modest motor outcomes not only for SMA1 but also SMA2 and SMA3, because at the end of the day in the real world, your respiratory wellbeing determines morbidity and mortality.References1. LoMauro A, Mastella C, Alberti K, Masson R, Aliverti A, Baranello G. Effect of nusinersen on respiratory muscle function in different subtypes of type 1 spinal muscular atrophy. American Journal of Respiratory and Critical Care Medicine. 2019;200(12):1547-1550.2. Kolb SJ, Coffey CS, Yankey JW, Krosschell K, Arnold WD, Rutkove SB, et al. Natural history of infantile-onset spinal muscular atrophy. Ann Neurol. 2017; 82(6):883-8913. Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: Clinical laboratory analysis of >72 400 specimens. Eur J Hum Genet. 2012; 20 (1):27-324. Farrar MA, Park SB, Vucic S, Carey KA, Turner BJ, Gillingwater TH, et al. Emerging therapies and challenges in spinal muscular atrophy. Annals of Neurology. 2017; 81(3):355-3685. Lavie M, Diamant N, Cahal M, Sadot E, Be’er M, Fatal A, Sagi L, Domany KA, Amirav I. Nusinersen for Spinal muscular Atrophy Type 1: real World Respiratory Experience. Pediatr Pulmonol 2020; XXXX; doi xxxx6. Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017; 377:1723-17327. LoMauro A, Mastella C, Alberti K, Masson R, Aliverti A, Baranello G. Effect of nusinersen on respiratory muscle function in different subtypes of type 1 spinal muscular atrophy. American Journal of Respiratory and Critical Care Medicine. 2019 Dec 15;200(12):1547-508. Sansone VA, Pirola A, Albamonte E, Pane M, Lizio A, et al Respiratory Needs in Patients with Type 1 Spinal Muscular Atrophy Treated with Nusinersen. The Journal of Pediatrics. 2020; 219 P223-228. E49. K-A. Chen, J. Widger, A. Teng, D.A. Fitzgerald, A. D’Silva, M. Farrar, Real-world respiratory and bulbar comorbidities of SMA type 1 children treated with nusinersen: 2-year single centre Australian experience, Paediatric Respiratory Reviews (2020), doi: httpds://doi.org/10.1016/j.prrv.2020.09.00210. Fitzgerald DA, Doumit M, Abel F. Changing respiratory expectations with the new disease trajectory of nusinersen treated spinal muscular atrophy [SMA] type 1. Paediatric Respiratory Reviews. 2018 Sep 1;2 8:11-7.11. Hull J, Aniapravan R, Chan E, Chatwin M, Forton J, Gallagher J, Gibson N, Gordon J, Hughes I, McCulloch R, Russell RR. British Thoracic Society guideline for respiratory management of children with neuromuscular weakness. Thorax. 2012 Jul 1;67(Suppl 1):i1-40.12. Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, Aloysius A, Morrison L, Main M, Crawford TO, Trela A. Consensus statement for standard of care in spinal muscular atrophy. Journal of child neurology. 2007 Aug;22(8):1027-49.13. Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Muntoni F. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscular Disorders. 2018 Mar 1;28(3):197-207.14. Young HK, Lowe A, Fitzgerald DA, Seton C, Waters KA, Kenny E, Hynan LS, Iannaccone ST, North KN, Ryan MM. Outcome of noninvasive ventilation in children with neuromuscular disease. Neurology. 2007 Jan 16;68(3):198-201.15. Boemer F, Caberg JH, Dideberg V, Dardenne D, Bours V, Hiligsmann M, Dangouloff T, Servais L. Newborn screening for SMA in Southern Belgium. Neuromuscular Disorders. 2019 May 1;29(5):343-9.
An Unusual Case of Necrotizing Pneumonia Presenting with Acute Kidney InjuryUgur Berkay Balkanci, MDSchool of Public Health, University of Minnesota, Minneapolis, MNDavid J. Sas, DODivision of Pediatric Nephrology and Hypertension, Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MinnesotaNadir Demirel, MDDivision of Pediatric Pulmonology, Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MinnesotaCorresponding Author:Nadir Demirel, MDDivision of Pediatric Pulmonology200 First Street SWRochester, MN 55906Tel. No.: 5075380754Fax No.: 5072840727Demirel.email@example.comKey words: postinfectious glomerulonephritis, pneumothorax, complications, complicated pneumoniaFinancial Disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose.Funding: No external funding.Short title: “An unusual case of necrotizing pneumonia”To the Editor:Lower respiratory tract infections are the most common reason for hospitalization in the pediatric age group in the United States. Although pneumonia is prevalent, complicated pneumonia such as empyema, lung abscess and necrotizing pneumonia (NP) is uncommon in children1. The prevalence of complicated pneumococcal pneumonia decreased significantly after the introduction of the thirteen-valent pneumococcal vaccine in 20101. NP in the pediatric population is a severe disease characterized by extensive destruction and liquefaction of the lung tissue resulting in loss of the pulmonary parenchymal architecture, cavitation of the lung, and pleural involvement. Renal complications of complicated pneumonia are rare and mostly reported as atypical hemolytic uremic syndrome (HUS)2. Post-infectious glomerulonephritis (PIGN) is an unexpected complication of bacterial pneumonia3.We report a six-year-old otherwise healthy fully vaccinated girl with a 4-day history of fever, abdominal pain, vomiting, non-bloody diarrhea, and poor oral intake. Parents reported decreased urine output and dark-colored urine on the day of admission. Initial evaluation revealed serum creatinine of 5.01 mg/dL and blood urea nitrogen of 86 mg/dL, elevated acute phase reactants suggesting acute kidney injury (AKI) in the setting of an undiagnosed acute infectious process. The patient was admitted with decreased effective circulatory volume. Urinalysis revealed hematuria with <25% dysmorphic red blood cells (RBCs), proteinuria, pyuria, and RBC casts and granular casts, suggestive of acute glomerulonephritis.She was started on intermittent hemodialysis at day 2 of admission to address uremia, fluid overload, and hyperphosphatemia. A renal biopsy revealed diffuse exudative glomerulonephritis, consistent with infection-related glomerulonephritis. ASO, Anti-DNase B were negative; C3, C4 levels were low. She was treated with pulse IV methylprednisolone 10mg/kg/day for three days. The first 5 days in the hospital, the patient remained afebrile and her lung exam was normal without respiratory symptoms.On day six of admission, she developed acute right-sided chest pain and shortness of breath during hemodialysis. Chest x-ray (CXR) revealed a large right-sided tension pneumothorax, prompting therapeutic chest tube placement. Repeat CXR revealed reexpansion of the right lung and a significant right upper lobe consolidation with an ovoid hyperlucency and an air-fluid level. A chest CT scan confirmed the diagnosis of NP with multiple cavities (Image).Flexible bronchoscopy was performed with bronchoalveolar lavage revealing 42% neutrophils and negative cultures. She was treated with broad spectrum intravenous antibiotics.During admission, she developed hypertension, well-controlled with scheduled enalapril and amlodipine, as well as isradipine as needed. On day 14 of admission, hemodialysis was discontinued as kidney function improved, and chest tube was removed. She was discharged at day 26 of admission on intravenous ceftriaxone and oral metronidazole to complete 30 days of treatment. A repeat chest CT at end of treatment showed complete resolution of NP. Renal functions and blood pressure normalized on follow up.NP is characterized by persistent high fevers and prolonged hospitalizations even with appropriate antibiotic treatment1. Most often, NP affects immunocompetent children with no underlying risk factors4. The pathophysiology of this complication is acute liquefactive necrosis of the lung parenchyma which results in the development of pneumatoceles4. The most common pathogen causing NP is Streptococcus pneumoniae followed by Staphylococcus aureus and Streptococcus pyogenes. Other rarer bacterial and viral pathogens are Mycoplasma pneumonia, Influenza, and Adenovirus1. Identifying the microbiologic pathogen can be challenging and is only made in 50% of cases1. In our case, we did not isolate the causative microorganism. NP typically resolves without residual morbidity, even after a protracted course1,4.Pleural involvement is almost universal in NP, and the course of pleural disease often determines duration and outcome, particularly as it relates to the complication of bronchopleural fistula (BPF)1. BPF is most likely due to the necrotic development of a connection between bronchial space and pleural space4. BPF formation is associated with a significantly longer hospital stay in children with NP4. Yet, most cases heal without surgical intervention4. Tension pneumothorax has been observed as a rare complication of NP1.Renal involvement in complicated pneumonia is rare. Atypical HUS has been reported as a complication of pneumonia, particularly associated with empyema. (most commonly due to invasive Streptococcus pneumoniae)2. In a case series of 37 cases of atypical HUS, 34 patients (92%) had pneumonia with 10 patients (29%) with NP5. Less commonly, pneumonia can be associated with PIGN. PIGN is the most common glomerulonephritis in children worldwide. Pneumonia-associated PIGN is rare. In a case series from the US, PIGN accounted for 0.15% of admissions for pneumonia and 0.39% of admissions for glomerulonephritis6. Pneumonia-associated PIGN is known to be caused by various bacterial pathogens including Streptococcus pneumoniae, Staphylococcus aureus, Mycoplasma pneumoniae, Chlamydia pneumoniae, Nocardia, and Coxiella burnetii3. Different from the usual presentation of the PIGN (in which the time interval between a pharyngeal group A Streptococcal infection and PIGN is 6 to 10 days), pneumonia-associated PIGN is usually concomitant with the pulmonary disease3,6.Our case is unusual in several ways: pneumonia-associated PIGN typically presents with respiratory symptoms first, and acute kidney injury developing during the course of pneumonia3. More surprisingly, the patient developed NP which is characterized by even more severe respiratory symptoms1. Yet, our patient presented without respiratory complaints and pneumonia became apparent only after the development of pneumothorax. We could only identify 2 cases of pneumonia-associated PIGN who presented with renal involvement before pulmonary complaints6,7. Also, previous cases in the literature of pneumonia-associated PIGN report mostly a non-complicated course of pulmonary disease3,6. In a case series of 11 children with pneumonia-associated PIGN, only one case developed a small empyema6. Similarly, the majority of the reported cases of pneumonia-associated PIGN describe a benign course of renal disease3,6. Our patient’s kidney failure progressed rapidly, and she required 2 weeks of intermittent hemodialysis and a three-day course of pulse steroid therapy. At present, systemic corticosteroids are not recommended for patients with complicated pneumonia. A Cochrane review including 17 randomized controlled trials, of which four were conducted on children, found that corticosteroid therapy reduced mortality and morbidity in adults with severe CAP, and morbidity, but not mortality, in adults and children with non-severe CAP1. We speculate that pulse steroid treatment may have modified the course of NP in our patient.This case suggests an atypical presentation of NP with predominant renal complications is possible. Pediatricians should be aware of renal complications of respiratory diseases. Systemic steroids should be considered in the treatment of NP.References:1. de Benedictis FM, Kerem E, Chang AB, Colin AA, Zar HJ, Bush A. Complicated pneumonia in children. Lancet 2020;396:786-798.2. Spinale JM, Ruebner RL, Kaplan BS, Copelovitch L. Update on Streptococcus pneumoniae associated hemolytic uremic syndrome. Curr Opin Pediatr 2013;25:203-208.3. Carceller Lechón F, de la Torre Espí M, Porto Abal R, Écija Peiró JL. Acute glomerulonephritis associated with pneumonia: a review of three cases. Pediatr Nephrol 2010;25:161-164.4. Sawicki GS, Lu FL, Valim C, Cleveland RH, Colin AA. Necrotising pneumonia is an increasingly detected complication of pneumonia in children. Eur Respir J 2008;31:1285-1291.5. Banerjee R, Hersh AL, Newland J, Beekmann SE, Polgreen PM, Bender J, Shaw J, Copelovitch L, Kaplan BS, Shah SS. Streptococcus pneumoniae-associated Hemolytic Uremic Syndrome Among Children in North America. Pediatr Infect Dis J 2011;30:736-739.6. Srivastava T, Warady BA, Alon US. Pneumonia-associated acute glomerulonephritis. Clin Nephrol 2002;57:175-182.7. Schachter J, Pomeranz A, Berger I, Wolach B. Acute glomerulonephritis secondary to lobar pneumonia. Int J Pediatr Nephrol 1987;8:211-214.
Neuromuscular medicine is being revolutionized by new genetic and molecular therapies. The purpose of this Special Issue is to present an overview of these new therapies, to examine their cardiopulmonary effects, and to consider the future of neuromuscular cardiopulmonary care. The emphasis will be on Duchenne muscular dystrophy (DMD) and, to a lesser extent, spinal muscular atrophy (SMA), as these are the diseases with the most robust new drug development and related cardiopulmonary outcome data. This Special Issue contains articles on a number of relevant topics, including an overview of new genetic and molecular therapies for DMD, examining the currently available cardiopulmonary outcome data; and a critical examination of pulmonary outcome measures, assessing which outcomes should be used in treatment studies. We will provide an overview of cardiopulmonary phenotypic variability and discordance and their implications for assessing patient prognosis and response to therapies, and present a new perspective on neuromuscular-induced sleep-disordered breathing, viewed in the context of new and emerging therapies. Finally, we will consider which cardiac imaging modalities should be used as outcome measures in studies assessing DMD heart function, and take a look at novel therapeutic approaches to DMD heart disease, including management of rhythm disorders and heart failure, and the use of left ventricular assist devices.
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; firstname.lastname@example.orgAcknowledgements; 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.
Spirometry, a gold standard technique for measuring lung functions, has been restricted to a select cohort of patients in current COVID-19 pandemic due to the enhanced risk of disease dissemination. To monitor pulmonary functions in various obstructive (e.g., asthma) and restrictive diseases (e.g., COVID-19 pneumonia) on in- and out-patients serially, there is an urgent requirement of an alternate reliable test. Impulse Oscillometry (IOS) measures lung functions by working at tidal volumes and thus reduces the risk of potential aerosol generation. Feasibility of IOS in smaller children and its ability to detect parenchymal and peripheral airway involvement are other advantages over conventional spirometry. IOS could be a potential solution to periodically monitor lung functions in current pandemic situation to keep a check on diseases affecting lung functionality.
Background: Non-invasive ventilation (NIV) is a first-line therapy for sleep-related breathing disorders and chronic respiratory insufficiency. Evidence about predictors that may impact long-term NIV outcomes, however, is scarce. The aim of this study is to determine demographic, clinical, and technology-related predictors of long-term NIV outcomes. Methods: A ten-year multi-centred retrospective review of children started on long-term continuous or bilevel positive airway pressure (CPAP, BPAP) in Alberta. Demographic, technology-related, and longitudinal clinical data was collected. Long-term outcomes examined included ongoing NIV use, discontinuation due to improvement in underlying condition, switch to invasive mechanical ventilation (IMV) or death, patient/family therapy declination, transfer of services, and hospital admissions. Results: 622 children were included. Both younger age and CPAP use predicted higher likelihood for NIV discontinuation due to improvement in underlying conditions. Children with upper airway disorders or bronchopulmonary dysplasia were less likely to require NIV continuation while presence of central nervous system (CNS) disorders resulted in higher likelihood of hospitalizations and switch to IMV or death. The presence of obesity/metabolic syndrome and early NIV-associated complications predicted higher risk for NIV declination. Children with more co-morbidities or use of additional therapies required more hospitalizations and the latter also predicted higher risk to be switched to IMV or death. Conclusions: Demographic, clinical data, and NIV type impact long-term NIV outcomes and need to be considered during the initial discussions about therapy expectations with families. Knowledge of factors that may impact long-term NIV outcomes might help to better monitor at-risk patients and minimize adverse outcomes.
Congenital pulmonary airway malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a rare developmental lung abnormality with the potential for malignant transformation. Bronchioloalveolar carcinoma (BAC), pleuropulmonary blastoma (PPB), rhabdomyomatous dysplasia/rhabdomyosarcoma (RMS) have been associated with CPAM. We report an unusual case of a 1-day-old male newborn who underwent lobectomy for a cystic lung lesion, which was found to be a mucinous BAC with K-ras mutation in a type 1 CPAM. The case supports the relationship between type 1 CPAM and BAC/KRAS mutant, and highlights that the malignant transformation can occur in very early stage of the infancy.
A 16-Year old with Lemierre’s Syndrome and Multiple Septic Pulmonary EmboliChristopher M Oermann, MDDepartment of Pediatrics, Children’s Mercy Kansas City, Kansas City MOCorresponding Author:Christopher M Oermann, MDChildren’s Mercy Kansas City2401 Gillham RoadKansas City, MO 64108816-302-3354 (telephone)816-302-9736 (fax)email@example.comRunning Head: Pulmonary Septic Emboli in Lemierre SnKey Words: Lemierre Syndrome, Septic EmboliWord Count: 1035To the Editor,Lemierre’s syndrome (LS) is a rare disease resulting from infective thrombophlebitis of the internal jugular vein (JV) following oropharyngeal infection. The incidence of LS has increased after decades of decline. Septic pulmonary emboli (PE) are common, but all organ systems can be involved. Although LS is most often caused byFusobacterium necrophorum , other pathogens have been implicated. Persistent high fever and organ-specific signs and symptoms result from the septic emboli (SE). The diagnosis is often suspected following growth of Fusobacterium from blood cultures and is confirmed by head/neck imaging. Therapy includes antimicrobials, drainage of abscesses, and anticoagulation. Significant morbidity/mortality occur if diagnosis and treatment are delayed. Pediatric pulmonologists must be familiar with the diagnosis and management of LS.A previously healthy 16-year old male was admitted to hospital following two weeks of fever, myalgia, nausea/vomiting/diarrhea with 10-pound weight loss, and dry cough. He had been evaluated by his primary care provider (PCP) ten days prior to admission for pharyngitis and fever of 40oC. Rapid streptococcal antigen and SARS-CoV-2 testing were negative, and he was treated with antipyretics. Continued symptoms led to PCP reevaluation after 7 days. Chest imaging demonstrated a single round pneumonia in the right lower lobe, and he received 3 days of azithromycin. He failed to improve and was referred to the emergency department 3 days later. Computed tomography (CT) of the chest/abdomen/pelvis demonstrated bilateral pulmonary nodules. He was admitted for evaluation and treatment.Considerations from the admitting team included atypical infection (fungal or mycobacterial) versus e-cigarette or vaping product use associated lung injury (EVALI), so Pulmonary Medicine service was consulted. EVALI was thought unlikely based on the radiographic appearance of the lesions (Figure 1). Additional considerations included septic PE, paragonimiasis, autoimmune disease with small vessel vasculitis (polyangiitis with granulomatosis), and inflammatory bowel disease. Evaluation for these potential diagnoses was initiated and empiric therapy with vancomycin and ceftriaxone was commenced. Echocardiogram, infectious diseases testing, and autoimmune evaluation were all normal. Painful swelling in the right, anterior neck and a tender spot on his upper right back developed the day after admission. His blood culture grew gram-negative anaerobic rods, raising concern for LS. Doppler ultrasound of the neck demonstrated occlusive thrombus within the right external JV with extension into the internal JV. Metronidazole was added to his intravenous antimicrobial regimen and anticoagulation therapy was initiated.CT Imaging demonstrated normal CNS with confirmation of thrombosis of the JVs and inflammation over the surrounding soft tissues of the anterior right neck and a large abscess involving the posterior spinal musculature of the upper thorax. A drain was placed, and 25 cc of pus removed. Magnetic resonance imaging of the spine demonstrated extension of the abscess into the T1 spinous process suggesting osteomyelitis. The blood culture grew Fusobacterium necrophorum and antibiotic coverage was changed to ampicillin/sulbactam to treat potential polymicrobial infection. Fevers resolved, pain and other symptoms improved, and the drain was removed after 3 days. He was discharged to continue 6 weeks of ampicillin/sulbactam and anticoagulation therapy.LS is a rare complication of infections of the head/neck, with a reported incidence of one per million people per year.1 Common during the “pre-antibiotic era”, LS had decreased in incidence for decades but has increased since the 1990s. This is possibly due to better antimicrobial stewardship and decreased use of antimicrobials for pharyngitis.1Disease is attributed to infections of the tonsils and peritonsillar tissue in 87% of cases and infections of the pharynx, parotid glands, sinuses, mastoids, middle ears, and teeth/gums in 13%.2 Males and females are equally affected.3 LS has been reported in individuals aged 2 months to 78 years, although it is most commonly reported among previously healthy adolescents and young adults.2,3LS originates with primary infection of the head/neck.4 This is followed by spread of the infection through the soft tissues of the neck resulting in thrombophlebitis of the internal JV. Dissemination of infection via SE occurs, with lung involvement in up to 80% and bones/joints in up to 27%.1-4 Additional sites of infection include cardiovascular, skin/muscles, central nervous system, abdominal organs (liver and spleen), and kidneys. Pulmonary involvement has included septic PE, abscess formation, necrotizing pneumonia, empyema, pneumothorax, pulmonary embolism, and acute respiratory distress syndrome. LS is most often caused by Fusobacterium necrophorum , part of the normal flora of the pharynx, accounting for up to 85%. Additional causes include other Fusobacterium species, anaerobes (Bacteroides , Peptococcus , and Peptostreptococcusspecies), and aerobes (Streptococcus , and Staphylococcusspecies), among others. Polymicrobial infections are reported in up to 30%.2 Significant morbidity results from delayed diagnosis. Mortality has been reported as 4-18%; more recent reviews suggest a lower rate.3,5LS often presents 4-12 days after the initiating oropharyngeal infection, which may have resolved by presentation. Symptoms include high fever (up to 80%), gastrointestinal (50%), pharyngitis with cervical adenopathy or neck pain/swelling, myalgia/arthralgia, rigors, and respiratory symptoms (cough or dyspnea).1,2,5Additional symptoms may be secondary to organ dysfunction caused by SE. Diagnosis is often made via Doppler ultrasound or CT imaging of the head/neck or the growth of Fusobacterium from blood/abscess cultures.Therapy for LS involves long term, intravenous antibiotics, surgical drainage of abscesses, and anticoagulation.1-5Metronidazole is often reported as standard therapy for LS. Other antibiotic considerations include carbapenems or penicillin/beta-lactamase inhibitor combinations, which provide broader coverage for polymicrobial infections. Duration of therapy is 4-6 weeks, allowing for adequate penetration of thrombi and treatment of secondary problems such as osteomyelitis. Anticoagulation therapy is more controversial; some data suggest that anticoagulation hastens overall response while others indicate adequate clinical response without additional therapy.LS is a rare disorder of the head/neck that may be associated with significant morbidity/mortality if diagnosis and treatment are delayed. Pediatric pulmonologists will typically encounter LS in patients hospitalized with prolonged fever and multiple septic PE. LS must be considered in every child with multiple cavitary nodules identified on chest imaging. This is particularly true if there is a history of preceding oropharyngeal infection or signs/symptoms suggesting pathology in the head/neck. The growth of Fusobacterium species from blood culture or abscesses should also suggest LS. Doppler ultrasound examination of the neck and CT imaging of the head/neck should be obtained. Therapy is long-term, intravenous antibiotics. Adjuvant therapy includes surgical incision and drainage of abscesses and anticoagulation therapy.
Mainstem bronchial atresia (MBA) is a rare and fatal entity with no survivors reported to date. We describe a neonate born at 36 weeks gestational age (GA) with right MBA who underwent successful slide tracheobronchoplasty at 32 days of life. It is theorized that during fetal life a transient fistulous connection developed, allowing right lung decompression and left lung development.
Improving synchrony in young infant supported by noninvasive ventilation for severe bronchiolitis: Yes we can… so we should!C Milési, MD1, J Baleine, MD1, G Cambonie, MD, PhD11Department of Neonatal Medicine and Pediatric Intensive Care, Arnaud de Villeneuve Hospital, Montpellier University Hospital Center, Montpellier, FranceCorrespondence: Christophe Milési, MD, Department of Neonatal Medicine and Pediatric Intensive Care Unit, Arnaud de Villeneuve Hospital, Montpellier University Hospital, 371 Avenue du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, FranceTel: +33 467 336 556, Fax: +33 467 336 228, e-mail:firstname.lastname@example.orgWord count: 1391; references: 43Keywords: asynchrony, bronchiolitis, noninvasive ventilation, neurally adjusted ventilatory assist, infantAdmission to a pediatric intensive care unit (PICU) is required for 9-14% of infants with acute viral bronchiolitis (AVB) and evolving respiratory distress.1,2 In this context, AVB generally presents as severe obstructive lung disease, which causes an increased load on the respiratory muscles.3,4 As no pharmaceutical treatment currently in use is able to rapidly reduce airway obstruction, the management of these patients is focused on providing respiratory support to reduce respiratory muscle fatigue and prevent intubation. Noninvasive ventilation (NIV), delivered by continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP), has traditionally been applied and is associated with reductions in intubation rates, ventilation-associated complications, and duration and cost of hospitalization.5,6 More recently, a third device was introduced to administer a heated and humidified mixture of air and oxygen with high-flow nasal cannulae (HFNC). PICU clinicians thus currently have at their disposal several respiratory assistance modalities for infants with moderate to severe AVB, but few high-grade evidence studies to guide their choice.7 Indeed, most of the studies carried out in this field have been observational, with comparisons with historical cohorts,5,6,8-10 or physiological, assessing differences with and without noninvasive respiratory support.4,11-13 In this issue of Pediatric Pulmonology , Delacroix et al. re-evaluates the use of BiPAP as the first-line respiratory support in less-than-6-months patients with bronchiolitis.14 In their single-center retrospective study, they report longer durations of noninvasive support and longer PICU stays in the patients supported with BiPAP compared with CPAP and HFNC. The authors should be congratulated for this analysis covering more than 250 infants, one of the largest cohorts treated with this device. This work usefully complements the information provided by two recent observational studies that focused on the comparison of these three techniques in this specific group of patients.15,16 The inherent limitation of these retrospective studies, whether monocentric14,16 or database-driven,15 is the presence of confounders, which influence both the choice of the initial respiratory support and the outcome. It was particularly interesting to note in Delacroix et al.’s study that the clinicians’ preferred choice was BiPAP, although no local written protocol required it in this situation. However, the BiPAP-treated group also included a higher rate of premature infants, a condition associated with the immaturity of immune defenses and airway development and ventilation-induced airway injury that predisposes to more severe bronchiolitis.17Several national and multinational surveys have demonstrated that pediatric intensivists currently select HFNC for initial respiratory care in cases of severe bronchiolitis.18,19 This popularity among caregivers appears to be associated with the perception of a technique that is easy to implement, with comparable effectiveness and fewer complications than CPAP.20 The physiological background for using CPAP in this instance is that the application of nearly constant pressure support is associated with rapid unloading of respiratory muscles, increased expiratory time, and concomitantly improved respiratory distress.4,11,21 Reduced respiratory effort and a change in breathing pattern suggest that CPAP improves the work of breathing by offsetting the patient’s inspiratory effort to overcome intrinsic end-expiratory pressure (PEEPi). In addition, positive airway pressure helps maintain airway patency and alleviate bronchiolar obstruction, a ‘stenting’ effect that in turn reduces respiratory system resistance. HFNC also generates some degree of airway distenting pressure, which supports inspiratory effort. The reduced diaphragmatic electrical activity and decreased esophageal pressure swings also confirm the effectiveness of HFNC to reduce the work of breathing in AVB.12,13 Randomized controlled trials, however, have found that neither CPAP nor HFNC reduces the need for intubation in infants with bronchiolitis, probably due to the current low occurrence of this event1,2,21-24 In practice, CPAP and HFNC are introduced early in the course of the disease—even as a preemptive measure in some cases—in infants generally not exhausted. While NIV is widely used to treat bronchiolitis,25 most clinicians, unlike in Delacroix et al.’s study,14 consider BiPAP the next step for patients failing with HFNC or CPAP.19 Failure rates vary widely, from 10% to 50% in the major randomized controlled studies,1,2,22-24and depend on multiple factors, the most important probably related to the criteria and delays in defining failure. According to the TRAMONTANE study, the main causes of failure are worsening respiratory distress, especially in patients supported by HFNC; patient discomfort, the leading cause in patients treated with CPAP; and the occurrence of apnea in a minority of cases in both groups.22 The very large cohort of almost 6500 patients collected by Clayton et al.15 in more than 90 PICUs in North America and Saudi Arabia gives credit to clinicians who turn to NIV in the event of failure, since this strategy seems to avoid escalation to invasive mechanical ventilation (IMV) in more than 70% of cases. There is a rationale for using BiPAP in infants with bronchiolitis and worsening respiratory failure, but is this technique being used optimally?Delacroix et al. point out that the unfavorable results in their BiPAP group may have resulted from a suboptimal patient-ventilator interaction.14 Indeed, use of pressure support in spontaneous/timed modes requires inspiratory synchrony, expiratory synchrony, and rapid compensation for leaks in order to reach pre-established pressure values during inspiration.26Infants, especially when exhausted, have a higher respiratory rate, lower tidal volume, and weaker inspiratory efforts, making synchronization with their ventilator more complex.27Patient-ventilator asynchrony is frequent during IMV or NIV with pressure support in infants and children.28,29 In an elegant physiological study performed in infants with AVB, Baudin et al. characterized the main inspiratory asynchronies with noninvasive pressure assist control ventilation from diaphragmatic electrical activity recordings.30 Autotriggering, double triggering, and above all non-triggered breaths were observed for nearly 40% of the respiratory cycles, highlighting difficulties in detecting inspiratory effort in patients younger than 6 months, the targeted population in the study by Delacroix et al.14 These triggering asynchronies are associated with leaks, notably when BiPAP is performed with a nasal interface.31 This issue is explained by the insufficient sensitivity of the triggers with regard to the modest volumes and flows generated during inspiration at this young age.32 In addition, airway obstruction and dynamic hyperinflation may increase the frequency of ineffective respiratory efforts.30 The asynchrony index could be even higher if premature and late cycling are considered, i.e., asynchronies related to excessively long or short ventilator inspiratory times in relation to the neural command.28 These expiratory asynchronies are influenced by the ventilator’s mode and algorithm and may be improved by adjustments of the cycling-off criterion, which remains a difficult bedside challenge.28 In adults, patient-ventilator asynchrony has been associated with increased duration of mechanical ventilation, sleep disorders, prolonged ICU stay, and increased mortality.33 Such a demonstration has not been made in pediatrics, but recognition of this phenomenon and the analysis of its risk factors and consequences are much more recent.34 Currently, technological advances in ventilators have opened new horizons regarding synchronization, even in this group of patients. NIV software, management of leaks, and turbines specifically dedicated to NIV are indisputable advances.35 Neurally adjusted ventilatory assist (NAVA), initially developed for intubated patients, offers another option. In the field of severe AVB, an early report highlighted the interest of NAVA in providing less aggressive IMV and more comfort to the child.36 Discomfort during NIV is common in infants,22 and the prescription of sedatives is systematically considered by some teams.37 The discomfort may have multiple origins, including intolerance of the interface, skin breakdown, conjunctivitis, and gastric distension.38 Patient-ventilator asynchrony is another important source,39 which can be significantly improved with NAVA. Indeed, the direct analysis of diaphragmatic depolarization reduces the trigger delay, leading to more effective synchronization than with conventional NIV, even after careful optimization of the expiratory trigger setting.28,30,40 The asynchrony index may be reduced to 2%-8%, i.e., lower than the critical threshold of 10% defined in the adult population,41 with a nasal interface and in the presence of large leaks. One of the restraints on using NAVA is the extra cost it entails. However, the targeted population is limited to HFNC or CPAP failure, corresponding to 10-15% of moderate to severe AVB.15 A recent physiological study in severe AVB infants found that, compared to CPAP, NAVA was associated with a decreased work of breathing, lower neural drive and lower Ti/Ttot ratio.42 The promising results of this study suggest that pediatric intensivists must be as ambitious in combating asynchrony as they have been in combating pain and discomfort.43The impact on patient outcome will be judged in randomized controlled trials targeting severe forms of the disease.Disclosure: The authors declare no conflict of interest.
Pediatric pulmonologists, and, indeed, general pediatricians, are exposed to the causative virus of Covid-19 , SARS-CoV2, in their daily outpatient practices from both symptomatic and asymptomatic patients. This risk naturally increases with multiple exposures over time. We have developed a simple equation to calculate the probability of a practitioner remaining Covid free over a specified time interval, given the local population prevalence of virus, the transmissibility of the organism or “attack rate,” the mitigating effects of personal protective equipment (PPE), and the number of patients seen over the time interval. The equation can be used to construct a Kaplan Meier -like plot for remaining Covid free. Since studies of transmission of SARS-CoV2 suggest a spectrum between droplet and aerosol spread, even in asymptomatic patients and absence of aerosol generating procedures, the type of masks protection worn by medical practitioners may mitigate risk to different degrees. Eye protection may mitigate the risk further. While the risk of acquiring Covid-19 in a year of practice is low, it is not negligible. However it can be minimized. These considerations may be helpful in deciding local risk to the practitioner according to practice volume and in choosing the level of PPE that would result in minimizing that risk.
Rationale: Aerosolized albuterol is widely used, but its safety and efficacy in infants with severe bronchopulmonary dysplasia (sBPD) is not well established. Objectives: To compare the tolerability and efficacy of two dose levels of aerosolized albuterol to saline placebo in infants with sBPD. Methods: Single-center, multiple-crossover trial in 24 ventilated very preterm infants with sBPD. Albuterol (1.25mg, 2.5mg) and 3ml of normal saline were administered every 4 hours during separate 24-hour treatment periods assigned in random order with a 6-hour washout phase between periods. The primary outcome was the absolute change (post–pre therapy) in expiratory flow at 75% of exhalation (EF75). Secondary endpoints were changes in ventilator parameters, vital signs, and heart arrhythmia. Results: Average within subject EF75 values improved with each therapy: saline placebo (+0.45L/min 2.5, p=0.04), 1.25mg of albuterol (+0.70L/min 2.4, p<0.001), and 2.5mg of albuterol (+0.38L/min 2.4, p=0.06). However, 1.25mg of albuterol (0.26L/min; 95% CI -0.19, 0.72) and 2.5mg (-0.10L/min; 95% CI -0.77, 0.57) produced similar changes in EF75 when compared to saline. All secondary outcomes were similar between saline and 1.25mg of albuterol. Peak inspiratory pressure needed to deliver goal tidal volumes (7.5% relative decrease, 95% CI 2.6, 12.3) and heart rate (6.5% increase, 95% CI 2.2, 10.8) differed significantly between albuterol 2.5mg and saline. Conclusion: Albuterol at 1.25mg and 2.5mg, compared to aerosolized saline, did not affect EF75 in infants with sBPD receiving invasive ventilation. Greater improvement in inspiratory pressures with albuterol 2.5mg suggests benefit, but close heart monitoring is indicated.
Duchene muscular dystrophies (DMD) is a rare but devastating disease resulting in progressive loss of ambulation, respiratory failure, DMD-associated cardiomyopathy (DMD-CM) and premature death. The use of corticosteroid and supportive respiratory care has improved outcomes, such that DMD-CM is now the leading cause of death. Historically, most programs have focused on the skeletal myopathy with less attention to the cardiac phenotype. This omission is rather astonishing since boys with DMD possess an absolute genetic risk of developing cardiomyopathy. Unfortunately, heart failure signs and symptoms are vague due to skeletal muscle myopathy leading to limited ambulation and traditional assessment of cardiac symptoms by the New York Heart Association classification is of limited utility even in advance stages. Echocardiographic assessment can detect cardiac dysfunction late in the disease course, but this has proven to be a poor surrogate marker of early cardiovascular disease and an inadequate predictor of DMD-CM. Indeed, one explanation for the paucity of cardiac therapeutic trials for DMD-CM has been the lack of a suitable end-point. Improve outcomes requires a better proactive treatment strategy, however the barrier to treatment is lack of a sensitive and specific tool to assess efficacy of treatment. The use of cardiac imaging has evolve from echocardiography to cardiac magnetic resonance imaging to assess cardiac performance. The purpose of this article is to review the role of cardiac imaging in characterizing the cardiac natural history of DMD-CM, highlighting the prognostic implications and an outlook on how this field might evolve in the future.
Asthma assessment by spirometry is challenging in children as forced expiratory volume in one second (FEV1) is frequently normal at baseline. Bronchodilator (BD) reversibility testing may reinforce asthma diagnosis but FEV1 sensitivity in children is controversial. Ventilation inhomogeneity, an early sign of airway obstruction, is described by the upward concavity of the descending limb of the forced expiratory flow-volume loop (FVL)s, not detected by FEV1. The aim was to test the diagnosis ability of FVL shape indexes as β-angle and forced expiratory flow at 50% of the forced vital capacity (FEF50)/peak expiratory flow (PEF) ratio, to identify asthmatics from healthy children in comparison to “usual” spirometric parameters. Seventy-two asthmatic children and twenty-nine controls aged 8 to 11 years were prospectively included. Children performed forced spirometry at baseline and after BD inhalation. Parameters were expressed at baseline as z-scores and BD reversibility as percentage of change reported to baseline value (Δ%). Receiver operating characteristic curves were generated and sensitivity and specificity at respective thresholds reported. Asthmatics presented significantly smaller zβ-angle, zFEF50/PEF and zFEV1 (p≤0.04) and higher BD reversibility, significant for Δ%FEF50/PEF (p=0.02) with no difference for Δ%FEV1. zβ-angle and zFEF50/PEF exhibited better sensitivity (0.58, respectively 0.60) than zFEV1 (0.50), and similar specificity (0.72). Δ%β-angle showed higher sensitivity compared to Δ%FEV1 (0.72 vs 0.42), but low specificity (0.52 vs 0.86). Quantitative and qualitative assessment of FVL by adding shape indexes to spirometry interpretation may improve the ability to detect an airway obstruction, FEV1 reflecting more proximal while shape indexes peripheral bronchial obstruction.