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Association of childhood tracheomalacia with bronchiectasis: a case–control study | Archives of Disease in Childhood (bmj.com)

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paediatrics

respiratory medicine

Data availability statement

Data are available upon reasonable request. Data available from corresponding author of this manuscript.

What is already known on this topic?

The relationship between the structural airway disorders of tracheomalacia and bronchiectasis remains unclear in children.

While a possible relationship has been hypothesised, there have been no studies examining this in humans and particularly in children.

What this study adds?

Introduction

The structural airway disorders of tracheomalacia and bronchiectasis have been recognised increasingly in children in recent years, but whether there is a relationship between these two disorders remains unclear. 1-4 Bronchiectasis can have many underlying causes (eg, cystic fibrosis (CF), aspiration, immunodeficiency, retained foreign body and congenital syndromes), 2 and it has been suggested that tracheomalacia might also lead to bronchiectasis. 2 5-7 The postulated mechanism for tracheomalacia causing bronchiectasis is of impaired mucociliary clearance secondary to an ineffective cough from partial airway closure, 5 leading to retained secretions and subsequently to chronic lower airway infection and inflammation, 4 8 9 and airway wall injury. 5 10 However, an association between these two has not been evaluated by case-control or prospective studies.

Flexible bronchoscopy (FB) is the current gold standard for diagnosing tracheomalacia, 4 which is defined as either a deformity in the shape of the trachea at end-expiration during spontaneous respiration 11-13 or a reduction in the tracheal cross-sectional lumen during expiration. 4 Although there is no consistent evidence that the anatomical severity of tracheomalacia reflects clinical severity, 4 the European Respiratory Society (ERS) statement on tracheomalacia and bronchomalacia in children 4 defined tracheomalacia according to the degree of tracheal collapse observed during expiration (estimated >50% reduction in the cross-sectional luminal area).

There is acknowledged limited published evidence examining whether tracheomalacia is a cause or an outcome of airway suppuration found in bronchiectasis. 2 6 7 Animal model studies have demonstrated an association between tracheal collapse and bronchiectasis. 14While some retrospective cohort studies describe bronchoscopy-demonstrated airway malacia being more common in children with recurrent lower airway infections than in controls (52% vs 13%, p=0.001), 15 others have failed to observe this association. 6 A higher level of evidence is required to define if a relationship between tracheomalacia and bronchiectasis exists, since if confirmed clinicians will have to monitor their patients closely for symptoms and signs of underlying bronchiectasis. Indeed, prompt diagnosis, early treatment to avoid irreversibility and prevention of bronchiectasis are all emphasised in the ERS clinical practice guidelines for managing children and adolescents with bronchiectasis. 16

We therefore undertook a case-control study to determine if tracheomalacia is associated with bronchiectasis in children. Our hypothesis was that compared with controls, children with tracheomalacia (defined at bronchoscopy) have an increased risk of bronchiectasis.

Results

The median age of the 45 (56% male) bronchiectasis cases was 2.6 years (IQR 1.5-4.1), considerably younger than that of the 90 (52% male) controls of 7.8 years (IQR 3.4-12.8). There were three (7%) and nine (10%) Indigenous children in the case and control groups, respectively. The most common aetiology of bronchiectasis was post-infectious, while haematological malignancy was the predominant disorder in controls ( table 1). Four children had congenital heart disease (two each in case and control groups, see the online supplemental file 1 for further details).

The frequency of tracheomalacia in the bronchiectasis and control groups is presented in table 2. Using the Any-TM definition, tracheomalacia was diagnosed in 14 of 45 (31%) bronchiectasis cases and 3 of 90 (3%) controls. In contrast, the ERS-TM definition identified nine subjects with tracheomalacia, all of whom (9 of 45; 20%) were bronchiectasis cases. By either tracheomalacia definition, the most common shape abnormality in both groups was oval flattening. Bronchiectasis cases showed tracheomalacia mainly in the lower two-thirds of the trachea. The severity of tracheomalacia (Any-TM) in the three affected controls was deemed to be mild (<50% reduction in cross-sectional area), while 12 of 14 (86%) of the affected bronchiectasis cases had tracheomalacia of mild (<50%) or moderate (50%-75%) severity. Using the ERS-TM definition, seven of nine (78%) cases of tracheomalacia in those with bronchiectasis were of mild (50%-75%) severity.

Logistic regression for univariable and multivariable analyses was used to identify factors associated with bronchiectasis ( table 3). The first model used the Any-TM definition and demonstrated both age and tracheomalacia were associated with bronchiectasis, while there was no association with either sex or ethnicity. After adjusting for age, tracheomalacia remained significantly associated with bronchiectasis (OR adj=13.2 (95% CI 3.2 to 55)). As none of the controls had tracheomalacia when using the ERS-TM definition, exact logistic regression was performed. 24 The corresponding OR adj=24.4 (95% CI 3.4 to infinity) was higher than when the Any-TM definition was employed.

Discussion

Our case-control study involving 45 children with bronchiectasis (cases) and 90 'disease controls' found that tracheomalacia was significantly associated with bronchiectasis with an OR adj up to 24.2 (95% CI 3.4 to infinity) using the ERS-TM definition.

Our finding is important for several reasons. First, to our knowledge, there are no prior case-control or retrospective studies that have evaluated the association between tracheomalacia and bronchiectasis in children without CF. Second, the association between tracheomalacia and bronchiectasis was strong and increased further when the more stringent ERS-TM diagnostic criteria were used. Third, this finding is clinically relevant as clinicians managing children with tracheomalacia will need to consider the possibility of underlying bronchiectasis if the child develops a chronic (>4 weeks) or recurrent wet/productive cough that responds incompletely to antibiotics.

Tracheomalacia, being a significant risk factor for bronchiectasis in children, is not unexpected. A retrospective study of dogs with tracheal collapse reported a six-times higher than expected prevalence of bronchiectasis. 14 Tracheomalacia is also found commonly in children with recurrent or chronic respiratory symptoms, 7 15 which can be either a precursor or a marker of underlying bronchiectasis. 5 25 A retrospective Spanish study reported airway malacia (defined by >50% dynamic collapse of the airway lumen during expiration while breathing spontaneously) was more common in children with recurrent lower airway infections than in disease controls lacking this history, but undergoing FB for other clinical indications (52% vs 13%, p=0.001). 15 Another retrospective study using the same diagnostic criteria described tracheomalacia at the time of FB in 15 of 108 (14%) children with a chronic wet cough, 26 while in a review of 70 children with protracted bacterial bronchitis (PBB), 22 (31%) had tracheomalacia (defined as dynamic collapse of the trachea during spontaneous respiration) identified at FB. 27 Furthermore, a prospective cohort study reported children with malacia had increased likelihood of respiratory illness frequency, severity, 'clinically significant' cough and often a delayed recovery, although the site and severity of malacia did not impact on the illness profile. 20 Nevertheless, in the 5-year prospective follow-up of 166 patients with PBB, where 45% had tracheomalacia (defined as Any-TM), the presence of tracheomalacia was not associated with recurrent PBB episodes. 28 Finally, a retrospective study involving 109 children with CF reported the prevalence of bronchiectasis was similar in those with or without tracheomalacia. 29 However, this study 29 did not report a sample size calculation, bronchiectasis was not a primary outcome and CF itself is an independent risk factor for developing bronchiectasis, thus compromising the study findings.

It has been hypothesised that tracheomalacia impairs mucociliary clearance leading to retained secretions from secondary to airway closure during coughing, which can lead to recurrent and/or prolonged respiratory infections. Cole's 'vicious cycle hypothesis' 30 for the pathogenesis of bronchiectasis suggests a trigger event compromises mucociliary clearance, which perpetuates endobronchial infection and inflammation, further impairing mucociliary clearance and creating a vicious cycle of infection and inflammation resulting in airway wall destruction. Another suggested mechanism is developing squamous metaplasia, 4 which may interrupt mucociliary clearance. It is possible that tracheomalacia could predispose children to a similar vicious cycle of infection and inflammation and ultimately, bronchiectasis. Our study strengthens this biological plausibility, although a strong association does not automatically infer causality.

Given the strong association between bronchiectasis and tracheomalacia found in this study, it is reasonable to suggest that children with tracheomalacia are monitored closely for wet or productive cough. Indeed, the ERS statement on tracheomalacia and bronchomalacia 4 recommends a low threshold for commencing antibiotics in those with wet/productive cough. Another potential intervention is introducing airway clearance techniques to aid mucociliary clearance, such as positive expiratory pressure (PEP), as recommended for children with bronchiectasis. 4 16 Indeed, a PEP of 5-10 cm H ₂O has been shown to increase the peak cough expiratory flow of children with trachea-oesophageal repair accompanied by tracheomalacia. 31 Although more evidence is required, a proactive approach in children with tracheomalacia might prevent bronchiectasis developing in at least some children.

The strengths of our study include a-priori case-control design with sample size calculations and tracheomalacia characterised by experienced paediatric bronchoscopists (IBM, AC) blinded to the clinical history. Additionally, we used two different commonly used definitions of tracheomalacia and undertook a sensitivity analysis to further strengthen our findings. Nonetheless, there are important limitations. First, this was a retrospective case-control study and the controls and 'bronchiectasis cases' were not matched evenly for age. This is important as while the natural history of tracheomalacia has not been adequately studied, 4 32 its symptoms do improve with age. We accounted for this potential confounding factor by multivariable regression (correcting for age) and a sensitivity analysis demonstrated a higher OR and OR adj when tracheomalacia was defined using the ERS-TM criteria. Second, controls were children with a recent bone marrow transplant or cancer who had a c-HRCT and FB for febrile neutropaenia and thus were unlikely to be truly representative of the general population. However, this was the only feasible option as these were the only sizeable cohort of children in our centre who had the combined investigations (FB and c-HRCT) done without an underlying chronic respiratory condition. The controls had their FBs done via a laryngeal mask. In our experience, a laryngeal mask can distort the trachea which may create the appearance of tracheomalacia. However, this was not borne out in the results as there were less patients with tracheomalacia in the control group than in our cases group. Third, overall small case numbers and no tracheomalacia (using the ERS-TM definition) in controls posed a statistical challenge when performing univariable and multivariable analyses. Despite our sample size calculations with the reported incidence of airway malacia of 1 in 2100, 21 it is possible that with a larger cohort, this issue may not have risen. However, we were able to overcome the issue of no tracheomalacia cases (using ERS-TM definition) by performing exact logistic regression.

In conclusion, our case-control study found tracheomalacia is significantly associated with bronchiectasis. We suggest careful monitoring and follow-up (using a multidisciplinary model) of children with tracheomalacia. Airway clearance techniques and antibiotics for wet or productive cough should be considered, especially if these symptoms become chronic or recurrent, leading to investigations for underlying bronchiectasis. However, our findings require confirmation from prospective long-term observational and intervention studies.

Data availability statement

Data are available upon reasonable request. Data available from corresponding author of this manuscript.

# data[].attributes.attachment_link.title
Association of childhood tracheomalacia with bronchiectasis: a case-control study

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Objective Children with tracheomalacia can develop chronic lower airway infection and neutrophilic inflammation. It is plausible children with tracheomalacia are at increased risk of developing bronchiectasis. We hypothesised that compared with controls, tracheomalacia in children is associated with bronchiectasis. Design Single-centre, case-control study.

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Abstract

, . The presence of airway obstruction can result in and abnormalities in gas exchange, as well as exacerbation of already present feeding difficulties and failure to thrive, secondary to mismatch of Pierre Robin Sequence (PRS) is defined by a constellation of characteristics including micrognathia glossoptosis and airway obstruction. PRS can occur in isolation or can be associated with syndromes and another anomalies. Airway obstruction and feeding difficulties are the major presenting issues, and the severity of the condition ranges from mild, with minimal to no symptoms, to severe, with overt obstruction resulting in apnoeas, severe respiratory distress and cyanosis obstructive sleep apnoea caloric intake to energy usage associated with increased effort of breathing. Management of airway obstruction for infants with PRS varies between centres. This paper explores the surgical and non-surgical management options available, their effectiveness and pitfalls in children with PRS. Despite the pros and cons of each management option, it is evident that resource availability and multidisciplinary clinical support are key factors to successful management.

Introduction

In 1934, French dentist Pierre Robin first described a condition involving a constellation of features including micrognathia, glossoptosis, and upper airway obstruction, known today as Pierre Robin Sequence (PRS) [1], [2], [3]. Of those with PRS,up to 90% have an associated cleft palate [3], [4], [5]. Over the years there has been discrepancy in the literature regarding which features define PRS. In 2014, an international consensus meeting was held in the Netherlands, where an expert panel was convened to develop a consensus report on PRS. The report outlined the diagnostic characteristics of PRS which included micrognathia, glossoptosis and airway obstruction; cleft palate was not deemed to be a mandatory characteristic of the condition [6]. PRS occurs in 1:3000-1:30,000 live births [1], [2], [3], [4], [5], [6], [7], [8], the variation in rate is related in part to the inconsistent definition of PRS used previously.

Although PRS can occur as an isolated condition, more than 50% will have an associated syndromic condition or chromosomal abnormality [3]. Over 50 different syndromes have been identified to be associated with PRS [3], [4], [9]. The most commonly associated syndrome is Stickler syndrome,which represents 11-18% of the PRS population,other commonly associated syndromes include 22q11.2 deletion and Treacher Collins [1], [4]. Mortality rates for PRS of up to 21% have been reported, with the mortality rate for infants with syndromes or other anomalies being significantly higher than those with isolated PRS [3]. A study by Costa et al. [10] evaluated 181 infants with PRS, and found an overall mortality rate of 16%; with no deaths observed in infants with isolated PRS. This study also found that major risk factors for mortality in this population were cardiac anomalies, central nervous system anomalies and having 2 or more organ system abnormalities. The severity of OSA was not found to be an independent risk factor for mortality. Antenatal diagnosis of PRS is technically difficult and dependent on subjective ultrasound findings, hence PRS is often diagnosed postnatally [4].

The most common presenting issues for infants with PRS are airway obstruction and feeding difficulties. In PRS, the most common area of airway obstruction is at the level of the tongue base [3]. This is largely attributed to glossoptosis (posterior displacement of the tongue base) [6],resulting in the narrowing of the oropharynx and/or hypopharynx. Additionally, there is a dynamic component of the airway obstruction, in which the increased resistance to inspiratory airflow in the already narrow airway results in negative pressure within the pharynx and further posterior pull of the tongue, leading to collapse of the pharyngeal muscles [7]. Further airway narrowing progresses and becomes evident by the second month of life [3]. Staudt et al. demonstrated that despite the increase in airway size with growth over the first two years of life, children with PRS achieve lower limits of normal pharyngeal airway size in comparison to individuals without PRS. Clinically, obstruction in PRS presents as a spectrum from infants with no symptoms of airway obstruction; airway obstruction that only becomes evident with feeding or crying in the form of increased respiratory effort or stridor; sleep-related breathing disorder or obstructive sleep apnoea (OSA). Airway obstruction is most notable in the supine position. Some infants present with overt obstruction, cyanosis and apnoeas, requiring immediate intervention [6]. van Lieshout et al. found that the prevalence of OSA in infants with PRS can be 46-100%, regardless of the presence or absence of symptoms of a sleep-related breathing disorder. It is well known that within the first two years of life, the mandible and upper airway increase with size, resulting in natural, gradual improvement in airway obstruction with age [3], [11].

From birth, airway narrowing progresses and becomes more pronounced by the second month of life [3]. However, Staudt et al. demonstrated that despite the increase in airway size with growth, the pharyngeal airway size of children with PRS that they achieve is at the lower limits of normal in comparison to individuals without PRS. Therefore, not only is the early identification and management of airway obstruction important, especially in the context of potential neurocognitive, metabolic and cardiovascular complications associated with untreated OSA, but serial monitoring and review for persistent or re-emergence of symptoms of airway obstruction throughout childhood [eg with enlargement of tonsils and adenoids] and into adulthood is prudent.

Feeding difficulties are a common presenting issue for infants with PRS, and similar to airway obstruction, severity is variable among infants. Feeding difficulties may manifest as prolonged feeding time, reduced oral intake, unsafe swallow and subsequent failure to thrive [6]. The upper airway obstruction may also contribute to feeding difficulties due to the effort of breathing and associated energy expenditure exceeding that of the caloric intake [3], [7], [8]. In addition, if a cleft palate is present,there may be ineffective and insufficient intraoral pressure to allow for extraction of milk from the breast or bottle [3]. Up to 75% of infants with PRS have severe feeding difficulties and require assisted feeding via a nasogastric tube,with some requiring gastrostomy feeding [1], [3], [4]. In infants with isolated PRS, feeding difficulties often resolve after the first 12 months of life, in comparison to those infants with associated syndromic conditions who tend to continue to require ongoing feeding support [3], [4]. Given the high prevalence of feeding issues seen within the PRS population, early recognition, assessment and proactive management of feeding should be considered.

Additional issues faced by infants and children with PRS include gastro-oesophageal reflux, with a prevalence of up to 80% of infants, which not only exacerbates feeding difficulties but can also impact upper airway obstruction through the development of reflux laryngitis [3]. Speech and language skill development should be monitored with time, where velopharyngeal insufficiency can develop in up to 20% of individuals post cleft palate repair [12] and speech and language delay have been reported in up to 46% of patients with PRS [13].

Pierre Robin Sequence, with or without an associated syndrome, is a complex condition involving significant health sequelae, with airway obstruction being the greatest contributor to morbidity. Review of available literature has brought to light the differences in management of airway obstruction between different centres around the world. Given the significant impact of airway obstruction on growth and development of infants with PRS, the aim of this paper is to discuss the available treatment strategies to manage airway obstruction in this unique population.

Section snippets

Tongue lip adhesion

Tongue lip adhesion (TLA) involves the tongue being tethered to the lower lip, resulting in the advancement of tongue positioning and relief of the airway obstruction caused by glossoptosis [11], [23]. There has been large variability in reported success rates with TLA; ranging from 33 to 100% [15], [23], [24], [25], [26]. However, it is widely recognised that TLA does not result in complete resolution of OSA [24]. Camacho et al. demonstrated; that in patients with severe OSA, there was a mean

Future research

The availability of objective data to define "success" of treatment options were limited or ambiguous, in particular for prone positioning, NPA and CPAP. To further evaluate and improve comparability of these management strategies, future research should consider the use of polysomnography pre- and post- intervention to obtain objective data of their effectiveness.

Conclusion

Airway obstruction is one of the defining characteristics for a diagnosis of PRS. While the severity of airway obstruction varies, infants with PRS are at significant risk of upper airway obstruction and feeding difficulties, along with other significant comorbities in those with syndromic assocaitions. Given the multiple treatment options and variable effectiveness, the evaluation and initial management of infants with PRS would be most ideal in paediatric centres with access to

Educational aims

The reader will come to appreciate:

*
Definition and pathophysiology of syndromal and isolated Pierre Robin Sequence [PRS].

*
The different management options available for patients with PRS.

*
Evidence for the effectiveness of mandibular distraction osteogenesis, non-invasive ventilation and a nasopharyngeal airway as management options for PRS.

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# data[].attributes.attachment_link.title
The management of upper airway obstruction in Pierre Robin Sequence

# data[].attributes.attachment_link.description
The presence of airway obstruction can result in and abnormalities in gas exchange, as well as exacerbation of already present feeding difficulties and failure to thrive, secondary to mismatch of Pierre Robin Sequence (PRS) is defined by a constellation of characteristics including micrognathia glossoptosis and airway obstruction.

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Available online 5 October 2022

Abstract

Cystic Fibrosis-Related Diabetes (CFRD) is a unique type of diabetes mellitus that shares some features with both type 1 and type 2 diabetes. Yet, its distinguishing feature of acute pulmonary complications associated with hyperglycemia and the catabolic metabolism associated with a relative insulin deficiency poses challenges to the application of traditional definitions and treatments for diabetes mellitus. People with CF (pwCF) undergo rigorous annual screening starting at age 10, a process that is challenging for patients and limited by sensitivity, specificity, and reproducibility. As pwCF continue to live longer, over 50% are expected to develop CFRD over their lifetime, including up to 20% of adolescents. Increasing numbers of people with CFRD will make this disease increasingly relevant to diabetes practitioners. Evidence-guided practice in CFRD care is limited by small and short studies. Our current understanding of CFRD may change significantly with the recent introduction of CF Transmembrane Regulator (CFTR) modulator medications. This review will explore current challenges in the diagnosis and management of CFRD, specifically highlighting knowledge gaps in the pathophysiology of CFRD, optimal screening methods, priorities for research and provide guidance with regards to screening, diagnosis, and treatment.

Introduction

Cystic Fibrosis (CF) is the most common life-limiting autosomal recessive genetic disease. Major breakthroughs in nutrition, respiratory care, newborn screening, and the recent introduction of CF Transmembrane Conductance Regulator (CFTR) modulators continue to improve longevity and quality of life [1]. In the last decade, more people living with CF (pwCF) have survived beyond 50 years of age [1]. As the life expectancy for this population increases, the incidence and prevalence of CF-related diabetes (CFRD), the most important extra-pulmonary co-morbidity in patients with CF, is expected to increase. CFRD is associated with major impacts on respiratory and nutritional health and lifespan.

CFRD can be diagnosed at any age but becomes increasingly prevalent with age [2]. In the University of Minnesota cohort, it occurred in 2 % of children, 19 % of adolescents, and 40-50 % of adults [3]. Cystic Fibrosis Canada reported a prevalence of 3 % in children and 33 % in adults with CF in 2020 [4]. A recent study by Yi et al., however, suggests a prevalence of CFRD just under 10 % in children under 5 years of age [5]. Worldwide, the prevalence of CFRD is likely under-reported, as diabetes screening may not be conducted universally. In a contemporary cohort, patients with CFRD continue to demonstrate a fivefold increased risk of mortality as compared to individuals with CF alone [6].

This review will explore current challenges in the diagnosis and management of CFRD, specifically highlighting knowledge gaps in the pathophysiology of CFRD, optimal screening methods, priorities for research and provide guidance with regards to screening, diagnosis, and treatment.

Section snippets

Oral glucose tolerance tests

Major issues with current OGTT screening protocols include significant variability on repeat testing [50]. The OGTT is perceived as a major burden by both pwCF and their healthcare teams [49]. Thresholds to define diabetes are also discussed because they are based on the risk of retinopathy in patients living with type 2 diabetes, though pwCFRD can develop diabetic retinopathy [9]. Glycemic thresholds related to decline in BMI and FEV1 would be more pertinent to optimization of CF care. Many

A) Dietary and other lifestyle recommendations

Dietary recommendations for adults with CFRD suggest a daily caloric goal of 1.2-1.5-fold greater than a healthy counterpart. Unlike T2D, pwCFRD should not restrict their caloric or carbohydrate intake and they should continue to consume the high calorie, high fat and high salt diet recommended for pwCF [69]. The only recommended dietary changes at diagnosis of CFRD are to learn carbohydrate counting for insulin dosing if mealtime dosing is implemented [69]. Specific recommendations for insulin

Screening and risk stratification

Major priorities for screening are to develop alternate or adjunctive screening tests, to reduce the need for or replace OGTT which balance utility to detect high risk individuals with patient acceptability. The most promising current evidence comes from HbA1c (to reduce the number of OGTT) and/or CGM (to reduce or replace OGTT). To date, all patients with CF are treated equally in the screening process. As studies continue to identify factors reducing or increasing the risk of CFRD, research

Educational aims

The reader will come to appreciate that:

*

Up to 50 % of people living with CF will develop CFRD.

*

Consistent screening protocols for CFRD are an important part of routine CF care from the age of 10 years.

*

Wider consensus is needed for the optimal evidence-based management of CFRD.

*

CFRD is associated with a five-fold increased risk of mortality.

*

CFTR modulators may increase beta cell mass and mitigate some of the risk of developing CFRD.

References (90)

Canada CF. Cystic Fibrosis Canada 2020 Annual Data Report....

Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, et al. Clinical care guidelines for cystic...

Terliesner N, Vogel M, Steighardt A, Gausche R, Henn C, Hentschel J, et al. Cystic-fibrosis related-diabetes (CFRD) is...

Kelsey R, Manderson Koivula FN, McClenaghan NH, Kelly C. Cystic fibrosis-related diabetes: pathophysiology and...

Yung B, Noormohamed FH, Kemp M, Hooper J, Lant AF, Hodson ME. Cystic fibrosis-related diabetes: the role of peripheral...

View more references

View full text

# data[].attributes.attachment_link.title
Cystic Fibrosis-Related Diabetes: Clinical approach and knowledge gaps

# data[].attributes.attachment_link.description
Available online 5 October 2022 Cystic Fibrosis-Related Diabetes (CFRD) is a unique type of diabetes mellitus that shares some features with both type 1 and type 2 diabetes. Yet, its distinguishing feature of acute pulmonary complications associated with hyperglycemia and the catabolic metabolism associated with a relative insulin deficiency poses challenges to the application of traditional definitions and treatments for diabetes mellitus.

# data[].attributes.attachment_link.title
Recent advances in paediatric sleep disordered breathing

# data[].attributes.attachment_link.description
This article reviews the latest evidence pertaining to childhood sleep disordered breathing (SDB), which is associated with negative neurobehavioural, cardiovascular and growth outcomes. Polysomnography is the accepted gold standard for diagnosing SDB but is expensive and limited to specialist centr…

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Pre-operative screening for sleep disordered breathing: obstructive sleep apnoea and beyond

# data[].attributes.attachment_link.description
Sleep disordered breathing describes an important group of conditions that causes abnormal nocturnal gas exchange, with important implications in the peri-operative management plan. An understanding of the pathophysiology behind obstructive sleep apnoea and other disorders that may lead to hypoventi…

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1. 1Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA

2. 2Department of Emergency Medicine, Columbia Irving Medical Center, New York, NY, USA

3. 3Department of Humanities, Health and Society, Florida International University Herbert Wertheim College of Medicine, Miami, Florida, USA

4. 4Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China

5. 5Zhangjiang Institute, Fudan University, Shanghai, China

6. 6Centre for Community Medicine, All India Institute of Medical Sciences, New Delhi, India

7. 7Department of Cardiology, University Medical Center, Johannes Gutenberg University, Mainz, Germany

8. 8Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

9. 9Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, USA

10. 10Harvard Medical School, Boston, MA, USA

11. 11Harvard Global Health Institute, Cambridge, MA, USA

12. 12Harvard T.H. Chan School of Public Health, Boston, MA, USA

Correspondence to C Sorensen CJS2282{at}cumc.columbia.edu

Inhaling polluted ambient air has many health effects, including childhood onset of asthma, and onset and progression of atherosclerosis

Vulnerable people can consider using well fitted N95 face masks, avoiding outdoor exercise on days when the air quality is poor, and using indoor HEPA air filters

Consider establishing air quality monitoring and warning systems for use by clinicians and in hospitals

-A man in his late 50s with a history of chronic stable angina, arterial hypertension, and a family history of cardiovascular disease presents with acute onset chest pain and is diagnosed with NSTEMI myocardial infarction. He lives in an industrialised city with annual particulate matter (PM2.5) levels higher than 50 µg/m³, which spiked to 90 µg/m³ in the days before his myocardial infarction. -A 9 year old girl with constant cough that interferes with her sleep visits the general practitioner with her mother. Her symptoms have caused tiredness and school absences. The family recently moved to a large city where annual PM2.5 is 85 µg/m³, from a region with annual PM2.5 of 20 µg/m³. The cough began after their move. She has no known allergy or previous similar complaint. Examination reveals a mildly inflamed throat and mild wheezing.
What you need to know

Ambient air pollution is the fifth highest risk factor for death (after hypertension, smoking, high fasting glucose, and high total cholesterol), according to the Health Effects Institute.1

Annually, 8.7 million global deaths are thought to be caused by inhalation of particulate matter released into the air from combustion of fossil fuels.2 In Europe, particulate matter and ozone account for almost 800 000 excess deaths annually.3 Additionally, an exposure-response study has estimated that particulate air pollution has contributed to approximately 15% (95% confidence interval, 7% to ...

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Reducing the health impacts of ambient air pollution

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What you need to know Case 1 -A man in his late 50s with a history of chronic stable angina, arterial hypertension, and a family history of cardiovascular disease presents with acute onset chest pain and is diagnosed with NSTEMI myocardial infarction.

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Data availability statement

Data are available upon reasonable request. All data sets are available upon reasonable request to the corresponding author.

https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

Introduction

Children's complex care needs have been defined as 'multidimensional health and social care needs in the presence of a recognized medical condition or where there is no unifying diagnosis. They are individual and contextualized, are continuing and dynamic, and are present across a range of settings, impacted by healthcare structure'. 1 Many children with complex care needs also have life-limiting conditions, that is, a condition for which there is no reasonable hope for cure and from which they will die. The prevalence of children with life-limiting conditions in the UK is increasing. 2

Decision-making in such cases can be medically, socially and ethically complex. Decisions may be misunderstood and/or contested. Disputes, either between different professional teams or between clinicians and the child's family, are common across clinical settings. 3 4 Although the broad legal framework for making decisions has remained relatively consistent for three decades, society has radically changed. Successive National Health Service reforms have sought to reshape health provision 'in the business of customer service'. 5 While the welfare of the child remains the 'paramount consideration' in law, 6 decisions for and on behalf of children are guided by principles of shared decision-making, where the parent and clinician are on a nominally equal footing. 7 8 This welcomes recognition of partnership notwithstanding, movements within society assert absolute parental rights to decide what is best for their child's health. 9

Against this background, advances in medicine mean that increasing numbers of children with complex care needs are surviving for longer and occupying a greater proportion of hospital bed-days. 10 Invariably, such patients fall under numerous medical teams and social agencies, each trying to serve the needs and wishes of the child and their family. Commonly, a lack of dedicated leadership results in incoordinate decision-making, the family confused and the best interests of the child overlooked. Such factors might exacerbate professional-parental disharmony and contribute to complaints and litigation, while compromising the well-being of all concerned parties. 11

While much has been written on how best to manage conflict in paediatric practice, 12 13 there is less consensus on the best approach to decision-making in children with complex needs. Best practice should help clinicians to compassionately deliver high-quality, medically appropriate clinical care, while successfully collaborating with children, families and colleagues.

Methods

We used a modified Delphi process to determine consensus across key professional groups. 14 An initial face-to-face meeting of selected clinical leaders (doctors, nurses, managers) was arranged to identify the key themes underpinning decision-making. Participants received short lectures on essential law and ethics, the evidence base for partnership working and the factors contributing to conflict. There followed three facilitated discussions. In the first discussion, five groups of participants, each containing six to eight professionals from mixed disciplinary and clinical backgrounds, shared experiences among themselves of managing complexity. In the second discussion, groups fed back to one another the problems faced and approaches used in their own practice. Finally, participants developed consensus opinions around key themes, which were then developed after the meeting by CM, ST-U, GB and JF into normative 'statements' around standards and approaches to managing complexity. The resultant themes and statements were finally shared back with the meeting participants who were invited to check them for accuracy. In two cases, additional statements were suggested by participants. These were checked against existing themes and incorporated into the supporting statements.

Two sequential Delphi rounds were used to rank supporting statements within each theme. Participants scored their agreement with each statement using a 5-point Likert scale: 1=strongly disagree, 2=disagree, 3=neutral, 4=agree, 5=strongly agree. Participants also had the option to select 6=don't know. Invitations to take part in the survey were sent by email to multiprofessional staff members across the children's hospital. This survey involved senior managers, all medical consultants, all ward nursing managers, all clinical nurse specialists (CNS), all psychologists, senior allied healthcare professionals, family liaison team members and the chaplaincy. The email invitation directed each staff member to a REDCap portal where they registered their professional group and level of experience, and were assigned a unique identifying survey number. After 16 weeks the survey was closed. Agreement that a particular statement should be supported and carried forward to the second round was based on the following: 70% of respondents had scored that statement ≥3 with exclusion of those who had indicated 'don't know' .

All participants who participated in the first round of the survey were then emailed an invitation to participate in a second Delphi round. In the second round, participants were asked to again score their agreement with each ranked statement from round 1. In round 2, they were additionally provided with the median score for each statement from all participants, alongside their own score from round 1, to explicitly allow participants to revise their scores on the strength of emerging consensus. The final scores for each statement, from all participants in round 2, were analysed to determine their mean, median and IQRs.

Results

The initial consensus forming face-to-face meeting proposed 69 normative statements grouped into seven key themes (themes summarised in box 1 and full listing of normative statements in table 1).

In the first Delphi round, surveys were sent to 390 professionals and 163 (42%) replied. In the second Delphi round, the 163 professionals who had participated in the first round were surveyed again, and 99 (60%) returned the surveys with all Delphi items scored. Across the 69 Delphi items answered by 99 participants there were only 66 responses (0.9%) of 6=don't know. There was no statistical difference between the responses of those participants who only responded to round 1 of the Delphi survey and those who responded to both rounds 1 and 2.

The professional background of the 99 participants is shown in table 2.

Statistical analysis showed reasonable evidence that professional background affected the median value being assigned for two normative statements. Statement 5 ( table 1) was more strongly supported by those from a consultant, clinical nurse specialist or 'other' background, while statement 56 ( table 1) was more strongly supported by those from psychology backgrounds.

The years of experience of the participants are shown in table 3.

Statistical analysis showed little evidence that years of experience affected the median values for any of the normative statements.

All normative statements met the a priori threshold (>70% of respondents scoring each statement greater than or equal to 3) for proceeding to the second Delphi round. In the second round, while the mean score for each statement ranged from 3.0 (neutral) to 4.9 (strong agreement) (see detail in table 1), there was little evidence of differences across median scores in the manner participants ranked their responses, either across themes or within themes.

Discussion

The most notable finding in our study was the uniform degree of consensus across a group of hospital professionals on how best to approach decision-making in children with complex care needs. The seven major themes (standardising the approach to communication with families, communication between professionals, shared decision-making, the role of the multidisciplinary team (MDT), managing conflict, the role of clinical psychology and staff well-being) resonated with colleagues and provided a useful framework for exploring specific principles. While the level of consensus created by the discussions in the workshop and subsequently measured in all themes was striking, there is perhaps some merit for observing those that carried weight and discussing their implications.

The survey highlights the essential importance of good communication both with the family and between professionals. Concepts such as the 'team around the child', a liaison or 'key worker' and a single defined clinical lead are not new but do require some committed resource and intent. All too often parental-professional disharmony arises due to misunderstandings or perceived poor coordination of care. While the survey talks of a 'standardised' approach to communication, this is not intended to imply a 'one size fits all' solution. Each family is unique and good communication is successful because the needs of each participant are individually recognised. 16 There is a delicate balance between structure and intimate spontaneity that must be achieved in practice.

There was a strong agreement that clinicians and parents should work in partnership for the best interests of the child. This is particularly pertinent in the wake of recent court cases 17 where some voices within academic, ethical and legal circles have argued that a shift in authority towards parents in shared decision-making is needed. 18 Participants supported the principle that children have rights that might require independent advocacy. However, while there was a strong consensus that transparency was important, professionals were more ambivalent about the importance of this reflecting their own values and goals (statement 24). Finally, there was a consensus that good care for children might imply a willingness to consider the child in isolation as well as within a family unit, and that one should not automatically assume that children will share their parents' values.

Although children were therefore recognised to be central to professionals' considerations, there was also a strong consensus on the importance of discussing the family's wishes (statements 13, 17, 21 and 22) within a process of shared decision-making (statement 18). While there was an acknowledgement of the importance of seeking parents' views, our survey was not able to adequately explore professionals' insight into the 'lived experience' of a family navigating the distress of caring for a critically ill child in hospital. We suggest that grading of parental behaviour using a 'traffic light system' (statement 51) should not be misinterpreted as a judgemental critique of a family's behaviour but rather as an opportunity for professionals to think about their own assumptions and approaches and a hospital to think about whether extra resources are required to assist mediation. Furthermore, while the effects of conflict on professionals are well reported (statements 61 and 62), we acknowledge that there is less attention to the effect of conflict on the well-being of parents and families.

While there was a clear consensus for most statements (mean scores >/=4) there were some where support was more ambivalent. An example of this was statement 14 that reflected the importance of listening to the child's voice. We interpret this apparent ambivalence as professionals taking a pragmatic view in that children with complex needs often have cognitive and communication deficits, or are ventilated on intensive care, which makes knowing the views of the child challenging. That said, an alternative interpretation might be that some professionals are not appropriately inclusive. We would support future studies that look to how the perspectives of parents and children are represented. Engagement of parents and, especially, children may require research processes, such as deliberative methods, that are less demanding and more resource intense than a Delphi process. 19 20

There was a strong agreement about the importance and structure of the MDT although there was a predominant view that such a meeting need not be chaired by a professional outside the child's primary clinical team (statement 33). Interestingly, there was some ambivalence expressed regarding the inclusivity of these meetings with regard to the attendance of the wider team and the giving of weight to all views (statement 29 or 30). This might reflect a pragmatic view around the logistics of holding such meetings in a timely fashion, or an adherence to intraprofessional considerations of hierarchy and expertise, and where ultimately professionals regard decision-making to lie. In our view, MDT meetings with or without families form the vital platform on which clinical decisions are taken. They should involve all key professionals. Yet it should be acknowledged that they therefore require much planning, should be recognised in job plans and be granted sufficient resources.

When things go wrong, complaint and conflict too often arise. These are challenging for both families and members of the clinical team. There was a tacit acknowledgement that, despite best intentions and optimal circumstances, conflict will occasionally still arise. Organisations should give conflict resolution the highest priority and consider standardised approaches to clinical ethics consultation and external second opinions. Referral for external second opinions has been a consistent recommendation for reducing conflict in many previous publications. 12 21 22 However, in our study, while there was a strong consensus for such processes to be standardised at a national level (statement 45), there was slightly more ambivalence around these being introduced as a component of an automatic conflict resolution pathway at a local level (statements 49 and 50). Participants in our study were also supportive of involving national peer-reviewed MDTs where these were available (statement 46) or establishing such bodies where they were not (statement 48).

There was a consensus for clinical psychology support to be integrated within clinical teams, and for them to take an active role in exploring family goals and values and supporting complex decision-making discussions. Finally, there was a strong agreement around the importance of supporting staff, and that in situations of professional-parental disharmony, poor morale and staff attrition result. The deleterious impact on clinicians of difficult relationships and challenging dilemmas in practice has been previously noted. 23-25 A primary focus on individual resilience may miss the importance of investment in institution-wide structures. 26 Healthcare professionals' intrinsic desire to 'do the right thing' through leading in complex cases may over-ride their regard for their personal well-being, and increase their vulnerability to experiencing moral distress, compassion fatigue and burnout.

Conclusion

The number of children with complex care needs in our hospitals is increasing. Our study of a large mixed group of healthcare professionals in a tertiary children's hospital demonstrates a strong consensus across seven key themes towards developing best practice in decision-making in children with complex care needs: standardising the approach to communication with families, communication between professionals, shared decision-making, the role of the MDT, managing conflict, the role of clinical psychology and staff well-being. Within each of these themes there are notable elements of practice that healthcare teams might engage with to better support the patients and families in their care. In some situations, a comprehensive adoption of a standardised approach might mitigate against professional-parental disharmony.

Data availability statement

Data are available upon reasonable request. All data sets are available upon reasonable request to the corresponding author.

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Factors affecting decision-making in children with complex care needs: a consensus approach to develop best practice in a UK children's hospital

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Background Children with complex care needs are a growing proportion of the sick children seen in all healthcare settings in the UK. Complex care needs place demands on parents and professionals who often require many different healthcare teams to work together. Care can be both materially and logistically difficult to manage, causing friction with parents.

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Homepage - International Respiratory Coalition (IRC)

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The official website of the International Respiratory Coalition - a new movement to transform respiratory outcomes in the post pandemic world

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Lung Facts - International Respiratory Coalition (IRC)

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Lung Facts is an online resource from the IRC - presenting the latest epidemiological and economic data on a range of lung conditions.

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Timothy M Uyeki, David S Hui, Maria Zambon, David E Wentworth, Arnold S Monto

Annual seasonal influenza epidemics of variable severity caused by influenza A and B virus infections result in substantial disease burden worldwide. Seasonal influenza virus circulation declined markedly in 2020-21 after SARS-CoV-2 emerged but increased in 2021-22. Most people with influenza have abrupt onset of respiratory symptoms and myalgia with or without fever and recover within 1 week, but some can experience severe or fatal complications. Prevention is primarily by annual influenza vaccination, with efforts underway to develop new vaccines with improved effectiveness. Sporadic zoonotic infections with novel influenza A viruses of avian or swine origin continue to pose pandemic threats. In this Seminar, we discuss updates of key influenza issues for clinicians, in particular epidemiology, virology, and pathogenesis, diagnostic testing including multiplex assays that detect influenza viruses and SARS-CoV-2, complications, antiviral treatment, influenza vaccines, infection prevention, and non-pharmaceutical interventions, and highlight gaps in clinical management and priorities for clinical research.

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Timothy M Uyeki, David S Hui, Maria Zambon, David E Wentworth, Arnold S Monto Annual seasonal influenza epidemics of variable severity caused by influenza A and B virus infections result in substantial disease burden worldwide. Seasonal influenza virus circulation declined markedly in 2020-21 after SARS-CoV-2 emerged but increased in 2021-22.

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130 QSM Home NIV (Bi-level)  CPAP devices

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Talking Point is a programme of monthly get togethers to discuss particular topics.

The idea behind the initiative is to share knowledge within the Trust and to promote discussion.

The sessions are open to all Trust staff and there is no need to book a place.

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We know that there can be a lot to take in when you visit the hospital so our services produce helpful information leaflets that you can download and read in your own time.

Our patient information leaflets are listed below. You can also use the search function to find the leaflet you are looking for. Simply search for a service or key word.

If you would like the information in another language, please use BrowseAloud™ by clicking on the symbol on your screen.

BrowseAloud™will translate text on the webpage into other languages. Browsealoud will also read the text aloud in the required language and you can download it as an MP3 file.

Please be aware that Browsealoud may not always translate accurately.

If you would like information in large print please ask the department that you are attending.

If you can't find an information leaflet the service or condition you're looking for, please let the service know so that we can add make this available for you and other patients.

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We know that there can be a lot to take in when you visit the hospital so our services produce helpful information leaflets that you can download and read in your own time. Our patient information leaflets are listed below. You can also use the search function to find the leaflet you are looking for.

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Acta Paediatrica - 2022 - Lewis - Clinical trials and outcome reporting in congenital diaphragmatic hernia overlook

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Reducing the environmental impact of asthma inhalers  FAQs and resources

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Duration of amoxicillin-clavulanate for protracted bacterial bronchitis in children 

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Pseudomonas in non-CF patients: when to treat

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Pseudomonas in non-CF patients: when to treat

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Currently there’s no cure for rare types of cystic fibrosis, but researchers are making advances

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We still don't really know why children have been less affected by CV19

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Abstract

Context

In contrast with other respiratory viruses, children infected with SARS-CoV-2 are largely spared from severe COVID-19.

Objectives

To critically assess age-related differences in three host proteins involved in SARS-CoV-2 cellular entry: angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2) and furin.

Methods

We systematically searched Medline, Embase, and PubMed databases for relevant publications. Studies were eligible if they evaluated ACE2, TMPRSS2 or furin expression, methylation, or protein level in children.

Results

Sixteen papers were included. Age-dependent differences in membrane-bound and soluble ACE2 were shown in several studies, with ACE2 expression increasing with age. TMPRSS2 and furin are key proteases involved in SARS-CoV-2 spike protein cleavage. TMPRSS2 expression is increased by circulating androgens and is thus low in pre-pubertal children. Furin has not currently been well researched.

Limitations

High levels of study heterogeneity.

Conclusions

Low expression of key host proteins may partially explain the reduced incidence of severe COVID-19 among children, although further research is needed.

Recommended articles Citing articles (0)
View Abstract

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Age-related differences in SARS-CoV-2 binding factors: an explanation for reduced susceptibility to severe COVID-19 among children?

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In contrast with other respiratory viruses, children infected with SARS-CoV-2 are largely spared from severe COVID-19. To critically assess age-related differences in three host proteins involved in SARS-CoV-2 cellular entry: angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2) and furin. We systematically searched Medline, Embase, and PubMed databases for relevant publications.

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Feel free to discuss and comment on the journals below

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Objective To compare the effects of switching from a pressurised metered dose inhaler (pMDI)-based to a dry powder inhaler (DPI)-based maintenance therapy versus continued usual care on greenhouse gas emissions (carbon dioxide equivalents, CO ₂ e) and asthma control.

Methods This post-hoc analysis was based on a subset of 2236 (53%) patients from the Salford Lung Study in Asthma who at baseline were using a pMDI-based controller therapy. During the study patients were randomised to fluticasone furoate/vilanterol (FF/VI) via the ELLIPTA DPI (switched from pMDI to DPI) (n=1081) or continued their usual care treatment (n=1155), and were managed in conditions close to everyday clinical practice. Annual CO ₂ e (kg) was calculated for the total number of maintenance and rescue inhalers prescribed. Asthma control was assessed by the proportion of ACT responders (composite of ACT total score ≥20 and/or increase from baseline ≥3).

Results The groups were well matched for demographic characteristics and baseline Asthma Control Test (ACT) total score (mean age: 49 years; mean ACT score: usual care, 16.6; FF/VI, 16.5). Annual CO ₂ e kg per patient (maintenance plus rescue therapy) was significantly lower with FF/VI DPI treatment ('switch' group) than usual care (least squares geometric mean 108 kg (95% CI 102 to 114) vs 240 kg (95% CI 229 to 252), p<0.001). Asthma control was consistently superior over the 12 months in the FF/VI DPI group compared with usual care.

Conclusions Patients switching from a pMDI-based to a DPI-based maintenance therapy more than halved their inhaler carbon footprint without loss of asthma control. The remaining inhaler carbon footprint could be reduced through switches from pMDI to DPI rescue medications or alternative lower-carbon footprint rescue inhalers if available. Asthma control improved in both groups, with greater control demonstrated in those initiated on FF/VI DPI.

What is the key question?

Under conditions close to routine clinical practice, what are the effects of switching from a pressurised metered dose inhaler (pMDI)-based to a dry powder inhaler (DPI)-based maintenance therapy versus continued usual care on greenhouse gas emissions (carbon dioxide equivalents) and asthma control?

What is the bottom line?

Study design and study population

Full details of the study design and results for the primary study have been published previously. 20 21 In brief, the study was a 12-month, open-label, primary care study in which adults with symptomatic asthma who were taking regular maintenance therapy (inhaled corticosteroids (ICS) or ICS/long-acting beta-agonist) were randomised to either a combination of fluticasone furoate/vilanterol (FF/VI) via the ELLIPTA DPI or to continue their usual care as prescribed by their general practitioner. For this post-hoc analysis, all patients who used a pMDI-based controller therapy prior to screening and randomisation were the subset of interest. At the randomisation visit, the study staff trained patients in both treatment groups to follow the correct inhaler techniques. During the 1-year treatment period, patients could have their maintenance treatment adjusted, including dose or inhaler type, at the physician's discretion; that is, they were managed in conditions close to normal everyday clinical practice with no additional prompts or reminders to encourage adherence. The groups included in this analysis were based on the treatment at randomisation.

The study also measured the clinical outcomes of asthma control and rescue medication use. Asthma control was assessed using the Asthma Control Test (ACT) 22 at baseline and at 12, 24, 40 and 52 weeks of treatment. Rescue medication use was measured as the total number of salbutamol inhalers prescribed over the whole treatment period.

Carbon footprint analysis

Total carbon footprint over 12 months was calculated separately for the total number of maintenance and rescue therapy inhalers prescribed during the study, using previously published carbon footprint data expressed as carbon dioxide equivalents (CO ₂e kg), 5 11 summarised in table 1. For each subject, the total CO ₂e of each inhaler was calculated as the following: (number of inhalers prescribed) × (CO ₂e per inhaler), where the CO ₂e per inhaler was adjusted for the number of actuations in each inhaler, according to inhaler category ( table 1). Within the primary study, there were a wealth of inhalers prescribed in the usual care arm, and given the data came from patients' medical records it could not always be made certain which inhaler type the treatment was contained in. A medical expert review was performed on the prescription data to determine which inhaler the treatments were associated with based on dose, frequency of inhalation, total number of actuations, etc, and they determined which were in DPI, metered dose inhaler (MDI) or undeterminable. The inhalers were then associated to one of the CO ₂e categories listed in table 1 and adjusted based on the total number of actuations. For example, if the inhaler had 60 actuations and the category it was associated with was one based on 200 actuations, the inhaler was adjusted to a lower level of carbon emission, as less actuations result in lower levels of emission.

There was no imputation for missing data. Instead, this emission was adjusted for the subjects' time on study medication, so it corresponded to 12 months on treatment. This approach was taken due to the real-world nature of the study as participants could have ended treatment before or after 12 months of study duration. Treatment groups were compared using a generalised linear model (GLM) assuming a log-normal distribution and by implementing an identity link function adjusting for randomised treatment, age, gender, and both ACT total score and asthma maintenance therapy at baseline per randomisation stratification. The carbon footprint data were analysed on the log scale, and the least square (LS) means of the treatment effects were computed from the GLM. The LS treatment means and 95% CI results on the log scale were back-transformed via the exponential to obtain least squares geometric means (LS GM) and 95% CI for the results to be interpretable on the original scale. Similarly, for the log difference between the LS treatment means and 95% CI, the results were back-transformed via the exponential to obtain the ratio of the LS GM and 95% CI.

Clinical outcomes analysis

Treatment differences in the percentage of patients defined as an ACT responder (an ACT total score ≥20 and/or an increase from baseline in ACT total score of ≥3 23 24) were analysed using a logistic regression model for all assessment time points (weeks 12, 24, 40 and 52). The model was adjusted for randomised treatment, asthma maintenance therapy at baseline (per randomisation stratification), baseline ACT total score, baseline ACT total score squared, gender and age. The time point for the primary analysis was 24 weeks. Changes from baseline in ACT total score were analysed via a mixed model repeated measures assuming an unstructured covariance matrix and adjusted for randomised treatment, asthma maintenance therapy at baseline per randomisation stratification, baseline ACT total score, randomised treatment by baseline ACT total score interaction, gender, age, visit, and randomised treatment by visit interaction, with visit included as a repeated measures factor. The number of salbutamol inhalers (adjusted to an equivalence of 200 actuations) prescribed per patient over the 12-month treatment period was analysed using an analysis of covariance model adjusted for randomised treatment, asthma maintenance therapy at baseline per randomisation stratification, ACT total score at baseline per randomisation stratification, gender, age and number of salbutamol inhalers prescribed in the year prior to randomisation.

Patient and public involvement

For this post-hoc analysis, the authors had no direct contact information of the study participants because anonymised data were used in accordance with strict confidentiality guidelines. Therefore, it was not appropriate for any patient to have involvement in developing the hypothesis, specific aims, research questions or plans for the study's design or implementation. No patient was involved in the interpretation or writing of the results. There are no plans to disseminate the results of this study to the individual study participants.

Analysis groups and treatment pathways

We studied patients from the Salford Lung Study in Asthma taking MDI-based controller therapy prior to randomisation. This subset of patients (2236 of 4233, 53%) comprised 1155 and 1081 patients randomised to the usual care and FF/VI DPI groups, respectively. The groups were well matched for demographic characteristics and baseline ACT total score (mean age: 49 years; mean ACT score: usual care, 16.6; FF/VI, 16.5) ( table 2). During this real-world study, patients were able to shift from FF/VI DPI to usual therapy as per normal clinical practice, and on usual therapy some patients switched to DPI controller medications (not FF/VI which was not permitted). Over 1 year, the majority of patients in each group remained on the same inhaler type, that is, 80% remained on a pMDI in the usual care group and 85% remained on a DPI in the FF/VI group ( table 3). The analysis was based on the prescribed treatment.

Carbon footprint

Over the 12-month treatment period, the LS GM total carbon footprint (maintenance plus rescue therapy) was more than halved in patients taking FF/VI (108 kg, 95% CI 102 to 114) ('switch' group) compared with those continuing usual care treatment (240 kg, 95% CI 229 to 252; LS GM ratio usual care vs FF/VI 2.23, 95% CI 2.08 to 2.39, p<0.001) ( figure 1 and table 4). The carbon footprint of maintenance therapy alone was 10-fold lower for FF/VI compared with usual care (LS GM 118 kg (95% CI 112 to 125) vs 11 kg (95% CI 10 to 12) for usual care and FF/VI groups, respectively; LS GM ratio of 10.65 (95% CI 9.86 to 11.50), p<0.001). The amount of rescue medication (almost all salbutamol MDIs) was also lower in the FF/VI group (LS GM 88 kg (95% CI 82 to 93) vs 109 kg (95% CI 103 to 116), respectively; LS GM ratio usual care vs FF/VI of 1.25 (95% CI 1.15 to 1.35), p<0.001).

The data for the carbon footprint analyses demonstrated variable levels of skewness and kurtosis. The quantile-quantile plots of the residuals showed adequate evidence of normality for the combined and rescue inhaler analyses; however, the maintenance alone analysis showed some evidence of kurtosis, indicating inferences should be interpreted with caution in this group.

Clinical outcomes

Asthma control improved in both treatment arms ( table 5). At week 24, the odds of being an ACT responder (ACT total score of ≥20 and/or an increase from baseline of ≥3) in the FF/VI group (76%) were approximately twice that of being a responder in the usual care group (63%) (adjusted OR: 1.91 (95% CI 1.57 to 2.33), p<0.001), and this difference was consistent over the 12-month treatment period ( figure 2). Patients who switched to FF/VI were prescribed approximately one fewer salbutamol inhalers over the 12-month treatment period compared with those who continued on usual care (LS mean of 7.2 vs 8, respectively).

Patient consent for publication

Not required.

Ethics approval

The Salford Lung Study in Asthma involved human participants and was approved by the National Research Ethics Service Committee North West, Greater Manchester South (reference 12/NW/0455; IRAS ID 106072). Participants gave informed consent to participate in the study before taking part.

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Effects of switching from a metered dose inhaler to a dry powder inhaler on climate emissions and asthma control: post-hoc analysis

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Objective To compare the effects of switching from a pressurised metered dose inhaler (pMDI)-based to a dry powder inhaler (DPI)-based maintenance therapy versus continued usual care on greenhouse gas emissions (carbon dioxide equivalents, CO2e) and asthma control.

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Second hand vape exposure and respiratory symptoms

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Rationale Despite high prevalence of e-cigarette use (vaping), little is currently known regarding the health effects of secondhand nicotine vape exposure.

Objective To investigate whether exposure to secondhand nicotine vape exposure is associated with adverse respiratory health symptoms among young adults.

Method We investigated the effect of secondhand nicotine vape exposure on annually reported wheeze, bronchitic symptoms and shortness of breath in the prospective Southern California Children Health Study cohort. Data were collected from study participants (n=2097) with repeated annual surveys from 2014 (average age: 17.3 years) to 2019 (average age: 21.9). We used mixed effect logistic regression to evaluate the association between secondhand nicotine vape and respiratory symptoms after controlling for relevant confounders.

Results Prevalence of secondhand nicotine vape increased from 11.7% to 15.6% during the study period in this population. Prevalence of wheeze, bronchitic symptoms and shortness of breath ranged from 12.3% to 14.9%, 19.4% to 26.0% and 16.5% to 18.1%, respectively, during the study period. Associations of secondhand nicotine vape exposure with bronchitic symptoms (OR 1.40, 95% CI 1.06 to 1.84) and shortness of breath (OR 1.53, 95% CI 1.06 to 2.21) were observed after controlling for vaping, active and passive exposure to tobacco or cannabis, and demographic characteristics (age, gender, race/ethnicity and parental education). Stronger associations were observed when analysis was restricted to participants who were neither smokers nor vapers. There were no associations with wheezing after adjustment for confounders.

Conclusion Secondhand nicotine vape exposure was associated with increased risk of bronchitic symptoms and shortness of breath among young adults.

Study design

A baseline (wave 1) population of 2097, 11-12th grade Children Health Study participants (mean age 17.3 years, SD 0.6 years), were enrolled in this study from a cohort from schools throughout Southern California. 15 Detailed exposure and health data were collected using self-completed paper questionnaires in classrooms for wave 1 and online using research electronic data capture (REDCap) 16 tools hosted at the University of Southern California across three additional waves of follow-up through 2019. The current analysis was limited to 2090 participants who provided data on secondhand nicotine vape exposure in at least one of the four waves. The total number of participants was 2090 in wave 1 (year 2014), 1609 in wave 2 (year 2015), 1502 in wave 3 (year 2017) and 1637 (78.3% of the original sample) in wave 4 (year 2018). An initial loss of 481 participants (23%) in wave 2 occurred during the transition from classroom to online collection after completing high school, some of whom participated in later follow-up. Those who were lost to follow-up at wave- 2 were more likely to be male, Hispanic whites and parents not having any college education, compared with those who remained in the study ( online supplemental table S1). The prevalence of secondhand nicotine vape exposure, bronchitic symptoms and wheeze did not differ substantially between those who were lost to follow-up in wave 2 and those who remained at wave 2. Additional description of the cohort has been reported previously. 15 17

Sociodemographic information

Information was available on participants' gender, ethnicity (Hispanic white, non-Hispanic white, Asian, African American and other (ie, Pacific Islander, native American/Alaska Native, multiracial or not defined)), and highest parental educational level, as previously described. 15

Statistical analysis

Mixed effect logistic regression models were used to evaluate the association between secondhand nicotine vape exposure in each wave and each respiratory symptom (bronchitic symptoms, wheeze and shortness of breath) in that wave. All models included a participant-level intercept (random effect) to account for multiple observations over time, with adjustment (fixed effect) for sex, race/ethnicity, baseline age and parental education. All models were additionally adjusted for primary vaping or smoking and secondhand smoking/secondhand cannabis exposure. To assess the impact of the timing of exposure, we also fitted a model containing a four-level categorical exposure variable based on the joint distribution of 1-year lagged and current secondhand nicotine vape exposure: no secondhand nicotine vape exposure in the previous and current year (reference group), secondhand nicotine vape exposure in previous year only, secondhand nicotine vape exposure in current year only and secondhand nicotine vape exposure in both previous and current year. As sensitivity analyses, we additionally restricted the sample to participants (1) without primary vaping or smoking, (2) who were not lost to follow-up in wave 2 and (3) who reported no history of physician diagnosed asthma at wave 1. Statistical analyses were conducted using SAS V.9.4 (SAS Institute).

Study population

Among the 2090 study participants, about half were Hispanic white (51.8%) and male (50.4%; table 1). The distribution of the demographic factors of participants with respiratory symptoms was largely similar to that of the overall population, except that participants with shortness of breath were more likely to be female (shortness of breath participants: 70.2% female versus non-shortness of breath participants: 43.4% female, p<0.01).

Prevalence of vaping and smoking exposure

The prevalence of secondhand nicotine vape exposure increased from 11.7% to 15.6% from wave 1 to wave 4 in the study population ( figure 1), while the prevalence of secondhand smoking decreased from 26.6% to 20.6%. Past 30-day use of cigarettes, e-cigarettes and cannabis (wave 3 to wave 4) increased over the study period. None of those changes were statistically significant except for the observed increase of primary vaping or smoking from 12.1% in wave 1 to 34.0% in wave 4 (p<0.001).

A majority of the participants (76.0%-93.1%) who had secondhand nicotine vape exposure during any of the study waves was also likely to have personal use of tobacco or cannabis products or secondhand exposure to combustible products ( online supplemental table S2). For example, during wave 4, out of the participants who reported secondhand nicotine vape (n=223), only 6.9% had no other vaping or smoking related exposures, while 11.5% had primary vaping or smoking, but no secondhand smoking exposure, 33.2% had secondhand smoking, but no primary vaping or smoking exposure, and 48.4% had both secondhand smoking and primary vaping or smoking exposure.

Discussion

To our knowledge, this is the first report of effects of secondhand nicotine vape exposure on respiratory symptoms among adolescents and young adults from a prospective study. We show associations of exposure to secondhand nicotine vape with bronchitic symptoms and shortness of breath, after controlling for sociodemographic characteristics, past 30-day active vaping and smoking of tobacco or cannabis products, and secondhand cigarette or cannabis smoke exposure. These results have important public health implications for the population exposed to secondhand nicotine vape. Unlike active vaping and smoking, secondhand nicotine vape exposure is not a voluntary exposure. Therefore, if the associations we observed are causal, prohibiting e-cigarette use in public places is warranted, just as secondhand tobacco smoke exposure has been prohibited in public spaces for decades, and reducing use indoors would reduce the burden of respiratory illness in the households of e-cigarette users. Further epidemiological study is needed to assess the replicability and generalisability of these findings to other age groups. Experimental studies are needed to help determine whether the effects are causal.

secondhand nicotine vape exposure reported at the time of symptom reporting was associated with statistically significant 40% greater odds of bronchitic symptoms and 53% greater odds of shortness of breath, but not with wheeze, compared with individuals with no currently reported secondhand nicotine vape exposure, after controlling for confounders and coexposures. Because this is the first study of effects of secondhand nicotine vape exposure on wheeze, bronchitic symptoms and shortness of breath, we cannot directly compare our results to previous findings. The observed association between secondhand nicotine vape exposure and wheeze (OR 1.21, 95% CI 0.84 to 1.72) in the current study was similar to the association between secondhand nicotine vape exposure and asthma exacerbation in a recent cross-sectional study (OR 1.27, 95% CI 1.11 to 2.47). 3 The estimated effects of secondhand nicotine vape exposure on bronchitic symptoms in this study were similar in magnitude to those of secondhand smoking. For example, in a recent study of bronchitic symptoms among Chinese adolescents, the OR for secondhand smoking, compared with adolescents with no secondhand smoking exposure, was 1.53 (95% CI 1.25 to 1.87). 19 Bronchitic symptoms are a response to irritant exposures such as secondhand smoking, active smoking and ambient particulate matter, among others.

Increased risk of shortness of breath has also been associated with secondhand smoking. 20 The interpretation of shortness of breath associated with secondhand nicotine vape exposure is not clear, but shortness of breath is a central feature of bronchiolitis obliterans that has been reported in workers heavily exposed to diacetyl and 2, 3-pentanedione, which are flavourings that have also been measured in e-cigarette liquids. 9 13 21-24 There is a growing body of evidence that vaping is associated with a number of pulmonary diseases, including bronchiolitis obliterans, 25 acute respiratory distress syndrome 26 and acute eosinophilic pneumonia. 27 A recently published report described a case of hypersensitivity pneumonitis with secondhand nicotine vape exposure. 28 While only 3 years of data were collected in the current analysis to assess the effect of secondhand nicotine vape exposure on shortness of breath, the observed associations were both moderately strong and robust to confounders. Further study is warranted to determine potential causes of shortness of breath associated with secondhand nicotine vape exposure.

Many study participants with secondhand nicotine vape exposure were also exposed to a variety of other tobacco and cannabis products ( online supplemental table S2). Disentangling the effect of secondhand nicotine vape exposure on respiratory symptoms from effects of other products was challenging. However, the models provided stable estimates of secondhand nicotine vape effects after adjustment for coexposures. We also observed stronger effects of secondhand nicotine vape exposure on respiratory symptoms among study participants who reported no past 30-day use of e-cigarette or combustible products (comparing table 3, sensitivity analysis 1 with table 2, model 2).

A potential explanation for the observed association between secondhand nicotine vape exposure and respiratory symptoms is selection bias due to the lost to follow-up of 481 participants following high-school graduation (at wave 2). However, those who remained in the study at wave 2 and those who were lost to follow-up had similar secondhand nicotine vape exposure and respiratory symptoms ( online supplemental table S1). There were some modest differences in sociodemographic characteristics between those retained and those lost to follow-up, but all analyses were adjusted for those factors. Furthermore, secondhand nicotine vape exposure effect estimates in analyses restricted to participants not lost to follow-up at wave-2 ( table 3, model 2) were similar to the estimates in the entire population ( table 2). Therefore, selection bias is not likely to explain the associations with secondhand nicotine vape exposure we observed.

We also assessed whether the associations between secondhand nicotine vape exposure and respiratory symptoms were due to secondhand nicotine vape exposure induced asthma exacerbation. 3 However, when we restricted the analysis to participants without any history of asthma at study entry, the secondhand nicotine vape exposure effect estimates ( table 3, sensitivity analysis 3) were similar to effects in the entire sample ( table 2, model 2). Asthma status of the subjects did not substantially affect the effect estimates observed between secondhand nicotine vape exposure and the respiratory outcomes ( online supplemental table S4).

Measurement error due to self-reported exposure and respiratory outcomes could have occurred. Because respiratory health outcomes were reported for last 12 months, it is possible that the participants under-reported symptoms occurring many months back. Exposure misclassification was likely to be small as exposure was assessed for the previous 30 days and seems unlikely to have been substantially differential with respect to outcome that could have biased the estimated effects of exposure.

Patient consent for publication

Not applicable.

Ethics approval

This study was approved by the institutional review board of the University of Southern California (HS-18-00706). Written informed consent was obtained for all participants prior to data collection.

# data[].attributes.attachment_link.title
Secondhand nicotine vaping at home and respiratory symptoms in young adults

# data[].attributes.attachment_link.description
Rationale Despite high prevalence of e-cigarette use (vaping), little is currently known regarding the health effects of secondhand nicotine vape exposure. Objective To investigate whether exposure to secondhand nicotine vape exposure is associated with adverse respiratory health symptoms among young adults.

# data[].attributes.body
Echinococcosis — Review of current diagnosis and management

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ScienceDirect.com | Science, health and medical journals, full text articles and books.

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ScienceDirect is the world's leading source for scientific, technical, and medical research. Explore journals, books and articles.

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Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3

# data[].attributes.body
The introduction of nusinersin results in reduction in the decline of lung function, seen most prominently in Type 2. Nearly all Type 1 SMA children required NIV.

# data[].attributes.attachment_link.readable_text
Abstract

Introduction Nusinersen is used in spinal muscular atrophy (SMA) to improve peripheral muscle function; however, respiratory effects are largely unknown.

Aim To assess the effects of nusinersen on respiratory function in paediatric SMA during first year of treatment.

Methods A prospective observational study in paediatric patients with SMA who began receiving nusinersen in Queensland, Australia, from June 2018 to December 2019. Outcomes assessed were the age-appropriate respiratory investigations: spirometry, oscillometry, sniff nasal inspiratory pressure, mean inspiratory pressure, mean expiratory pressure, lung clearance index, as well as polysomnography (PSG) and muscle function testing. Lung function was collected retrospectively for up to 2 years prior to nusinersen initiation. Change in lung function was assessed using mixed effects linear regression models, while PSG and muscle function were compared using the Wilcoxon signed-rank test.

Results Twenty-eight patients (15 male, aged 0.08-18.58 years) were enrolled: type 1 (n=7); type 2 (n=12); type 3 (n=9). The annual rate of decline in FVC z-score prior to nusinersen initiation was −0.58 (95% CI −0.75 to −0.41), and post initiation was −0.25 (95% CI −0.46 to −0.03), with a significant difference in rate of decline (0.33 (95% CI 0.02 to 0.66) (p=0.04)). Most lung function measures were largely unchanged in the year post nusinersen initiation. The total Apnoea-Hypopnoea Index (AHI) was reduced from a median of 5.5 events/hour (IQR 2.1-10.1) at initiation to 2.7 events/hour (IQR 0.7-5.3) after 1 year (p=0.02). All SMA type 1% and 75% of SMA types 2 and 3 had pre-defined peripheral muscle response to nusinersen.

Conclusion The first year of nusinersen treatment saw reduced lung function decline (especially in type 2) and improvement in AHI.

paediatric physician

rare lung diseases

paediatric lung disaese

respiratory muscles

respiratory measurement

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Additional individual patient data are available in deidentified format on reasonable request.

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Key messages

What is the key question?

What is the bottom line?

Why read on?

Spinal muscular atrophy (SMA), especially SMA type 1, is no longer a palliative condition, and although not curative, nusinersen is now widely used to treat these children and pulmonary physicians should be aware of the real-world changes in respiratory function seen with treatment.

Introduction

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by deletion or mutation of the SMN1 gene which reduces full-length survival motor neuron (FL SMN) protein levels. The survival motor neuron 2 ( SMN2) gene produces FL SMN protein but more if it is in its truncated, non-functional isoform. Increased SMN2 copy numbers produce more functional FL SMN protein, leading to reduced disease severity; thus, the SMN2 gene has been the principal target for therapies. 1 Nusinersen is an antisense oligonucleotide that alters SMN2 splicing to favour expression of stable FL SMN protein. 2

Reduction in SMN protein levels leads to spinal anterior horn cell atrophy and subsequent lower motor neuron weakness. 1 SMA is classified into SMA types 0-4 depending on age of onset and the maximal motor milestone achieved. SMA type 0-3 comprise the paediatric forms: type 0 is lethal in the neonatal period; type 1 being the most severe infant form (survival <2 years old); survival into adolescence and adulthood is increasingly common with SMA type 2 with two thirds living through their mid-twenties and survival for type 3 is normal. SMA type 4 comprises of minor weakness in early adulthood. The cause of mortality in the severe phenotypes is predominantly due to respiratory complications. 3

However, the SMA disease phenotype and prognosis appears to be improving with disease-modifying medications. Nusinersen has documented short-term efficacy in SMA, improving peripheral muscle function (Nusinersen Versus Sham Control in Infantile-Onset SMA (ENDEAR trial); Nusinersen Versus Sham Control in Later-Onset SMA (CHERISH trial)) . 4 5 Event-free and overall survival improved in infants; effects on survival in older children are unknown (as there were no deaths in the CHERISH trial). 4 6 Greater benefits were seen in those treated early (with shorter disease duration). 5 Although there are limited longer term follow-up studies, early evidence suggests that initial improvements are maintained. 7 8 Nusinersen may reduce respiratory impairment, with improved survival and reduced need for respiratory support in infants. However, this has not been well characterised. Nusinersen treatment is demanding (regular intrathecal administration) and expensive, and long-term efficacy or respiratory outcomes are yet to be evaluated. As respiratory complications are the leading cause of morbidity and mortality, 9-11 it is imperative that treatment effects on respiratory function are characterised.

The aim of the present study was to assess the effect of nusinersen on respiratory function in a real-world population of children with SMA.

Methods

Study design and patients

A prospective, observational study of all children with SMA types 1-3 starting treatment with nusinersen at the Queensland Children's Hospital Brisbane (QCH), Australia, was conducted between June 2018 and December 2019. Catchment for this tertiary hospital includes all children in Queensland and northern New South Wales (population ~5 million). At enrolment, children had/were

1. Under 19 years of age.

2. Genetically confirmed homozygous SMN1 gene alteration.

3. Clinical features of SMA.

4. Receiving specialist care at QCH.

5. Nusinersen naïve.

Children were not excluded if they required either invasive or non-invasive ventilation (NIV), or unable to perform lung function.

Study exclusion criteria are as follows:

1. Lack of consent/assent.

2. Unwell or unable to receive doses of nusinersen within reasonable proximity to scheduled dosing.

The parents of all children gave written informed consent. Research was funded by Biogen Global as an investigator-initiated project.

Clinical assessment

Retrospective review of medical records was undertaken for each participant recording demographic data, clinical deterioration events, including lower respiratory tract infections or initiation of NIV in the 2 years prior to nusinersen initiation. All pulmonary function tests (PFTs) performed in the 2 years prior to nusinersen initiation were extracted. Usual clinical management continued throughout the study period with admissions, NIV initiation, surgery and survival noted prospectively during the 12-month follow-up period.

Children underwent peripheral muscle function assessments and lung function tests, timed to nusinersen dosing schedule (see table 1).

Study objectives

The primary objective is as follows:

To assess the effect of nusinersen on respiratory function (with lung function testing and PSG) in children with type 1, 2 and 3 SMA starting on nusinersen.

The secondary objectives are as follows:

1. To establish if there was a relationship between respiratory muscle function and peripheral muscle function.

2. To establish if there was a respiratory muscle function response in peripheral muscle function non-responders.

3. To establish if there was an effect in children with SMA type 3, where the clinical evidence for treatment is limited.

Pulmonary function tests

A qualified paediatric respiratory scientist conducted PFT according to the American Thoracic Society and European Respiratory Society Technical Statement. 12 Multiple modalities were used to evaluate respiratory function, depending on age and cooperation of the child. Tests included spirometry for FVC, oscillometry (Osc) (respiratory reactance at 8 Hz (Xrs8), respiratory resistance at 8 Hz (Rrs8)), peak cough flow (PCF), sniff nasal inspiratory pressure (SNIP), mean inspiratory pressure (MIP)/mean expiratory pressure (MEP) and multiple breath washout (lung clearance index (LCI), functional residual capacity (FRC)). Raw scores, percent predicted or z-scores were reported. Both measures of lung function are reported to allow comparison with previous literature.

See online supplemental 1 for details on testing procedures.

Polysomnography

Children underwent level 1 diagnostic PSG. Those treated with NIV had a diagnostic component (priori duration set-study start to end of two rapid eye movement (REM) stage sleep cycles) with NIV removed during PSG (split study). Only diagnostic component was used for analysis and for determining the relationships with lung function and peripheral muscle function. PSG was performed in QCH paediatric sleep laboratory using EMBLA (N7000, Natus Neuro, Middleton, Wisconsin, USA) equipment and attended by trained paediatric sleep nurses (see online supplemental 1 for details on the PSG set-up). For study purposes, two experienced paediatric sleep physicians scored each PSG from raw data independently. The PSG was scored using the American Academy of Sleep Medicine (AASM) V.2.6 (see further details in online supplemental 1) paediatric criteria. 13

PSG was evaluated for sleep-disordered breathing (SDB), obstructive (OSA), central (CSA) and mixed sleep apnoea and hypoventilation. To avoid misclassification, an obstructive hypopnea was scored if they met the AASM 2020 criteria for an obstructive hypopnoea and the following were also present in the setting of muscle weakness 14:

Increasing phase difference between chest and abdominal movements; or

Stable/increasing submental EMG (particularly at end of the event); or

Phasic diaphragmatic EMG activity.

Peripheral muscle function

Qualified paediatric neuromuscular physiotherapists tested peripheral muscle function using tests validated in SMA 15-18: the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND (type 1)) 16; Hammersmith Functional Motor Scale-Expanded (HFMSE (types 2 and 3)) 17 or Revised Upper Limb Module (RULM) for SMA (types 2 and 3) 18 were used at discretion of the physiotherapist depending on baseline peripheral muscle function (see online supplemental 1 for details on muscle function test scoring). Definition used for motor response was adopted from CHERISH and ENDEAR trials 4 5:

CHOP INTEND score increase of at least four points from baseline.

HFMSE score increase of at least three points from baseline.

Any increase in RULM from baseline.

Sample size

OSc values were used for priori sample size justification, as many children are too young to perform spirometry. In a previously published case series involving 12 children with SMA type 2 who were followed up for a 12-month period, the mean rate of change of Rsr8 was 0.51 z-scores per year, with SD=0.83. 19 To reject the null hypothesis that there is no change over the 12-month study period, assuming alpha=0.05 and the mean (SD) change=0.51 (0.83) z-scores, then 12-month follow-up data were required on 14 participants.

Statistical analysis

Descriptive statistics for continuous data are reported as either mean (SD), median (IQR) or median (range) as appropriate, or as frequency (percentage (%)) for categorical data. The primary outcome, change in FVC z-score, was assessed using a linear spline with a knot at day 0 of treatment. Linear splines assume the change in FVC z-score is constant in the 2 years prior to treatment initiation, and, separately, constant in the 1 year post initiation, and that the two linear segments are constrained to have the same value at the knot. The model was calculated using mixed effects to account for the repeated measures on some children; time since initiation was entered as the fixed effect and participant was entered as the random effect. Results are reported as mean difference (MD) and 95% CI. Assumptions underlying linear regression models were tested and confirmed.

To test the difference in lung function and AHI total score for muscle responder and non-responder group and to test the difference in sleep events by SMA type between treatment initiation and 12-month follow-up, we used Mann-Whitney test.

Bland-Altman agreement methods were used to assess agreement between sleep events scoring from the two paediatric sleep physicians who scored each participant's PSG. Inter-rater agreement is reported as 95% limits of agreement (LOA).

For all analyses, statistical significance was determined at the 0.05 level. All analyses were conducted using Stata/SE V.16.1 (StataCorp LLC, College Station, Texas, USA).

Results

During the study period, QCH had 30 patients start nusinersen. Twenty-eight patients were enrolled with SMA type 1 (n=7), type 2 (n=12) and type 3 (n=9). Two siblings with SMA type 2 were not approached due to severe social disharmony. Follow-up data at 12 months were available for 27/28 patients: one participant with SMA type 1 died shortly after the start of nusinersen, her parents had declined use of NIV and opted for palliative comfort care but continued nusinersen. She was excluded from analyses as no follow-up PSG or PFT was obtained. One patient with SMA type 3 underwent scoliosis surgery shortly after the start of the study and was excluded from further statistical analysis due to the potential effects of spinal surgery on lung function (26/28 remaining for statistical analysis).

Rate of lung function decline

The combined rate of annual decline in FVC z-score in the 2 years prior to the start of nusinersen was −0.58 (95% CI −0.75 to −0.41) compared with −0.25 (95% CI −0.46 to −0.03) in the year post initiation, with a significantly slower rate of annual decline of 0.33 (95% CI 0.02 to 0.66); p=0.04 (see table 4). When analysed by SMA type, rates of decline were similar for types 2 and 3 prior to nusinersen initiation, but post initiation, the decreased in the rate of decline was particularly marked in children with SMA type 2. A similar finding was observed for percent predicted FVC. Rates of decline for Osc, MIP, MEP and SNIP variables during first year of treatment only (due to limited pre-study data) are listed in online supplemental table 1.

Polysomnography

There was agreement in the scoring between the two sleep physicians (total AHI (95% LOA 0-1)). Total and REM stage AHI and central apnoea index improved at both a clinically and statistically significant level in SMA type 1 ( figure 1). The median AHI reduced from 4.4 (IQR 0.8-8.3) at nusinersen initiation to 3.4 (IQR 1.3-6.3) after 1 year (p=0.04). Total and REM stage minimum recorded oxygen saturations made a clinically meaningful improvement both for the total cohort and children with type 1 SMA. Changes in sleep study variables are summarised in online supplemental table 1. There was no association observed between AHI and age (0.26 (−0.19, 0.71)) (p=0.25).

Association between respiratory and PSG assessments and muscle response to nusinersen

When participants were grouped according to whether or not they were peripheral muscle function responders, children who were responders had a greater reduction in total AHI and FVC z-score tended to improve. For the five participants considered as non-responders, AHI total tended to reduced in the year post nusinersen initiation, while FVC z-score increased ( online supplemental table 2).

Discussion

This study reports changes in lung function and PSG parameters in the first year of nusinersen treatment. These preliminary 'real world' findings show that nusinersen appears to stabilise respiratory function and improve SDB in children with SMA.

Decline in FVC prior to nusinersen initiation was reduced during the first year of treatment, particularly in type 2 SMA; however, these results must be treated cautiously due to the lack of precision (and consequently wide 95% CI) for some subanalyses. Comparison between retrospective spirometry data to prospective results was required due to lack of good quality published reference data and significant disease variability between individuals. Comparison was able to be made for the same patient in two different conditions (no treatment and nusinersen).

Previous spirometry literature in SMA types 2 and 3 is primarily reported as cross-sectional statistics. In earlier reports, SMA type 2 and 3 patients were pooled and reported retrospectively. Rates of FVC decline varied between −1.1% predicted per annum (pa) in children and adults 20 and −3.1% at 2 years and −2.95% at 3 years. 21 22 Children and young adults with SMA type 2 have a steeper decline (FVC of −3.3% to −9.8% pa) than SMA type 3 (−1.8% to −4.2% pa). 23 24 In addition to SMA type variation, there is a difference in median percent predicted FVC based on the continuum of patient phenotype (SMA subtypes), with poorest values noted in non-sitter SMA type 2 and higher values in ambulant SMA type 3. 25 Recently, the effect of age on lung function decline has been noted. FVC % predicted decline is most pronounced at younger ages, followed by a slower rate of decline or even stable course during adulthood in SMA types 2a and 3a, whereas FVC remained relatively stable in type 3b throughout life. 23 24 26 Annual decline of FVC % predicted has been reported between −0.23 and −1.32% from SMA type 3b to 2a. 26 Our pretreatment FVC decline is similar to that reported by Khirani et al. 23

The mechanisms for lung function response differences in SMA type 2 compared with type 3 include the following: (1) participants with type 3 had normal range at initiation, thus have less margin for improvement; (2) nusinersen may take longer to manifest in type 3 (as less severe disease); or (3) nusinersen response is less in type 3, although a biologically plausible explanation is elusive. Tendency to slower peripheral muscle function response in type 3 is reported, giving plausibility to the rationale for a lesser response in type 3 over the first 12 months of treatment. 8 22

The introduction of nusinersen was associated with a significant reduction in the rate of lung function decline. Nusinersen may have halted the expected progression of disease. Natural history would suggest ongoing decline. A lack of improvement in baseline lung function could be due to the chronic changes occurring in neuromuscular diseases. Reduction in chest wall muscle contraction leads to fibrotic, shortened and stiffened muscles, while reduced movement of chest wall results in articular contractures. Neither effect may be reversible. 27

Our results showed a treatment-related fall in resistance with trends towards improvement in reactance and increase in FRC. Again, limited published literature using Osc in SMA exists with none on rates of decline. 19 28 Current study group mean Osc z-scores at baseline suggest reduced lung volumes during tidal breathing, fitting with respiratory muscle weakness expected in SMA. Prior Osc studies in SMA showed that FRC reduces over time. 23 Our findings suggests increased lung volume during tidal breathing from improvement in respiratory muscle strength. SMA type 2 tended to have higher LCI values (more abnormal) than SMA type 3, similar to previous report. 28

SMA type 2 has lower baseline results for PCF, SNIP, MIP and MEP (MIP lower than MEP) compared with SMA type 3 19 23 25 due to weakness of intercostal muscles±diaphragmatic muscles. 29 30 Although mean annual SNIP percent predicted decline is similar between type 2 and type 3 (5.4% vs 6.4% respectively), the decline is later in type 3. 23 Lower values in SMA type 2 for PCF, SNIP, MIP and MEP were shown in our population with tendency for improvement with treatment in SMA type 3 for all values and SNIP in type 2. Results may be influenced by the imprecision due to the small sample (not all children were able to perform techniques). Also variability between tests is expected due to the large variation in the spectrum of peripheral muscle weakness seen in SMA and possibly differences in respiratory muscle function profiles. 30

This is the first study to show an improvement in SDB with nusinersen treatment. All SMA types have central and mixed SDB. 14 31 32 Our study showed improvements in central apnoea index, total AHI and oxygen saturation. Reduction in total AHI was largely attributed to reduction in REM stage AHI/central indices and not surprising since respiratory pump failure is pronounced in REM sleep. 33 AHI total reduction was greater in type 1 possibly due to known age-related reduction in AHI. 34 35 It may also be that type 2 or type 3 SMA eitherdid not have severe SDB at baseline so AHI reduction was less dramatic or as they had prolonged time between diagnosis and first dose of nusinersen, consequently, had reduced efficacy of respiratory muscle response to nusinersen. 4 Increased peripheral muscle response is shown with shorter disease duration. 5 No participants had hypoventilation 36 on PSG. Indications for NIV initiation were recurrent chest infections needing PICU admissions for continuous NIV or SDB, and thus, our centre is likely starting NIV early prior to signs of hypoventilation and raised TcCO ₂.

One participant death occurred after the start of nusinersen. The child's family elected against NIV, which likely impacted mortality risk. All other children with SMA type 1 started NIV following identification of SDB on initial sleep study or for recurrent chest infections requiring PICU admissions. This improved their survival when compared with historical mortality data 37 but in keeping with improved survival noted in ENDEAR trial and real-world Italian experience. 5 38

We were unable to assess whether peripheral muscle response was associated with a lung function or PSG change as a large proportion of children fit peripheral muscle response definition, making subgroup analysis difficult. A large group of responders suggested that the definition adopted from the ENDEAR/CHERISH trials (validated testing but subjective clinically meaningful change) 4 5 may not reflect objective changes seen with FVC and AHI measurements; or peripheral muscle function tests may not be sensitive enough to detect differences in respiratory muscle function over a short period of time. This may be especially true in slowly progressive subtypes, which have shown different trajectories based on ambulation and at different age groups. 21 22 39 Electrophysiological outcome measures (compound muscle action potential) may be more accurate and improve with nusinersen. 4 5 However, electrodiagnostic studies require considerable evaluator skill and participant discomfort, which is compounded by the young population of interest who may not cooperate. The present study attempted to use age-appropriate and disease relevant outcome measures 15 used in previous studies. The variety of scales used in the present study also made detecting changes within same SMA type difficult, but scales needed to be appropriate to child's age and level of function. No single scale spans across the entire paediatric age range.

The primary limitation of this study was the small sample size, due largely to the rarity of SMA. As a consequence, the effect estimates are often imprecise, and we have limited power to detect statistical differences for some subtype analyses. Although participants are a representative sample of children with SMA in Queensland, Australia, our findings may not generalise to patients elsewhere. Infant lung function was not measured, so lung function measurements were limited to older, cooperative children. At present, only one study has assessed the effect of nusinersen on infant lung function. 40 Trials in nusinersen have shown greater peripheral muscle function response in those treated early with shorter disease duration. 5 This may also be true for respiratory muscle function. However, as nusinersen was only widely introduced in Australia in 2018, most Queensland children with SMA type 2 and type 3 had a delay of 8-9 years before treatment. Retrospective collection of lung function data prior to nusinersen initiation is not ideal. However, as nusinersen is available and offered to all children in most countries, all future trials will likely involve children receiving a disease-modifying medication, so it is unethical to perform studies with a placebo group. Historical controls or retrospective data will need to be used. Lastly, the effect of SMN2 copy number was not assessed due to small numbers.

Conclusion

First year of nusinersen treatment led to reduction in lung function decline as measured by FVC z-scores and improvement in PSG (total AHI and central indices). Other lung function parameters remained largely stable. Larger, multicentre studies are needed to further characterise the effects of nusinersen on respiratory muscle function, especially in SMA type 3 where effects may be smaller or slower to respond.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Additional individual patient data are available in deidentified format on reasonable request.

Ethics statements

Patient consent for publication

Not required.

Ethics approval

The study was approved by Children's Health Queensland Ethical Committee (HREC/18/QRCH/90).

Acknowledgments

The authors would like to thank the patients and their families and the Neuromuscular Department at the Queensland Children's Hospital, Brisbane, Australia.

Supplementary materials

Supplementary Data

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# data[].attributes.attachment_link.title
Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3

# data[].attributes.attachment_link.description
Introduction Nusinersen is used in spinal muscular atrophy (SMA) to improve peripheral muscle function; however, respiratory effects are largely unknown. Aim To assess the effects of nusinersen on respiratory function in paediatric SMA during first year of treatment. Methods A prospective observational study in paediatric patients with SMA who began receiving nusinersen in Queensland, Australia, from June 2018 to December 2019.

# data[].attributes.attachment_caption
Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3

# data[].attributes.body
The introduction of nusinersin results in reduction in the decline of lung function, seen most prominently in Type 2. Nearly all Type 1 SMA children required NIV.

# data[].attributes.attachment_link.readable_text
Abstract

Introduction Nusinersen is used in spinal muscular atrophy (SMA) to improve peripheral muscle function; however, respiratory effects are largely unknown.

Aim To assess the effects of nusinersen on respiratory function in paediatric SMA during first year of treatment.

Methods A prospective observational study in paediatric patients with SMA who began receiving nusinersen in Queensland, Australia, from June 2018 to December 2019. Outcomes assessed were the age-appropriate respiratory investigations: spirometry, oscillometry, sniff nasal inspiratory pressure, mean inspiratory pressure, mean expiratory pressure, lung clearance index, as well as polysomnography (PSG) and muscle function testing. Lung function was collected retrospectively for up to 2 years prior to nusinersen initiation. Change in lung function was assessed using mixed effects linear regression models, while PSG and muscle function were compared using the Wilcoxon signed-rank test.

Results Twenty-eight patients (15 male, aged 0.08-18.58 years) were enrolled: type 1 (n=7); type 2 (n=12); type 3 (n=9). The annual rate of decline in FVC z-score prior to nusinersen initiation was −0.58 (95% CI −0.75 to −0.41), and post initiation was −0.25 (95% CI −0.46 to −0.03), with a significant difference in rate of decline (0.33 (95% CI 0.02 to 0.66) (p=0.04)). Most lung function measures were largely unchanged in the year post nusinersen initiation. The total Apnoea-Hypopnoea Index (AHI) was reduced from a median of 5.5 events/hour (IQR 2.1-10.1) at initiation to 2.7 events/hour (IQR 0.7-5.3) after 1 year (p=0.02). All SMA type 1% and 75% of SMA types 2 and 3 had pre-defined peripheral muscle response to nusinersen.

Conclusion The first year of nusinersen treatment saw reduced lung function decline (especially in type 2) and improvement in AHI.

paediatric physician

rare lung diseases

paediatric lung disaese

respiratory muscles

respiratory measurement

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Additional individual patient data are available in deidentified format on reasonable request.

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Key messages

What is the key question?

What is the bottom line?

Why read on?

Spinal muscular atrophy (SMA), especially SMA type 1, is no longer a palliative condition, and although not curative, nusinersen is now widely used to treat these children and pulmonary physicians should be aware of the real-world changes in respiratory function seen with treatment.

Introduction

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by deletion or mutation of the SMN1 gene which reduces full-length survival motor neuron (FL SMN) protein levels. The survival motor neuron 2 ( SMN2) gene produces FL SMN protein but more if it is in its truncated, non-functional isoform. Increased SMN2 copy numbers produce more functional FL SMN protein, leading to reduced disease severity; thus, the SMN2 gene has been the principal target for therapies. 1 Nusinersen is an antisense oligonucleotide that alters SMN2 splicing to favour expression of stable FL SMN protein. 2

Reduction in SMN protein levels leads to spinal anterior horn cell atrophy and subsequent lower motor neuron weakness. 1 SMA is classified into SMA types 0-4 depending on age of onset and the maximal motor milestone achieved. SMA type 0-3 comprise the paediatric forms: type 0 is lethal in the neonatal period; type 1 being the most severe infant form (survival <2 years old); survival into adolescence and adulthood is increasingly common with SMA type 2 with two thirds living through their mid-twenties and survival for type 3 is normal. SMA type 4 comprises of minor weakness in early adulthood. The cause of mortality in the severe phenotypes is predominantly due to respiratory complications. 3

However, the SMA disease phenotype and prognosis appears to be improving with disease-modifying medications. Nusinersen has documented short-term efficacy in SMA, improving peripheral muscle function (Nusinersen Versus Sham Control in Infantile-Onset SMA (ENDEAR trial); Nusinersen Versus Sham Control in Later-Onset SMA (CHERISH trial)) . 4 5 Event-free and overall survival improved in infants; effects on survival in older children are unknown (as there were no deaths in the CHERISH trial). 4 6 Greater benefits were seen in those treated early (with shorter disease duration). 5 Although there are limited longer term follow-up studies, early evidence suggests that initial improvements are maintained. 7 8 Nusinersen may reduce respiratory impairment, with improved survival and reduced need for respiratory support in infants. However, this has not been well characterised. Nusinersen treatment is demanding (regular intrathecal administration) and expensive, and long-term efficacy or respiratory outcomes are yet to be evaluated. As respiratory complications are the leading cause of morbidity and mortality, 9-11 it is imperative that treatment effects on respiratory function are characterised.

The aim of the present study was to assess the effect of nusinersen on respiratory function in a real-world population of children with SMA.

Methods

Study design and patients

A prospective, observational study of all children with SMA types 1-3 starting treatment with nusinersen at the Queensland Children's Hospital Brisbane (QCH), Australia, was conducted between June 2018 and December 2019. Catchment for this tertiary hospital includes all children in Queensland and northern New South Wales (population ~5 million). At enrolment, children had/were

1. Under 19 years of age.

2. Genetically confirmed homozygous SMN1 gene alteration.

3. Clinical features of SMA.

4. Receiving specialist care at QCH.

5. Nusinersen naïve.

Children were not excluded if they required either invasive or non-invasive ventilation (NIV), or unable to perform lung function.

Study exclusion criteria are as follows:

1. Lack of consent/assent.

2. Unwell or unable to receive doses of nusinersen within reasonable proximity to scheduled dosing.

The parents of all children gave written informed consent. Research was funded by Biogen Global as an investigator-initiated project.

Clinical assessment

Retrospective review of medical records was undertaken for each participant recording demographic data, clinical deterioration events, including lower respiratory tract infections or initiation of NIV in the 2 years prior to nusinersen initiation. All pulmonary function tests (PFTs) performed in the 2 years prior to nusinersen initiation were extracted. Usual clinical management continued throughout the study period with admissions, NIV initiation, surgery and survival noted prospectively during the 12-month follow-up period.

Children underwent peripheral muscle function assessments and lung function tests, timed to nusinersen dosing schedule (see table 1).

Study objectives

The primary objective is as follows:

To assess the effect of nusinersen on respiratory function (with lung function testing and PSG) in children with type 1, 2 and 3 SMA starting on nusinersen.

The secondary objectives are as follows:

1. To establish if there was a relationship between respiratory muscle function and peripheral muscle function.

2. To establish if there was a respiratory muscle function response in peripheral muscle function non-responders.

3. To establish if there was an effect in children with SMA type 3, where the clinical evidence for treatment is limited.

Pulmonary function tests

A qualified paediatric respiratory scientist conducted PFT according to the American Thoracic Society and European Respiratory Society Technical Statement. 12 Multiple modalities were used to evaluate respiratory function, depending on age and cooperation of the child. Tests included spirometry for FVC, oscillometry (Osc) (respiratory reactance at 8 Hz (Xrs8), respiratory resistance at 8 Hz (Rrs8)), peak cough flow (PCF), sniff nasal inspiratory pressure (SNIP), mean inspiratory pressure (MIP)/mean expiratory pressure (MEP) and multiple breath washout (lung clearance index (LCI), functional residual capacity (FRC)). Raw scores, percent predicted or z-scores were reported. Both measures of lung function are reported to allow comparison with previous literature.

See online supplemental 1 for details on testing procedures.

Polysomnography

Children underwent level 1 diagnostic PSG. Those treated with NIV had a diagnostic component (priori duration set-study start to end of two rapid eye movement (REM) stage sleep cycles) with NIV removed during PSG (split study). Only diagnostic component was used for analysis and for determining the relationships with lung function and peripheral muscle function. PSG was performed in QCH paediatric sleep laboratory using EMBLA (N7000, Natus Neuro, Middleton, Wisconsin, USA) equipment and attended by trained paediatric sleep nurses (see online supplemental 1 for details on the PSG set-up). For study purposes, two experienced paediatric sleep physicians scored each PSG from raw data independently. The PSG was scored using the American Academy of Sleep Medicine (AASM) V.2.6 (see further details in online supplemental 1) paediatric criteria. 13

PSG was evaluated for sleep-disordered breathing (SDB), obstructive (OSA), central (CSA) and mixed sleep apnoea and hypoventilation. To avoid misclassification, an obstructive hypopnea was scored if they met the AASM 2020 criteria for an obstructive hypopnoea and the following were also present in the setting of muscle weakness 14:

Increasing phase difference between chest and abdominal movements; or

Stable/increasing submental EMG (particularly at end of the event); or

Phasic diaphragmatic EMG activity.

Peripheral muscle function

Qualified paediatric neuromuscular physiotherapists tested peripheral muscle function using tests validated in SMA 15-18: the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND (type 1)) 16; Hammersmith Functional Motor Scale-Expanded (HFMSE (types 2 and 3)) 17 or Revised Upper Limb Module (RULM) for SMA (types 2 and 3) 18 were used at discretion of the physiotherapist depending on baseline peripheral muscle function (see online supplemental 1 for details on muscle function test scoring). Definition used for motor response was adopted from CHERISH and ENDEAR trials 4 5:

CHOP INTEND score increase of at least four points from baseline.

HFMSE score increase of at least three points from baseline.

Any increase in RULM from baseline.

Sample size

OSc values were used for priori sample size justification, as many children are too young to perform spirometry. In a previously published case series involving 12 children with SMA type 2 who were followed up for a 12-month period, the mean rate of change of Rsr8 was 0.51 z-scores per year, with SD=0.83. 19 To reject the null hypothesis that there is no change over the 12-month study period, assuming alpha=0.05 and the mean (SD) change=0.51 (0.83) z-scores, then 12-month follow-up data were required on 14 participants.

Statistical analysis

Descriptive statistics for continuous data are reported as either mean (SD), median (IQR) or median (range) as appropriate, or as frequency (percentage (%)) for categorical data. The primary outcome, change in FVC z-score, was assessed using a linear spline with a knot at day 0 of treatment. Linear splines assume the change in FVC z-score is constant in the 2 years prior to treatment initiation, and, separately, constant in the 1 year post initiation, and that the two linear segments are constrained to have the same value at the knot. The model was calculated using mixed effects to account for the repeated measures on some children; time since initiation was entered as the fixed effect and participant was entered as the random effect. Results are reported as mean difference (MD) and 95% CI. Assumptions underlying linear regression models were tested and confirmed.

To test the difference in lung function and AHI total score for muscle responder and non-responder group and to test the difference in sleep events by SMA type between treatment initiation and 12-month follow-up, we used Mann-Whitney test.

Bland-Altman agreement methods were used to assess agreement between sleep events scoring from the two paediatric sleep physicians who scored each participant's PSG. Inter-rater agreement is reported as 95% limits of agreement (LOA).

For all analyses, statistical significance was determined at the 0.05 level. All analyses were conducted using Stata/SE V.16.1 (StataCorp LLC, College Station, Texas, USA).

Results

During the study period, QCH had 30 patients start nusinersen. Twenty-eight patients were enrolled with SMA type 1 (n=7), type 2 (n=12) and type 3 (n=9). Two siblings with SMA type 2 were not approached due to severe social disharmony. Follow-up data at 12 months were available for 27/28 patients: one participant with SMA type 1 died shortly after the start of nusinersen, her parents had declined use of NIV and opted for palliative comfort care but continued nusinersen. She was excluded from analyses as no follow-up PSG or PFT was obtained. One patient with SMA type 3 underwent scoliosis surgery shortly after the start of the study and was excluded from further statistical analysis due to the potential effects of spinal surgery on lung function (26/28 remaining for statistical analysis).

Rate of lung function decline

The combined rate of annual decline in FVC z-score in the 2 years prior to the start of nusinersen was −0.58 (95% CI −0.75 to −0.41) compared with −0.25 (95% CI −0.46 to −0.03) in the year post initiation, with a significantly slower rate of annual decline of 0.33 (95% CI 0.02 to 0.66); p=0.04 (see table 4). When analysed by SMA type, rates of decline were similar for types 2 and 3 prior to nusinersen initiation, but post initiation, the decreased in the rate of decline was particularly marked in children with SMA type 2. A similar finding was observed for percent predicted FVC. Rates of decline for Osc, MIP, MEP and SNIP variables during first year of treatment only (due to limited pre-study data) are listed in online supplemental table 1.

Polysomnography

There was agreement in the scoring between the two sleep physicians (total AHI (95% LOA 0-1)). Total and REM stage AHI and central apnoea index improved at both a clinically and statistically significant level in SMA type 1 ( figure 1). The median AHI reduced from 4.4 (IQR 0.8-8.3) at nusinersen initiation to 3.4 (IQR 1.3-6.3) after 1 year (p=0.04). Total and REM stage minimum recorded oxygen saturations made a clinically meaningful improvement both for the total cohort and children with type 1 SMA. Changes in sleep study variables are summarised in online supplemental table 1. There was no association observed between AHI and age (0.26 (−0.19, 0.71)) (p=0.25).

Association between respiratory and PSG assessments and muscle response to nusinersen

When participants were grouped according to whether or not they were peripheral muscle function responders, children who were responders had a greater reduction in total AHI and FVC z-score tended to improve. For the five participants considered as non-responders, AHI total tended to reduced in the year post nusinersen initiation, while FVC z-score increased ( online supplemental table 2).

Discussion

This study reports changes in lung function and PSG parameters in the first year of nusinersen treatment. These preliminary 'real world' findings show that nusinersen appears to stabilise respiratory function and improve SDB in children with SMA.

Decline in FVC prior to nusinersen initiation was reduced during the first year of treatment, particularly in type 2 SMA; however, these results must be treated cautiously due to the lack of precision (and consequently wide 95% CI) for some subanalyses. Comparison between retrospective spirometry data to prospective results was required due to lack of good quality published reference data and significant disease variability between individuals. Comparison was able to be made for the same patient in two different conditions (no treatment and nusinersen).

Previous spirometry literature in SMA types 2 and 3 is primarily reported as cross-sectional statistics. In earlier reports, SMA type 2 and 3 patients were pooled and reported retrospectively. Rates of FVC decline varied between −1.1% predicted per annum (pa) in children and adults 20 and −3.1% at 2 years and −2.95% at 3 years. 21 22 Children and young adults with SMA type 2 have a steeper decline (FVC of −3.3% to −9.8% pa) than SMA type 3 (−1.8% to −4.2% pa). 23 24 In addition to SMA type variation, there is a difference in median percent predicted FVC based on the continuum of patient phenotype (SMA subtypes), with poorest values noted in non-sitter SMA type 2 and higher values in ambulant SMA type 3. 25 Recently, the effect of age on lung function decline has been noted. FVC % predicted decline is most pronounced at younger ages, followed by a slower rate of decline or even stable course during adulthood in SMA types 2a and 3a, whereas FVC remained relatively stable in type 3b throughout life. 23 24 26 Annual decline of FVC % predicted has been reported between −0.23 and −1.32% from SMA type 3b to 2a. 26 Our pretreatment FVC decline is similar to that reported by Khirani et al. 23

The mechanisms for lung function response differences in SMA type 2 compared with type 3 include the following: (1) participants with type 3 had normal range at initiation, thus have less margin for improvement; (2) nusinersen may take longer to manifest in type 3 (as less severe disease); or (3) nusinersen response is less in type 3, although a biologically plausible explanation is elusive. Tendency to slower peripheral muscle function response in type 3 is reported, giving plausibility to the rationale for a lesser response in type 3 over the first 12 months of treatment. 8 22

The introduction of nusinersen was associated with a significant reduction in the rate of lung function decline. Nusinersen may have halted the expected progression of disease. Natural history would suggest ongoing decline. A lack of improvement in baseline lung function could be due to the chronic changes occurring in neuromuscular diseases. Reduction in chest wall muscle contraction leads to fibrotic, shortened and stiffened muscles, while reduced movement of chest wall results in articular contractures. Neither effect may be reversible. 27

Our results showed a treatment-related fall in resistance with trends towards improvement in reactance and increase in FRC. Again, limited published literature using Osc in SMA exists with none on rates of decline. 19 28 Current study group mean Osc z-scores at baseline suggest reduced lung volumes during tidal breathing, fitting with respiratory muscle weakness expected in SMA. Prior Osc studies in SMA showed that FRC reduces over time. 23 Our findings suggests increased lung volume during tidal breathing from improvement in respiratory muscle strength. SMA type 2 tended to have higher LCI values (more abnormal) than SMA type 3, similar to previous report. 28

SMA type 2 has lower baseline results for PCF, SNIP, MIP and MEP (MIP lower than MEP) compared with SMA type 3 19 23 25 due to weakness of intercostal muscles±diaphragmatic muscles. 29 30 Although mean annual SNIP percent predicted decline is similar between type 2 and type 3 (5.4% vs 6.4% respectively), the decline is later in type 3. 23 Lower values in SMA type 2 for PCF, SNIP, MIP and MEP were shown in our population with tendency for improvement with treatment in SMA type 3 for all values and SNIP in type 2. Results may be influenced by the imprecision due to the small sample (not all children were able to perform techniques). Also variability between tests is expected due to the large variation in the spectrum of peripheral muscle weakness seen in SMA and possibly differences in respiratory muscle function profiles. 30

This is the first study to show an improvement in SDB with nusinersen treatment. All SMA types have central and mixed SDB. 14 31 32 Our study showed improvements in central apnoea index, total AHI and oxygen saturation. Reduction in total AHI was largely attributed to reduction in REM stage AHI/central indices and not surprising since respiratory pump failure is pronounced in REM sleep. 33 AHI total reduction was greater in type 1 possibly due to known age-related reduction in AHI. 34 35 It may also be that type 2 or type 3 SMA eitherdid not have severe SDB at baseline so AHI reduction was less dramatic or as they had prolonged time between diagnosis and first dose of nusinersen, consequently, had reduced efficacy of respiratory muscle response to nusinersen. 4 Increased peripheral muscle response is shown with shorter disease duration. 5 No participants had hypoventilation 36 on PSG. Indications for NIV initiation were recurrent chest infections needing PICU admissions for continuous NIV or SDB, and thus, our centre is likely starting NIV early prior to signs of hypoventilation and raised TcCO ₂.

One participant death occurred after the start of nusinersen. The child's family elected against NIV, which likely impacted mortality risk. All other children with SMA type 1 started NIV following identification of SDB on initial sleep study or for recurrent chest infections requiring PICU admissions. This improved their survival when compared with historical mortality data 37 but in keeping with improved survival noted in ENDEAR trial and real-world Italian experience. 5 38

We were unable to assess whether peripheral muscle response was associated with a lung function or PSG change as a large proportion of children fit peripheral muscle response definition, making subgroup analysis difficult. A large group of responders suggested that the definition adopted from the ENDEAR/CHERISH trials (validated testing but subjective clinically meaningful change) 4 5 may not reflect objective changes seen with FVC and AHI measurements; or peripheral muscle function tests may not be sensitive enough to detect differences in respiratory muscle function over a short period of time. This may be especially true in slowly progressive subtypes, which have shown different trajectories based on ambulation and at different age groups. 21 22 39 Electrophysiological outcome measures (compound muscle action potential) may be more accurate and improve with nusinersen. 4 5 However, electrodiagnostic studies require considerable evaluator skill and participant discomfort, which is compounded by the young population of interest who may not cooperate. The present study attempted to use age-appropriate and disease relevant outcome measures 15 used in previous studies. The variety of scales used in the present study also made detecting changes within same SMA type difficult, but scales needed to be appropriate to child's age and level of function. No single scale spans across the entire paediatric age range.

The primary limitation of this study was the small sample size, due largely to the rarity of SMA. As a consequence, the effect estimates are often imprecise, and we have limited power to detect statistical differences for some subtype analyses. Although participants are a representative sample of children with SMA in Queensland, Australia, our findings may not generalise to patients elsewhere. Infant lung function was not measured, so lung function measurements were limited to older, cooperative children. At present, only one study has assessed the effect of nusinersen on infant lung function. 40 Trials in nusinersen have shown greater peripheral muscle function response in those treated early with shorter disease duration. 5 This may also be true for respiratory muscle function. However, as nusinersen was only widely introduced in Australia in 2018, most Queensland children with SMA type 2 and type 3 had a delay of 8-9 years before treatment. Retrospective collection of lung function data prior to nusinersen initiation is not ideal. However, as nusinersen is available and offered to all children in most countries, all future trials will likely involve children receiving a disease-modifying medication, so it is unethical to perform studies with a placebo group. Historical controls or retrospective data will need to be used. Lastly, the effect of SMN2 copy number was not assessed due to small numbers.

Conclusion

First year of nusinersen treatment led to reduction in lung function decline as measured by FVC z-scores and improvement in PSG (total AHI and central indices). Other lung function parameters remained largely stable. Larger, multicentre studies are needed to further characterise the effects of nusinersen on respiratory muscle function, especially in SMA type 3 where effects may be smaller or slower to respond.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. Additional individual patient data are available in deidentified format on reasonable request.

Ethics statements

Patient consent for publication

Not required.

Ethics approval

The study was approved by Children's Health Queensland Ethical Committee (HREC/18/QRCH/90).

Acknowledgments

The authors would like to thank the patients and their families and the Neuromuscular Department at the Queensland Children's Hospital, Brisbane, Australia.

Supplementary materials

Supplementary Data

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# data[].attributes.attachment_link.title
Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1-3

# data[].attributes.attachment_link.description
Introduction Nusinersen is used in spinal muscular atrophy (SMA) to improve peripheral muscle function; however, respiratory effects are largely unknown. Aim To assess the effects of nusinersen on respiratory function in paediatric SMA during first year of treatment. Methods A prospective observational study in paediatric patients with SMA who began receiving nusinersen in Queensland, Australia, from June 2018 to December 2019.

# data[].attributes.body
Every child has a right to breathe clean air. Lung health should be considered routinely as part of child development.

# data[].attributes.attachment_link.readable_text
Giving lungs the best start-parental health and health in pregnancy

Healthy lung growth and development starts before birth. Healthy babies require healthy parents. Addressing inequality, social deprivation, structural racism and the corporate determinants of health 6 is fundamental to this, so that preconception and pregnancy risk factors like poverty, poor housing, smoking, dietary factors, obesity and stress can be reduced or avoided. Parents must have the capabilities to live in as healthy a way as possible, in all aspects of daily life, in the home and at work.

Growing lungs need to breathe clean air

Exposure to particulate and other forms of pollution harms lung growth, increases the risk of developing lung disease and causes acute attacks in children who have lung disease. Exposure to pollution must be brought down by legally enforcing WHO limits. This requires action across government on areas including transport, energy generation, farming practices as well as action more broadly to reduce global heating, which itself increases ground-level pollution. Indoor air quality is also vital, and no child should have to live in a cold, damp home or be exposed to passive smoke. 7

This will require the development of local/personalised plans for reducing the impact of these factors. Examples include enforcement of housing regulations; action to reduce and help people avoid areas of high pollution; provision of smoking cessation support. Closer relationships between health and local authority services should identify common local trends and help populations/individuals to address them.

Raising a smoke-free generation-supporting steps to achieve the Smokefree 2030 ambition

Smoking, both active and passive, increases the risk of lung disease in children, impairs lung growth and increases the risk of infections. To prevent child uptake of smoking, action is needed to reduce the appeal, affordability and accessibility of smoking. 8 Measures include raising the age of sale from 18 to 21 to take smoking completely out of schools, increasing prices, expanding smoke-free spaces and preventing the targeting of children and young people by the tobacco industry. E-cigarettes and similar devices must only be marketed to adults as alternatives to smoking, not be packaged and marketed in a way that appeals to children.

Improving community and long-term care for respiratory disease

Lung health should be considered routinely as part of child development. Most care for children with breathing problems takes place in the community. Community care must be able to ensure timely and accurate diagnosis including access to appropriate investigations and referral for specialist support where necessary. Long-term care for lung conditions should both acknowledge differences between the care of adult and paediatric conditions and ensure that transitions to adult care are seamless. The identification of children with respiratory conditions needs to be proactive.

Improving emergency care for children with lung disease

Children need universal, timely access to safe, high-quality care based on their needs. This must apply from acute self-limiting illnesses through to life-threatening conditions requiring complex intensive care support. Children and carers should have the information to monitor and self-manage their condition and know when and from whom to seek care in a timely way. Pathways of acute care for conditions like asthma, bronchiolitis and pneumonia must be subjected to a transparent process of audit and improvement. Following discharge from hospital, children and their carers must receive the information, support and follow-up that they need.

Improving management of rare diseases

The care of children with some rare diseases can be complex. Bronchiectasis, parenchymal lung disease, cystic fibrosis and home ventilation services for children with neuromuscular problems are examples of this. Ensuring access to high quality expert care, wherever in the country children live, is essential. There needs to be coordination of care and sharing of information across acute and long-term services and settings and support for palliative and end of life care. Services must support the transition from paediatric to adult care.

Support for carers

The healthcare system must address the needs of families and carers of children with lung disease. This must include providing sources of high quality, clear information, emotional support and counselling as well as respite where this is needed. Provision of this must match individuals' language needs, literacy and varying digital access. Support should extend to formal and informal carers, so that the needs and responsibilities of, for example, teachers and youth club leaders around lung health are included.

Facilities should be provided to allow carers to support children in hospital.

The healthcare workforce needed to support children with lung disease

Children with lung conditions need support from a range of health and social care professionals. This requires training and recruitment to a range of roles within the multidisciplinary care team, including, but not limited to, nurses, paediatricians, general practitioners, physiotherapists, paediatric respiratory physiologists, play specialists, occupational therapists and social workers. Substantial staffing gaps that have been allowed to develop in the healthcare workforce need to be reversed urgently.

Research priorities need to be identified and pursued

Urgent attention is needed to address knowledge gaps including, but not limited to (1) research that will influence policy, for example, estimated costs of preventable poor lung health, and the mechanisms that impair healthy lung development, (2) better diagnostics for paediatric lung disease and lung function assessment in early life, (3) facilitating digital health recording of child lung health parameters to enable data linkage to advance knowledge of the impact of early child lung health for adult health, (4) the case for routine lung health checks including spirometry around secondary school entrance as a marker of a poor respiratory outcome, (5) behavioural studies for prevention and treatments/activation, (6) the management of both common conditions and rare high impact diseases, (7) addressing the fact that the evidence for many medications used by children is based only on extrapolation from adult data, (8) health services research to consider optimum delivery across primary and secondary care.

Research is required across the whole translational range from underpinning biology, through therapeutic innovation to health services research on implementation.

Research prioritisation should be a transparent process, including children, young people and their carers.

Child health in all policies

The health of children is fundamental to the future health of society and is a matter for us all. The impact of any policy on the health of children and young people, particularly their respiratory health, should be considered prior to implementation and considered in the post-implementation evaluation of their impact. This will require closer working between adult and paediatric respiratory leaders and researchers and policymakers. Opportunities should be taken, where appropriate, to align policies and programmes for adult respiratory health to paediatrics, for example, severe asthma services and diagnostic hubs, especially given that much adult lung disease has its roots in childhood.

Patient consent for publication

Not applicable.

# data[].attributes.attachment_link.description
Every child and young person has the right to breathe clean air, with healthy lungs. Preconception, in utero and early life exposures, affect children's lungs, their lung growth and their long-term health.

# data[].attributes.body
Every child has a right to breathe clean air. Lung health should be considered routinely as part of child development.

# data[].attributes.attachment_link.readable_text
Giving lungs the best start-parental health and health in pregnancy

Healthy lung growth and development starts before birth. Healthy babies require healthy parents. Addressing inequality, social deprivation, structural racism and the corporate determinants of health 6 is fundamental to this, so that preconception and pregnancy risk factors like poverty, poor housing, smoking, dietary factors, obesity and stress can be reduced or avoided. Parents must have the capabilities to live in as healthy a way as possible, in all aspects of daily life, in the home and at work.

Growing lungs need to breathe clean air

Exposure to particulate and other forms of pollution harms lung growth, increases the risk of developing lung disease and causes acute attacks in children who have lung disease. Exposure to pollution must be brought down by legally enforcing WHO limits. This requires action across government on areas including transport, energy generation, farming practices as well as action more broadly to reduce global heating, which itself increases ground-level pollution. Indoor air quality is also vital, and no child should have to live in a cold, damp home or be exposed to passive smoke. 7

This will require the development of local/personalised plans for reducing the impact of these factors. Examples include enforcement of housing regulations; action to reduce and help people avoid areas of high pollution; provision of smoking cessation support. Closer relationships between health and local authority services should identify common local trends and help populations/individuals to address them.

Raising a smoke-free generation-supporting steps to achieve the Smokefree 2030 ambition

Smoking, both active and passive, increases the risk of lung disease in children, impairs lung growth and increases the risk of infections. To prevent child uptake of smoking, action is needed to reduce the appeal, affordability and accessibility of smoking. 8 Measures include raising the age of sale from 18 to 21 to take smoking completely out of schools, increasing prices, expanding smoke-free spaces and preventing the targeting of children and young people by the tobacco industry. E-cigarettes and similar devices must only be marketed to adults as alternatives to smoking, not be packaged and marketed in a way that appeals to children.

Improving community and long-term care for respiratory disease

Lung health should be considered routinely as part of child development. Most care for children with breathing problems takes place in the community. Community care must be able to ensure timely and accurate diagnosis including access to appropriate investigations and referral for specialist support where necessary. Long-term care for lung conditions should both acknowledge differences between the care of adult and paediatric conditions and ensure that transitions to adult care are seamless. The identification of children with respiratory conditions needs to be proactive.

Improving emergency care for children with lung disease

Children need universal, timely access to safe, high-quality care based on their needs. This must apply from acute self-limiting illnesses through to life-threatening conditions requiring complex intensive care support. Children and carers should have the information to monitor and self-manage their condition and know when and from whom to seek care in a timely way. Pathways of acute care for conditions like asthma, bronchiolitis and pneumonia must be subjected to a transparent process of audit and improvement. Following discharge from hospital, children and their carers must receive the information, support and follow-up that they need.

Improving management of rare diseases

The care of children with some rare diseases can be complex. Bronchiectasis, parenchymal lung disease, cystic fibrosis and home ventilation services for children with neuromuscular problems are examples of this. Ensuring access to high quality expert care, wherever in the country children live, is essential. There needs to be coordination of care and sharing of information across acute and long-term services and settings and support for palliative and end of life care. Services must support the transition from paediatric to adult care.

Support for carers

The healthcare system must address the needs of families and carers of children with lung disease. This must include providing sources of high quality, clear information, emotional support and counselling as well as respite where this is needed. Provision of this must match individuals' language needs, literacy and varying digital access. Support should extend to formal and informal carers, so that the needs and responsibilities of, for example, teachers and youth club leaders around lung health are included.

Facilities should be provided to allow carers to support children in hospital.

The healthcare workforce needed to support children with lung disease

Children with lung conditions need support from a range of health and social care professionals. This requires training and recruitment to a range of roles within the multidisciplinary care team, including, but not limited to, nurses, paediatricians, general practitioners, physiotherapists, paediatric respiratory physiologists, play specialists, occupational therapists and social workers. Substantial staffing gaps that have been allowed to develop in the healthcare workforce need to be reversed urgently.

Research priorities need to be identified and pursued

Urgent attention is needed to address knowledge gaps including, but not limited to (1) research that will influence policy, for example, estimated costs of preventable poor lung health, and the mechanisms that impair healthy lung development, (2) better diagnostics for paediatric lung disease and lung function assessment in early life, (3) facilitating digital health recording of child lung health parameters to enable data linkage to advance knowledge of the impact of early child lung health for adult health, (4) the case for routine lung health checks including spirometry around secondary school entrance as a marker of a poor respiratory outcome, (5) behavioural studies for prevention and treatments/activation, (6) the management of both common conditions and rare high impact diseases, (7) addressing the fact that the evidence for many medications used by children is based only on extrapolation from adult data, (8) health services research to consider optimum delivery across primary and secondary care.

Research is required across the whole translational range from underpinning biology, through therapeutic innovation to health services research on implementation.

Research prioritisation should be a transparent process, including children, young people and their carers.

Child health in all policies

The health of children is fundamental to the future health of society and is a matter for us all. The impact of any policy on the health of children and young people, particularly their respiratory health, should be considered prior to implementation and considered in the post-implementation evaluation of their impact. This will require closer working between adult and paediatric respiratory leaders and researchers and policymakers. Opportunities should be taken, where appropriate, to align policies and programmes for adult respiratory health to paediatrics, for example, severe asthma services and diagnostic hubs, especially given that much adult lung disease has its roots in childhood.

Patient consent for publication

Not applicable.

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Every child and young person has the right to breathe clean air, with healthy lungs. Preconception, in utero and early life exposures, affect children's lungs, their lung growth and their long-term health.

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Dr Emma Guys session on the latest Asthma updates

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Every Wednesday 8.30-9am on Microsoft Teams

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Recent teaching by Dr Saikiran Gopalakaje

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Recent teaching by Dr Tim Lee

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Dr Aoife Khellers teaching on CFRD

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NORD (National Organization for Rare Disorders)

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The symptoms, severity, and age of onset of collagen type VI-related disorders vary greatly. In most cases, affected individuals have muscle weakness and degeneration and skeletal abnormalities such as curvature of the spine (scoliosis) and contractures.

Bethlem Myopathy (Benign Congenital Myopathy with Contractures)
Bethlem myopathy is a disorder characterized by mild weakness of the proximal muscles. Proximal muscles are the muscles that are closest to the center of the body such as the muscles of the shoulder, pelvis, and upper arms and legs. Muscle weakness may eventually affect the distal muscles to a lesser degree. Distal muscles are those farther from the center of the body and include the muscles of the lower arms and legs and the hands and feet.

The symptoms of Bethlem myopathy may be apparent before birth (prenatally), shortly after birth (neonatally), or during adolescence or adulthood. In addition to muscle weakness, newborns and infants with Bethlem myopathy may develop diminished muscle tone (hypotonia), repeated mild contractures of certain joints especially the fingers, elbows, ankles, and knees, a twisted or tilted neck (torticollis), and delays in achieving motor milestones.

Bethlem myopathy is slowly progressive. In some adults, noticeable muscle weakness may not occur until after 40 years of age. Many individuals with Bethlem retain the ability to walk either independently or with assistance (e.g., cane or crutches) throughout life. Some individuals may eventually require a wheelchair.

In rare cases, breathing (respiratory) difficulties may occur late in life due to weakness of the diaphragm muscles. Heart (cardiac) function, which may become impaired in other forms of myopathy, is usually unaffected in individuals with Bethlem myopathy.

In some cases, a skin condition may occur that is characterized by thickening and hardening (hyperkeratosis) of hair follicles, resulting in the development of rough, elevated growths (papules) on the skin.

Ullrich Congenital Muscular Dystrophy (UCMD)
Ullrich CMD is characterized by diminished muscle tone (hypotonia), weakness and degeneration of the proximal muscles, and abnormally flexible (hyperelastic) joints of the wrists and ankles. Additional early symptoms of Ullrich CMD include the failure to gain weight and grow at the expected rate (failure to thrive), abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis), a twisted or tilted neck (torticollis), congenital dislocation of the hip, contractures of the joints, and stiffness (rigidity) of the spine.
Intelligence is normal in most cases. The amount of motor development varies from case to case. Some children are able to walk independently; others require assistance to walk. In some cases, affected children may never be able to walk. In addition, some children who develop the ability to walk independently lose that ability because of the progression of the disease (e.g., worsening contractures, rigidity of spine).

Additional symptoms may occur including breathing (respiratory) difficulties and frequent chest infections. Breathing difficulties can result in life-threatening complications and may require respiratory support, especially at night.

As the disorder progress, previously flexible (lax) joints such as those of the wrists and ankles may stiffen. Some affected individuals may exhibit a skin condition characterized by thickening and hardening (hyperkeratosis) of hair follicles, resulting in the development of rough, elevated growths (papules). In some cases, scars may heal slowly or affected individuals may develop hardened, raised bumps at the site of an injury (hypertrophic keloid scars).

Some individuals with Ullrich CMD may have a distinctive facial appearance with a rounded face with prominent ears.

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Collagen Type VI-Related Disorders - NORD (National Organization for Rare Disorders)

# data[].attributes.attachment_link.description
The symptoms, severity, and age of onset of collagen type VI-related disorders vary greatly. In most cases, affected individuals have muscle weakness and degeneration and skeletal abnormalities such as curvature of the spine (scoliosis) and contractures. Bethlem Myopathy (Benign Congenital Myopathy with Contractures) Bethlem myopathy is a disorder characterized by mild weakness of the proximal muscles.

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Abstract

Nemaline myopathies are a heterogenous group of congenital myopathies caused by de novo, dominantly or recessively inherited mutations in at least twelve genes. The genes encoding skeletal α-actin ( ACTA1) and nebulin ( NEB) are the commonest genetic cause. Most patients have congenital onset characterized by muscle weakness and hypotonia, but the spectrum of clinical phenotypes is broad, ranging from severe neonatal presentations to onset of a milder disorder in childhood. Most patients with adult onset have an autoimmune-related myopathy with a progressive course. The wide application of massively parallel sequencing methods is increasing the number of known causative genes and broadening the range of clinical phenotypes. Nemaline myopathies are identified by the presence of structures that are rod-like or ovoid in shape with electron microscopy, and with light microscopy stain red with the modified Gömöri trichrome technique. These rods or nemaline bodies are derived from Z lines (also known as Z discs or Z disks) and have a similar lattice structure and protein content. Their shape in patients with mutations in KLHL40 and LMOD3 is distinctive and can be useful for diagnosis. The number and distribution of nemaline bodies varies between fibres and different muscles but does not correlate with severity or prognosis. Additional pathological features such as caps, cores and fibre type disproportion are associated with the same genes as those known to cause the presence of rods. Animal models are advancing the understanding of the effects of various mutations in different genes and paving the way for the development of therapies, which at present only manage symptoms and are aimed at maintaining muscle strength, joint mobility, ambulation, respiration and independence in the activities of daily living.

Keywords: Nemaline myopathy, Congenital myopathy, Rods, Rod bodies, Z line, Z disc, Animal models

Introduction

Nemaline myopathies are a group of congenital myopathies defined by structures known as nemaline rods or nemaline bodies that stain red with the modified Gömöri trichrome technique (Dubowitz et al. 2013, 2019 in press). The spectrum of clinical phenotypes is wide and mutations in many genes (at least 12) are known to be associated with their presence in muscle biopsies. Additional pathological features such as cores, caps and fibre type disproportion (FTD) as well as the presence of only a few fibres with rods overlap with other congenital myopathies and challenge the classification of all congenital myopathies. Although structural features such as rods can be identified in a muscle biopsy, it is the combination of clinical, histological and genetic features that define a disease entity.

Histopathological features have a major role in directing molecular analysis (Dubowitz et al. 2013), but the increasing use of gene panels and exome sequencing is identifying novel genes and expanding clinical phenotypes associated with known genetic defects that result in the formation of rods. Nemaline rods are not specific for nemaline myopathies and may also occur at normal myotendinous junctions, in normal extra-ocular (eye) muscles, in ageing muscle and occasionally in a variety of other inherited or acquired neuromuscular and other disorders (see Vandebrouck et al. 2010). In vitro studies of cultured cells have shown that rods can result from metabolic stress by depletion of adenosine triphosphate (Vandebrouck et al. 2010). The diagnosis of nemaline myopathies relies on a multidisciplinary approach with careful clinical, pathological and genetic correlations. Muscle magnetic resonance imaging (MRI) has also become an important contributor to diagnosis and highlights specific patterns of muscle involvement associated with particular mutated genes (Jungbluth 2017).

The term 'nemaline myopathy' is usually applied to the group of muscle disorders presenting at birth or early childhood with hypotonia and muscle weakness, but cases of adult onset have also been reported, including those referred to as sporadic late-onset nemaline myopathy, many of which are of autoimmune origin, or associated with HIV (see Schnitzler et al. 2017). In addition, some patients may not present until adulthood, but careful enquiry and clinical examination often identifies problems in childhood, albeit mild. This article focuses on the congenital and childhood onset forms.

What is a nemaline rod?

Nemaline rods were identified in the 1950s and 1960s in muscle biopsies from children with hypotonia (Conen et al. 1963; Shy et al. 1963; Schnell et al. 2000). Conen et al. ( 1963) described the appearance of rod-like structures in the biopsy of a child with hypotonia as 'myogranules' which would now be described as rod bodies. The term 'nemaline myopathy' was suggested by Shy and co-workers after the Greek word for thread, nema, as it was not clear whether the structures were separate rod-like structures or an undulating thread-like structure.

Rods stain red with the modified Gömöri trichrome technique but electron microscopy may be needed to distinguish them from mitochondria, which also stain red, especially in very small muscle fibres in neonates. Rods are considered to be derived from Z lines as they can show continuity with Z lines; they have a similar lattice structure and express similar proteins, including α-actinin, actin, tropomyosin, myotilin, γ-filamin, cofilin-2, telethonin and nebulin. Desmin is not present in the rods themselves but may be observed at their periphery. In some fibres in human muscle biopsies and in some animal models, the rod-like structures may appear as an integral part of the sarcomere, and as thickened Z lines compared with the normal width, which is usually fixed, according to the muscle fibre type (Luther 2009).

It is not yet clear how rods form, but myofibrillar rearrangement is considered to result in several abnormalities of the Z lines (Yu et al. 2004). Rods can be a secondary response to metabolic stress. Numerous rods were observed in a few patients with Complex I deficiency (Lamont et al. 2004) and in both muscle and non-muscle cells in vitro, they can be induced by a variety of substances that cause energy shortage, including ATP depletion and heat shock proteins (Vandebrouck et al. 2010). This in vitro study suggested that rods formed under different conditions vary with regard to their cofilin and α-actinin content. In addition, specific ACTA1 mutations affected the localization of rods (nuclear versus cytoplasmic).

Genetics

Nemaline myopathy may be caused by mutations in at least 12 genes (Table ) and some cases are still molecularly unresolved. A recently identified gene is TNNT3, the gene encoding fast skeletal troponin 3 (Sandaradura et al. 2018). In addition, a homozygous mutation in MYO18B, encoding an unconventional myosin, has been reported as a possible cause of nemaline myopathy in an atypical case (Malfatti et al. 2015). Nemaline rods were also observed in association with a mutation in MYO18B but the patient also had Klippel-Feil anomaly, dysmorphic features, microcephaly and short stature (Alazami et al. 2015). Furthermore, in experimental models, myofibre assembly failed in a way not characteristic of nemaline myopathy biopsies (Berger et al. 2017; Gurung et al. 2017) but animal models often do not recapitulate human diseases precisely.

Table 1

Other genes are also associated with the presence of nemaline rods or cap-like areas, but additional structural and clinical features are present in these patients and thus, they do not fulfil the criteria of nemaline myopathy as outlined at a European Neuromuscular Centre workshop (Wallgren-Pettersson et al. 1998), although publications may refer to them as such. For example RYR1 and TTN, encoding the ryanodine receptor 1 and titin, respectively, (Sewry and Wallgren-Pettersson 2017; Oates et al. 2018), EXOSC3 that encodes a component of the human RNA exosome complex (Pinto et al. 2019), PPA2 that encodes the mitochondrial pyrophosphatase (Guimier et al. 2016), and RYR3 encoding the ryanodine receptor 3 (Nilipour et al. 2018).

The commonest forms of nemaline myopathy are caused by mutations in the genes encoding skeletal muscle α-actin ( ACTA1) and nebulin ( NEB). Several of the other causative genes have only been shown to be mutated in a few families each, although the wide application of novel gene sequencing methods is increasing the number of patients with verified genetic diagnoses (Wallgren-Pettersson et al. 2011; Malfatti and Romero 2016). Most of the ACTA1 mutations are heterozygous dominantly inherited mutations, often arising de novo. NEB mutations are usually recessively inherited, but recently, the first dominantly inherited mutation was identified in NEB, causing a distal form of nemaline myopathy (Kiiski et al. 2019). A great number of different mutations have been identified in these two genes (Sparrow et al. 2003; Feng and Marston 2009; Nowak et al. 2013; Lehtokari et al. 2014; Moreno et al. 2017).

Nine of the genes for nemaline myopathy encode proteins of the sarcomere, in addition, MYO18B is also a sarcomeric protein localized to the Z lines (Ajima et al. 2008) and may yet prove to be a causative gene of nemaline myopathy, although the phenotype of affected patients is different from others reported. The other three genes encode Kelch-like proteins, a large family of proteins possibly associated with thin filament regulation (Wallgren-Pettersson et al. 2011; Gupta and Beggs 2014; Malfatti and Romero 2016).

Nemaline myopathies occur all over the world. Some mutations have arisen as founder mutations, such as the deletion of the entire exon 55 of NEB in persons of Ashkenazi Jewish ancestry, with a world-wide distribution (Anderson et al. 2004; Lehtokari et al. 2009), and the TNNT1 mutation (E180X in exon 11 causing a stop codon) in the Amish population (Johnston et al. 2000). Probable founder mutations have also been identified in TPM3 (deletion of the first nucleotide of the last exon, c.913delA) in the Turkish population (Lehtokari et al. 2008), KLHL40 (c.1582G>A) in the Japanese, Kurdish and Turkish populations (Ravenscroft et al. 2013), ACTA1 (p.Asp181fsX10) in the Pakistani population (Nowak et al. 2007), KBTBD13 (c.1222C>T) in the Low Countries of The Netherlands and Belgium (Sambuughin et al. 2010), three mutations in NEB (p.Ser6366Ile in ex122, p.Thr7382Pro in ex151, and p.Thr6350Profs*4 in ex122) in the Finnish population (Lehtokari et al. 2014) and in LMOD3 (c.1648c>T) in German and Austrian populations (Schatz et al. 2018).

Currently, many mutations are identified by screening panels of genes known to be associated with nemaline myopathy. There is often difficulty, however, with mutation detection, especially in NEB. It is an extremely large gene (183 exons), giving rise to many isoforms in both skeletal muscle and brain (Laitila et al. 2012). The gene has multiple splice sites and a triplicate repeat region, where the most common large variants of the gene are found (Kiiski et al. 2016). Identifying both mutations in NEB in a patient may also be difficult because most patients have two private mutations anywhere along the length of the gene, and some of them are easily missed using massive parallel sequencing methods (Kiiski et al. 2016). Determining the pathogenicity of especially missense variants, which are numerous in NEB, constitutes a further diagnostic challenge. Recent advances include a targeted array which, in many patients, has helped to identify the second mutation (Kiiski et al. 2016; Zenagui et al. 2018), and also the development of functional assays for testing the effects on the protein of missense variants. For example, a nebulin in super repeat panel reveals stronger actin binding toward the ends of the super repeat region (Laitila et al. 2019), and how disease-causing mutations in NEB alter interactions with actin and tropomyosin (Marttila et al. 2014).

Although mutations in ACTA1 are often dominant (and de novo, although sometimes inherited), a few rare instances of recessive transmission have also been reported (Nowak et al. 2013). Some of these recessive mutations are null mutations that result in no production of skeletal actin protein whilst in others it is present (Nowak et al. 2007; O'Grady et al. 2015).

Clinical features

The spectrum of clinical phenotypes of nemaline myopathies is wide, even in individuals with mutations in the same gene, or in the same family. It ranges from neonates with severe disease and onset in utero, sometimes with fetal akinesia, to mild childhood-onset forms (Colombo et al. 2015; Jungbluth et al. 2018).

Classification of nemaline myopathies

A clinical classification, mainly designed for gene discovery, was defined at an ENMC workshop in 1999 (Table ; Wallgren-Pettersson and Laing 2000). Since then, altogether twelve genes and numerous mutations have been identified, and it has turned out that genotype-phenotype correlations are weak, or few and far between. Thus, we propose a revised, simplified classification, based on current knowledge of the spectrum of identified patients with nemaline myopathy (Table ).

Among the categories in Table , the intermediate form was designated because there was a difference between typical (mainstream) nemaline myopathy and this group of patients, in that their course of the disease was more severe. This was exemplified by the use of a wheelchair from an earlier age than may occur in the typical form, where a wheelchair, if needed at all, is often only used from the pre-pubertal growth spurt. In other words, it was only possible to distinguish this category of patient in late childhood. It has turned out that no specific "intermediate" genes have been identified; the most common genes, NEB and ACTA1, may both cause this form. To our knowledge, there are few if any definite adult-onset cases with a proven genetic cause. The rapidly progressive adult-onset form (SLONM) is often immune-mediated and responsive to treatment (see Schnitzler et al. 2017).

Since the current classification was established, additional novel clinical forms have been described, not fitting into the current classification. Examples of this are the "Amish" form caused by mutations in TNNT1 with contractures, tremor and a progressive course (Johnston et al. 2000; Fox et al. 2018), and the form with slowness of movements and core-rod histology (Gommans et al. 2002; Sambuughin et al. 2010; de Winter and Ottenheijm 2017). There have also been publications describing patients with an unusual distribution of weakness, such as scapuloperoneal or distal weakness, or distal arthrogryposis, and it can be argued that these should be classified as separate entities. However, most forms of nemaline myopathy have individual variation in the distribution of weakness, and a number of patients may have distal contractures early or late in the course of the disease, so that lines of division are difficult to draw between such "novel" entities and the forms already described. Thus, we argue that it is time for a new and simplified classification of nemaline myopathy, which would be useful for yielding at least an estimate of prognosis in an individual patient (Table ).

The prognosis in the severe form is often grave, but there have been exceptions, where patients have shown improvement over time (Roig et al. 1987). The typical form often follows a static or only slowly progressive course, and some patients have shown improvement, e.g. related to active physical training. Onset in childhood or at juvenile age often implies a mild course, while recessively inherited TNNT1 (Amish) nemaline myopathy follows a relentlessly progressive course, with thoracic immobility, restrictive lung disease and often death in childhood (Johnston et al. 2000; Fox et al. 2018). The dominantly inherited form with slowness appears to follow a milder course.

Although most patients present with muscle hypotonia, there are rare patients with muscle hypertonia and a stiff gait (Marttila et al. 2014; Davidson et al. 2013), thought to stem from higher than normal calcium sensitivity (Jain et al. 2012; Donkervoort et al. 2015; Marston 2018). Muscle weakness is usually generalised, with involvement of the neck flexors, the face and proximal muscles, often with a later, additional distal involvement. Distal weakness is a particular presentation in some patients with mutations in NEB, but rods may not always be a present in their muscle biopsies (Wallgren-Pettersson et al. 2007). Weakness of respiratory muscles is common and an important clinical feature to monitor regularly and manage according to international guidelines (Wallgren-Pettersson et al. 2011). Insidious onset of hypoventilation is the greatest risk for this group of patients and the most common cause of death. Thus, in the absence of expert monitoring of respiratory function, respiratory insufficiency may ensue suddenly and without any preceding symptoms (Wallgren-Pettersson et al. 2004). Extraocular muscles are usually spared, except in patients with mutations in KLHL40 and LMOD3, who may have ophthalmoplegia (Ravenscroft et al. 2013; Yuen et al. 2014). Cardiac involvement is rare in patients with nemaline myopathy, but has been identified in a few patients with defects in ACTA1, MYPN or MYO18B (D'Amico et al. 2006; Kim et al. 2011; Finsterer and Stollberger 2015; Malfatti et al. 2015; Miyatake et al. 2017). Mutations in TNNT1 encoding troponin T were first identified in homozygous form in the Amish population, but a few patients of Dutch descent, and others of non-Amish origin have also been described (van der Pol et al. 2014; Abdulhaq et al. 2016). Characteristics are tremor and severe progressive contractures, muscle weakness and atrophy with stiffness and thoracic rigidity. A dominantly inherited TNNT1 mutation causing a different clinical picture has been reported, with similarities to the childhood onset form caused by mutations in other genes (Konersman et al. 2017). A severe clinical picture has been described in the patient with a homozygous TNNT3 mutation, with contractures, hip dislocation (unusual in nemaline myopathy) and ventilator dependence until death at the age of 8 months (Sandaradura et al. 2018). Patients with mutation of KBTDB13 often have an unusual slowness of muscle movements due to slow relaxation kinetics, and cores as well as rods (Gommans et al. 2003; Sambuughin et al. 2010; de Winter and Ottenheijm 2017). In all forms of nemaline myopathies, creatine kinase levels are usually normal or only slightly elevated.

Histopathology

The characteristic cytoplasmic nemaline rods that stain red with the Gömöri trichrome technique in nemaline myopathies are usually numerous but the number and distribution per fibre can be variable (Fig. ). The number also varies between muscles and there is no apparent correlation between clinical severity and the number of rods. Rods may be present in peripheral clusters, often near nuclei, or may be diffusely distributed, or in lines within fibres (Fig. ). They are usually not observed in intrafusal fibres of spindles. Rods need to be distinguished from other structures that also stain red with the Gömöri trichrome technique, such as mitochondria and cytoplasmic bodies. In biopsies with very small fibres, rods may only be apparent with very high power optics. Examination of resin sections stained with toluidine blue or with electron microscopy is then helpful. An occasional cytoplasmic body may be observed in a few fibres but in three severely affected patients with the same missense ACTA1 mutation (p.Asn94Lys), only dense accumulation of material reported as 'suggestive of cytoplasmic bodies' were seen, but no rods (Donkervoort et al. 2017). In addition to these patients, rods have not been observed in other patients, although mutations in genes that cause nemaline myopathy may be present. Repeat biopsies from a series of patients with NEB mutations and a distal myopathy did not reveal rods (Wallgren-Pettersson et al. 2007). Moreover, a family with progressive scapuloperoneal and distal weakness with an ACTA1 mutation had no rods visible with light or electron microscopy (Zukosky et al. 2015). Mutations in ACTA1 have also been found in cases with no rods but only cores (Kaindl et al. 2004). Sampling and variable distribution may also influence the detection of rods, for example rods may only be observed in the sample taken for electron microscopy.

Abnormal variation in fibre size is often present and type 1 atrophy or hypotrophy (fibres that have never attained normal dimensions) is common. Atrophy can be distinguished from hypotrophy by the presence of redundant basal lamina associated with atrophic fibres, using electron microscopy. There may also be hypertrophy of type 2 (fast myosin) fibres. This size variation may appear as FTD in which type 1 fibres are 12-25% smaller than type 2 and there are no additional pathological abnormalities such as rods or cores or central nuclei. FTD without structural defects can be associated with defects in several genes that cause a congenital myopathy, including several that are responsible for a nemaline myopathy (see Table ) (Clarke 2011). Type 1 predominance, a common feature in congenital myopathies, is often present, but is not universal (Malfatti et al. 2014). Antibodies to myosin isoforms may show co-expression of slow and fast isoforms in some fibres, and there is often a variable number of fibres with foetal myosin. In addition, recent studies of a few cases caused by NEB mutations have revealed a predominance of fibres with fast myosin and uneven distribution of fibre types in others (Fig. ). Involvement of type 2/fast fibres is also seen in patients with mutations in the TNNT3 gene encoding the troponin T isoform of fast fibres (Sandaradura et al. 2018).

Immunohistochemistry of nebulin does not show a total absence of protein, although an absence has been reported in rare patients which was dependent on the mutation and the antibody used (Sewry et al. 2001; Wallgren-Pettersson et al. 2002). Recent studies with antibodies specific to exons 143 and 144 of nebulin, that are differentially spliced, suggest that there is developmental regulation of these two exons, and that exon 143 appears later in myogenesis (Lam et al. 2018). In addition, there is a clear fibre typing pattern with the antibody to exon 143 that is highly expressed in fibres with fast myosin (Fig. ).

Rods are restricted to type 1 fibres in patients with TPM3 mutations, as the protein is only expressed in these fibres, and in patients expressing no TNNT3 they were reported to be restricted to type 2 fibres (Sandaradura et al. 2018), but in most biopsies they are seen in both fibre types. Rods in most biopsies of nemaline myopathy patients are present in the cytoplasm but in some cases electron microscopy reveals both nuclear and cytoplasmic rods, or very occasionally only nuclear rods (Hutchinson et al. 2006; Koy et al. 2007; Miyatake et al. 2017).

Areas with rods are often devoid of mitochondria, thus they may appear as core-like areas devoid of oxidative enzyme staining. Caution in interpretation is then needed. Sometimes cores and rods, however, may be in separate fibres or the core-like area lacking oxidative enzymes may be more extensive than the area with rods (Dubowitz et al. 2013; Scoto et al. 2013). Muscle biopsies from some nemaline myopathy patients show both rods and cores with disrupted myofibrils (Jungbluth et al. 2001; Agrawal et al. 2007; Romero et al. 2009; Dubowitz et al. 2013). Some of these patients have been classified as having a 'core-rod myopathy' (Hernandez-Lain et al. 2011), but they emphasise the overlapping pathological and clinical spectra of the nemaline myopathies and other congenital myopathies. Similarly, cap-like structures are regarded as being part of the histopathological spectrum of nemaline myopathies and not forming a distinct clinical entity. Although focal peripheral cap areas with myofibrillar disruption and thickened Z lines are associated with defects in the TPM2 and TPM3 genes (Marttila et al. 2014), they have also been described in association with defects in other genes associated with nemaline rods, ACTA1, NEB and MYPN. Both cap-like areas and rods can be present in the same sample and are part of the spectrum of Z-line abnormalities in nemaline myopathies (Malfatti et al. 2013).

Muscle fibre necrosis and regeneration are not usually features of nemaline myopathy. Similarly, fibrosis is rarely seen but can occasionally be extensive, for example in patients with mutations in the TNNT1 gene (Fig. ).

It is rarely possible to identify the defective gene from histopathological features and few of them are specific. Areas of accumulation of actin filaments suggest ACTA1 as the cause, although such accumulation has also been seen in the rare patients with CFL- 2 mutations and in an animal model for this gene defect (Agrawal et al. 2007; Gurniak et al. 2014). Nuclear rods can occur in nemaline patients with ACTA1 mutations but they have also been observed in the rare cases of MYPN mutation and in patients with a myofibrillar myopathy, although the clinical phenotype of these is not that of a congenital myopathy (Dominguez Rubio et al. 2016; Miyatake et al. 2017).

All fibres expressing cardiac actin without skeletal actin is a phenomenon seen in rare patients homozygous for ACTA1 null mutations (Nowak et al. 2007) but other patients with recessively inherited ACTA1 mutations retain skeletal actin (O'Grady et al. 2015). Zebra bodies are also part of the ACTA1 pathological spectrum and observed in ACTA1 null patients (Nowak et al. 2007). They defined the original case of 'zebra body myopathy' in whom an ACTA1 mutation has been identified (Sewry et al. 2015). They are not specific to ACTA1 nemaline myopathy, as occasional zebra bodies have been observed in a variety of disorders. Electron microscopy of biopsies from patients with KLHL40 mutations shows not only typical rods but also fibres with numerous small, rectangular rods in fibres with very few myofibrils (Fig. ). However, patients with LMOD3 mutations can also show similar rods (Fig. ; Malfatti and Romero 2016). LMOD3 biopsies have been reported to show rods with a fringe of myofibrils attached (Yuen et al. 2014), but we have observed similar rods associated with other nemaline myopathy gene mutations, in particular KLHL40 (Fig. ). Pairs of rods connected by thin filaments were also present in a patient with a homozygous LMOD3 mutation (Michael et al. 2019).

Animal and in vitro models of nemaline myopathy

To increase the understanding of the pathogenetic mechanisms leading to nemaline myopathy, several avenues of research have been opened. Animal and in vitro models of nemaline myopathy, in particular mouse and zebra fish models are being explored (Table ). Moreover, functional studies are being performed in relation to specific gene mutations and their proteins, in vitro contraction studies of muscle fibres in relation to altered actin and tropomyosin molecules has identified differences in calcium sensitivity as a mechanism by which disruption of sarcomeric proteins leads to muscle weakness (Marston et al. 2013; Chan et al. 2016; de Winter and Ottenheijm 2017). Efforts are concentrating on the most commonly mutated genes causing nemaline myopathy, ACTA1 and NEB, and descriptions have been published of a variety of knock-in and knock-out mouse models of causative mutations in these genes (Nowak et al. 2013; de Winter and Ottenheijm 2017). In addition, there are also mouse models of the more rarely affected genes CFL- 2, TPM2, TPM3, TNNT1, KLHL40, KLHL41, LMOD3 (see below).

Table 4

NM mouse model (publication)

Severity

Fibre type changes

Nemaline rods/Z-line features

In vitro force

Additional features

Severe/lethal

Stiff gait, kyphosis, progressive muscle weakness from days 10-20

(NR)

Rods, thickened Z lines, loss of myopalladin from Z line, abnormal Ca ²⁺ homeostasis

Shortened thin filament length

Upregulation of sarcolipin, S100A4/A9, desmoplakin, CARP/ankrd2

Tmod1 reduced and translocated towards Z line

Maximal active tension reduced. Overlap between thin and thick filaments 50% of maximum (result of shorter thin filaments). Ca ²⁺ dependent recruitment of cross-bridges perturbed

No observable phenotype in vivo, mild phenotype in vitro

-

-

Maximal force production reduced by around 16% in isolated muscle (related to shift toward slower proteomic phenotype)

Shift toward a slower proteomic phenotype

No impaired energy metabolism

Severe, appear normal at birth

Fibre type switching toward oxidative types, small 2B fibres

Rods, irregular, wavy and thickened Z lines

Large deficit in specific force, stiffness reduced, tension cost increased, lower number of force-generating cross-bridges

Hypotrophy of muscles rich in glycolytic fibres, hypertrophy of muscles rich in oxidative fibres

KLHL40 increased

Severe. Shortened lifespan, respiratory failure possibly caused by severe diaphragm weakness

Diaphragm and EDL: decrease in type 2B fibres, increase in type 2A(X). (Joureau et al. 2016)

Rods seen with EM, at the position of the Z line

Maximal force generating capacity reduced, changes in cross-bridge cycling kinetics (reduced number of bound cross-bridges), and reduction of Ca ²⁺ sensitivity of force generation. ktr lower, tension cost higher

Shortened thin filaments

No observable phenotype in vivo, mild phenotype in vitro

-

Normal

Slightly altered force-frequency relationship. Slightly blunted sensitivity to electrical stimulation but only in a narrow range of frequencies

No structural or histological skeletal muscle abnormalities and no changes in gene expression or localization of interaction partners of the nebulin SH3 domain

Mild to moderate

Significant shift toward slower fibre types

SOL: decrease in Z-line width; EDL: large increase in Z-line width. Loss of nebulin C-terminus may influence Z-line width to a small degree

EDL displayed a drastic loss of force, force loss in the SOL subtle

Loss of C-terminus may affect nebulin stability but length of thin filaments retained

Myotilin and KLHL41 increased

Neb Y2303H,Y935X (Laitila et al. submitted)

Mild to moderate

Smaller fast fibres in EDL, all fibres smaller in SOL

Rods predominantly in 2B fibres, thickened Z lines

Reduced specific force (single fibre level)

Core-like areas

Severe, early lethality, males more severe than females, decreased mobility and forearm grip

Fibre atrophy and increase in slow fibres

2B fibres atrophic in EDL but 2A hypertrophied in diaphragm (Lindqvist et al. 2013)

Cytoplasmic and intranuclear rods, Z-line streaming and widened. Rods in cardiomyocytes (Lindqvist et al. 2013)

Muscle weakness associated with an improved resistance to fatigue (+ 40%) and an increased energy cost (Gineste et al. 2013a, b)

Distinct eye and facial phenotypes; accumulation of thick and thin filaments

Mild to moderate, less active

(NR)

Rods, thickened Z lines, myofibrillar disruption

Weakness in both isolated muscles and single muscle fibres. Less sensitive to Ca ²⁺

Smaller number of myosin cross-bridges strongly bound to actin monomers (Ochala et al. 2012)

High αB-crystallin and desmin in some fibres

Severe

Large variations in myofibre size

Rods, Z-line fragmentation and streaming

(NR)

Increasing mutant protein load from 25 to 45% changes mild phenotype to severe. Actin accumulation

Mild to moderate, less active

Fibre type composition and fibre sizes altered

Rods, rods attached to Z line, thickened Z lines

Significantly weaker than wild-type muscle at 4 weeks of age

Core-like areas, ring fibres (2B fibres) common, internal nuclei and myofibrillar disruptions

Mild, late onset

Increase in slow fibres, compensatory hypertrophy of 2B and 2X fibres

Rods in clusters and areas surrounding the Z line, Z-line streaming and disruption of the sarcomeric register

Differences in normalized force. No changes in the Ca ²⁺ parameters. Lower force-generating capacity caused by decrease in force per cross-bridge rather than reduction in the number of cross-bridges (Gineste et al. 2014)

Cytoplasmic bodies

Reversible muscle weakness: endurance exercise alleviated muscle weakness and reduced the number of nemaline rods (Joya et al. 2004). In vivo muscle improvement not associated with changes in muscle volume or energy metabolism (Gineste et al. 2014)

(NR)

Atrophy and loss of slow fibres. Compensatory hypertrophy of fast fibres

(NR)

Force production lower at low stimulation frequency (40 Hz). Decreased fatigue tolerance and impaired recovery

Fast TnT increased by 60%

Increase in number of type1 characterized by small size and central nuclei

Severe weakness, little movement, possibly unable to suck

Elevated numbers of slow fibres, fibre size disproportion

Rods seen with EM, severe sarcomeric disruptions

(NR)

Accumulation of α-actin, α-actinin-2 and TPM

Fast-fibre specific genes downregulated, slow fibre genes upregulated

Mitochondrial abnormalities and internal nuclei. Muscle pathology differed from nemaline myopathy, but showed combined features of actin-associated myopathy and myofibrillar myopathy

Severe

Reduced myofibre size

Rods, disrupted sarcomeres

(NR)

Internal nuclei, accumulation of desmin, upregulation of sarcolipin

KLHL40-KO (Garg et al. 2014)

Severe/lethal

(NR)

Rods, thickened Z lines, Z-line streaming

> 50% reduction in hind limb strength

Complete disorganization in subset of fibres. Almost complete absence of LMOD3, nebulin 50% reduced. Increased expression of sarcomere genes. Klhl40 ± (heterozygous) mice also had reduced LMOD3, without growth defects or early lethality

KLHL41-KO (Ramirez-Martinez et al. 2017)

Severe/lethal (Het normal)

(NR)

Rods, Z-line streaming

(NR)

Aggregation and down-regulation of nebulin and only a slight decrease in LMOD3 protein but not RNA, decrease in ssTNT and β-TPM

Many of the mouse models have shown early lethality, precluding their use as testbeds for experimental therapies, while others are less severely affected. An ideal model for the most common (mainstream or typical) form of nemaline myopathy caused by two different mutations in NEB is being developed (Laitila et al. submitted for publication). Mice devoid of nebulin, and showing early lethality, mirror the human disease only to a limited extent and do not consistently show rods (Bang et al. 2006; Witt et al. 2006). As no human patients with mutations causing total absence of nebulin have been reported, and since it has been thought that nebulin works as a ruler for thin filament length and maintaining Z-line structure (Ottenheijm et al. 2012), it is remarkable that the knock-out mice do form sarcomeres despite the absence of nebulin.

In a mouse model of TPM3 nemaline myopathy (Gineste et al. 2014), the onset of muscle weakness, caused at least partially by hypotrophy of type 1 fibers, appeared to be delayed by compensatory hypertrophy of type 2 fibers, as in human patients.

In Tnnt1 mice, depicting the "Amish" form of nemaline myopathy, there was severe weakness of the diaphragm (Wei et al. 2014), as in human patients, and an increase in fast 2B fibre types, but this myosin isoform is not expressed in human limb muscle.

A mouse model of CFL- 2 nemaline myopathy showed severe weakness, small body size and early lethality. Histologically, there was actin accumulation (as seen in humans with CFL- 2 mutations) whereas nemaline bodies were small and only seen on EM in severely disrupted fibres (Agrawal et al. 2012; Gurniak et al. 2014).

Mouse models of LMOD3 nemaline myopathy showed atrophy of fibres with fast myosin, a 50% reduction of grip strength (Tian et al. 2015), small body size and normal lifespan (Cenik et al. 2015).

Mouse models of KLHL40 and KLHL41 nemaline myopathy showed early lethality (within days to weeks from birth). KLHL40-deficent mice had a secondary reduction in nebulin and LMOD3 whereas the KLHL41 knock-out mice only showed reduction of nebulin (Garg et al. 2014; Ramirez-Martinez et al. 2017). The rectangluar rods seen in human patients with nemaline myopathy caused by mutations in these two genes were not reported in the Klhl40 model but they were apparent in the Klhl41 knock-out mouse.

Development of therapies for nemaline myopathies

There is currently no curative treatment for patients with nemaline myopathy, but much can be achieved by a multidisciplinary approach, addressing the management of symptoms and maintaining muscle strength, mobility, joint movements, and independence in the activities of daily living through exercise and physiotherapy. Particularly important is regular monitoring of respiratory function and addressing orthopaedic problems, especially any scoliosis (Wallgren-Pettersson et al. 2004; Wang et al. 2012).

Tyrosine as a treatment for nemaline myopathy has been advocated, but an apparently beneficial effect in a limited clinical trial of dietary tyrosine supplementation (Ryan et al. 2008) was not supported up by studies of the nemaline myopathy Tg ACTA1 D286G mouse model, nor the zebrafish model based on the same mutation (Messineo et al. 2018; Sztal et al. 2018a). Other amino acid supplements tested in zebrafish also showed no clear positive effect (Sztal et al. 2018a). The improvement in skeletal Acta1 knock-out mice through upregulation of cardiac actin (Nowak et al. 2009) raises hopes for therapeutic implications for patients, but requires very early diagnosis. Another therapeutic option to explore is increasing the proportion of normal skeletal actin in heterozygous patients (Ravenscroft et al. 2011a, b). Interestingly, a zebrafish morpholino knock-down model of ACTA1 nemaline myopathy showed a milder phenotype because of a transcriptional upregulation of an actin paralogue, i.e. through genetic compensation (Sztal et al. 2018b).

Experimental trials with myostatin in two mouse models of Acta1 nemaline myopathy did not yield stronger mice, but in the Tg ACTA1 D286G mouse model the body size increased (Tinklenberg et al. 2018) and a similar trial in the Acta1 H40Y mouse model led to both larger size and longer life-span (Tinklenberg et al. 2016). The use of a myosin transgene to improve muscle function in an Acta1 mouse model for nemaline myopathy (Lindqvist et al. 2016) and the use of calcium sensitizers to improve diaphragm function (Ochala 2010; Doorduin et al. 2012) raise interesting perspectives for the future.

Conclusions

Our increasing understanding of the pathogenetic mechanisms, and the lines of therapeutic options explored hitherto make it timely to plan a natural history study of nemaline myopathy and an international patient registry. In doing so, the international collaborative effort will pave the way for therapeutic trials, once non-hazardous and potentially effective treatment modalities become available.

Acknowledgements

Financial support from Muscular Dystrophy UK, the Sigrid Jusélius Foundation, the Folkhälsan Research Foundation, the Finska Läkaresällskapet, the Medicinska understödsföreningen Liv och Hälsa, and l'Association Française contre les Myopathies (JL, CW-P) and the National Specialised Services to the Dubowitz Neuromuscular Centre and UCL Institute of Child Health and Great Ormond Street Hospital for Children (CAS) is gratefully acknowledged.

Footnotes
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References

Berger J, Berger S, Li M, Currie PD. Myo18b is essential for sarcomere assembly in fast skeletal muscle. Hum Mol Genet. 2017;26:1146-1156. doi: 10.1093/hmg/ddx025. [[PubMed] [CrossRef] Google Scholar]

Chan C, Fan J, Messer AE, Marston SB, Iwamoto H, Ochala J. Myopathy-inducing mutation H40Y in ACTA1 hampers actin filament structure and function. Biochem Biophys Acta. 2016;1862:1453-1458. doi: 10.1016/j.bbadis.2016.04.013. [[PMC free article] [PubMed] [CrossRef] Google Scholar]

Dominguez Rubio R, et al. Intranuclear protein aggregation in myofibrillar myopathies. Neuromuscul Disord. 2016;26:S191. [Google Scholar]

Dubowitz V, Sewry CA, Oldfors A. Muscle biopsy: a practical approach. 4. Oxford: Elsevier; 2013. [Google Scholar]

Messineo AM, et al. l-tyrosine supplementation does not ameliorate skeletal muscle dysfunction in zebrafish and mouse models of dominant skeletal muscle alpha-actin nemaline myopathy. [[PMC free article] [PubMed] Google Scholar]

Ochala J. Ca[²⁺ sensitizers: an emerging class of agents for counterbalancing weakness in skeletal muscle diseases? Neuromuscul Disord. 2010;20:98-101. [PubMed] Google Scholar]

Pinto MM, et al. Sarcomeric disorganization and nemaline bodies in muscle biopsies of patients with EXOSC3-related type 1 pontocerebellar hypoplasia. Muscle Nerv. 2019;59:137-141. doi: 10.1002/mus.26305. [[PubMed] [CrossRef] Google Scholar]

Ramirez-Martinez A, Cenik BK, Bezprozvannaya S, Chen B, Bassel-Duby R, Liu N, Olson EN. KLHL41 stabilizes skeletal muscle sarcomeres by nonproteolytic ubiquitination. Life. 2017;6:e26439. doi: 10.7554/elife.26439. [[PMC free article] [PubMed] [CrossRef] Google Scholar]

# data[].attributes.attachment_link.description
Nemaline myopathies are a heterogenous group of congenital myopathies caused by de novo, dominantly or recessively inherited mutations in at least twelve genes. The genes encoding skeletal α-actin ( ACTA1) and nebulin ( NEB) are the commonest genetic cause.

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Continuing Education Activity

Congenital myotonic dystrophy (CMD) is an autosomal dominant neuromuscular disorder with multisystem involvement. It is a subtype of myotonic dystrophy type 1. Features include severe hypotonia and generalized muscle weakness; myotonia is classically absent in infancy. This activity will review clinical features, pathophysiology, and management strategies in CMD. It also highlights the importance of the interprofessional team in achieving the best outcomes in patients suffering from CMD.

Objectives:

Describe the incidence of congenital myotonic dystrophy (CMD).

Summarize the causes of congenital myotonic dystrophy (CMD).

Outline the clinical features of congenital myotonic dystrophy (CMD).

Summarize how an interprofessional team is critical for the symptoms management, surveillance, and family support of patients with congenital myotonic dystrophy (CMD).

Access free multiple choice questions on this topic.
Introduction

Congenital myotonic dystrophy (CMD) is an autosomal dominant genetic disorder caused by trinucleotide repeat expansion of CTG (cytosine-thymine-guanine) in the DMPK (dystrophia myotonica protein kinase) gene on chromosome 19q 13.3. DM is more than just muscular dystrophy as the affected individuals show the involvement of other organ systems such as cataracts, cardiac conduction anomalies, insulin resistance, the congenital form being associated with developmental disabilities, etc.[1] Two major forms are described in the literature.

Myotonic dystrophy type 1 (DM1), also known as Steinert disease Myotonic dystrophy type 2 (DM2), which is a milder version of DM1.

Like any trinucleotide expansion repeat diseases, a larger number of repeats are associated with the severity of the disease.[2][3]

Natural History:The incidence of CMD is 1 in 47619 live births, and the mortality in the neonatal period is up to 40%. Severe CMD demonstrates a unique "biphasic" course; in which neonatal symptoms improve/stabilize in surviving neonates before adult-onset symptoms present in later life.[4]

Etiology

Congenital myotonic dystrophy is caused by the repeat expansion of trinucleotide "CTG" (cytosine-thymine-guanine) in the 3'-untranslated region of the myotonia dystrophy protein kinase (DMPK) gene located on chromosome 19q 13.3. Myotonic dystrophy type 2 is caused by a CCTG expansion in intron 1 of the ZNF9 (e zinc finger protein 9) gene. Parallels between these mutations indicate that microsatellite expansions in RNA can be pathogenic and cause the multisystemic features of DM1 and DM2.[5] Variability in the clinical expression of DM1 is thought to be caused by somatic mosaicism due to instability of CTG repeat expansion in the somatic cells during life due to an abnormality in the DNA repair.[6]

The severity of the disease is correlated with allele size (number of repeats) with <30 repeats in an average healthy person to >11,000 repeats in the affected person; however, mild cases were reported with long expansions.[7]

Two important terms are used in the description of autosomal dominant diseases, i.e., penetrance, and anticipation. Penetrance refers to the percentage of the individuals showing signs of the disease, from the mildest to the most severe phenotype. If all individuals who have a disease genotype exhibit the disease phenotype, then the disease is said to be 'fully penetrant' or to have a penetrance of 100%. Anticipation refers to the increased disease severity and decreased age of onset in successive generations.[8][4][9]

In DM1, all clinical phenotypes except premutation exhibit full penetrance and anticipation.[10][11]

Full penetrance alleles of more than 50 are associated with disease manifestations. In CMD, repeats are usually more than 1000, compared to less than 37 in normal individuals, and 38-49 in premutation allele patients (asymptomatic). Offspring of premutation patients can inherit longer repeats, increasing the risk of disease and decreasing the age of onset in the next generations (anticipation). Contrary to the classic (adult), the maternal transmission is up to ~90% of cases, and only 9-12% are paternal. The mechanism is not yet well understood; however, maternal and intrauterine environment are considered contributing factors.[3][12]

Epidemiology

Myotonic dystrophy is the most prevalent adult muscular dystrophy among the people of European ancestry with a minimum prevalence of 11.84/100,000[13][14]

The incidence of CMD is 1 in 47619 live births, higher in specific areas (Quebec, Canada) [4]

Canada - 2.1 in 100,000 (1 in 47,619) live births [16]

South Africa - 3 per 100,000 live births [17]

Taiwan 0.46/100,000 inhabitants (adult type) [18]

In a systemic review, the prevalence of all muscular dystrophies was 19.8 to 25.1 per 100,000 person-years. Myotonic dystrophy (0.5 to 18.1 per100 000), Duchenne muscular dystrophy (1.7 to 4.2), and facioscapulohumeral muscular dystrophy (3.2 to 4.6 in 100 000) were the most common types.[19]

Pathophysiology

Mutation in the 3′ untranslated, noncoding region of DMPK gene, located on chromosome 19q13.3, results in the expansion of DNA (CTG) repeats. Transcription of DNA results in a mutant RNA that disrupts the splicing of CUG binding protein (CUG-BP) and Musclebind-like protein (MBNL). This leads to the sequestration of splicing factors forming ribonuclear inclusions. In turn, this disturbs cellular signaling and causes toxic effects on muscle metabolism and RNA processing. This process is known as spliceopathy.

MBNL 1 protein is abundant skeletal muscle, whilst MBNL 2 in brain tissue. These proteins exhibit loss of function, as they are aggregated in the nucleus and unable to be utilized by the cell. Conversely, CUG-BP binds to cardiac troponin and exhibits gain of function via increased activation and phosphorylation. Elevated levels result in cardiac abnormalities, and abnormal insulin receptor function, elucidating the risk of diabetes. It also inhibits myoblast differentiation, resulting in loss of CIC-1 chloride channels through disruption of splicing. Defect in the splicing results in sustained muscle contraction with an inability to relax (myotonia).[4][12][20]

Histopathology

Muscle biopsy is required in certain cases where genetic testing comes out to be inconclusive. Microscopy can show increased internalized nuclei (boxcar appearance), ring fibers, sarcoplasmic masses, and type 1 fiber atrophy with a pyknotic clump and type 2 fiber hypertrophy in DM1 and type 2 fiber atrophy in DM2.[21][22]

Electron Microscopy Appearance: Sarcoplasmic masses composed of disorganized myofibrils, dilated sarcoplasmic reticulum, and free ribosomes.

History and Physical

History

It includes detailed birth history, medical/surgical history, and 3-generation family history.

Clinical features associated with CMD are as follow:[4]

Prenatal: polyhydramnios, reduced fetal movements, preterm delivery <36 weeks, small for gestational age.

Neonatal: hypotonia, hyporeflexia, muscle weakness (distal > proximal), neck muscle weakness (flexion), myopathic facies (ptosis, facial diplegia, atrophy of temporalis muscles, tent-shaped mouth), contractures, arthrogryposis, scoliosis, talipes equinovarus, visual impairment (cataract, lens opacification), respiratory distress, weak cough, sleep apnea, pulmonary hypoplasia, bronchopulmonary dysplasia, raised right hemidiaphragm, pneumothorax, recurrent infections/otitis media, aspiration pneumonia, feeding and sucking difficulties, gastroparesis, GERD, constipation/diarrhea, fecal incontinence, increased sensitivity to anesthesia (due to respiratory muscle compromise and central dysregulation of breathing), cardiac conduction disturbances, valve defects (mitral), and early death.

Infancy and childhood, age 1 to 10 years: usually, they are able to walk with improvement in motor function; however, progressive weakness restarts in the 2nd decade. Myotonia (by 10 years of age), intellectual disability (50-60%), autism, ADHD, psychiatric disorders, vision problems (hyperopia, astigmatism, cataract), excessive daytime sleepiness, cardiac and endocrine complications.

1. Respiratory: respiratory difficulties are found in 50% of neonates and are the main cause of neonatal mortality and used to distinguish between mild and severe CDM.

2. Musculoskeletal: proximal muscle weakness in DM1 indicates a poor prognosis. The biphasic course in CMD shows improved/stable disease until adolescence/young adult with gradual deterioration. Complications of muscle weakness may include scoliosis and contractures producing foot deformity and toe walking. Bulbar muscle weakness may produce swallowing, speech, and language difficulties.

3. Cognition: cognitive impairment is one of the most common and challenging manifestations of childhood DM1. CDM patients are most affected, with IQ range 40 to 80, mean 70 (average normal 100). Cognitive impairment correlates with the severity of weakness, size of CTG repeat, and maternal transmission.

4. Sleep: excessive sleep disorder and sleep apnea may adversely affect learning, memory, high-level cognitive processing, and physical functioning, exacerbating psychomotor and cognitive delays.

5. Psychosocial: 50% of children have psychiatric diseases (phobia, depression, anxiety), and ADHD. Avoidant personality, apathy, and autistic features may be present.

6. Cancer: There is an increased risk of cancer in patients with type 1 myotonic dystrophy, including thyroid, uterine, choroidal melanoma, colon, testicular, prostate, and basal cell cancer.

7. Others: features of adult "classic" DM are not evident in childhood, including cataracts, significant cardiac disorders, and diabetes mellitus. Lens pathology is evident in 40% and can predict future cataract. Conduction disturbances observed on ECG, or valve abnormalities may be symptomatic. Hypothyroidism, hypogonadism, growth hormone abnormalities, and androgen insensitivity are rare. In contrast, testicular atrophy and infertility are common in CDM males, as are irregular menses in CDM females.

Physical Exam: vital signs, weight, height, and head circumference measurements are essential. Comprehensive neonatal exam looking for dysmorphic features, contractures, scoliosis, pulmonary and cardiac evaluation for abnormal chest rise, or murmurs. Abdominal exam for organomegaly, back for scoliosis, the musculoskeletal system for contractures, detailed neurological exam assessing mental status, cranial nerves (myopathic facies, ptosis, dysphagia, weak cry/cough/gag, respiratory failure), motor (axial and appendicular hypotonia, frog-like posture, decreased movements), reflexes, Babinski response, sensory, coordination and primitive reflexes. Examine mother (myopathic facies, shake hand as myotonia prevents the prompt release of grip, percussion with a reflex hammer, by tapping thenar, wrist extensor will produce involuntary muscle contraction with a delay in relaxation, called percussion myotonia).[23]

Evaluation

Molecular Genetic Testing (first line): targeted analysis of the DMPK gene appears positive for a heterozygous pathogenic variant in nearly 100% of affected individuals. If the diagnosis is uncertain, the panel can be completed. The multigene panel can include testing for the DMPK CTG repeat expansion and other disorders of interest, depending on the laboratory.

Serum CK: normal to mildly elevated.

Muscle Biopsy (if negative genetic testing): increased internalized nuclei (boxcar appearance), ring fibers, sarcoplasmic masses, and type 1 fiber atrophy with a pyknotic clump.

Electromyography: records myopathic units (distal muscles), fibrillation potentials, and positive sharp waves. Fast runs of single-fiber discharges approaching the pattern of myotonic discharges are seen, without typical waxing and waning electrical myotonia.

Brain MRI: may show ventricular dilatation, cortical atrophy, hypoplasia of the corpus callosum, and white matter abnormalities.[2][8][4][12]

Treatment / Management

Severe congenital myotonic dystrophy (CDM) will require intensive care mainly for feeding and respiratory support. Gastric/jejunum feeding tube, tracheostomy for mechanical ventilation, and splinting of talipes is occasionally commenced. Genetic counseling and end of life counseling are essential.[8][23][24]

Thereafter, a multidisciplinary team approach is critical for symptom management, surveillance, and family support. The following recommendations are acquired from Consensus-based care recommendations for congenital and childhood-onset myotonic dystrophy type 1 published in 2019,[25], and 2- Consensus Statement on Standard of Care for Congenital Muscular Dystrophies, published in 2014.[26]

Neurology: disclosure of diagnosis should address five items: diagnosis, prognosis, recurrence risk, treatment plan, and family/community support. Patients should be followed by an experienced multidisciplinary team in the neuromuscular clinic. Routine surveillance every 3 to 4 months for infants less than 12 months, and 4 to 6 months in toddlers of more than 12 months. Allied health teams include nurses, physical and occupational therapists, speech and language therapists, social workers, and genetic counselors. Focusing on the financial burden and psychosocial aspects is vital. Referral to ophthalmology and other services, as discussed below, is recommended.

Respiratory: the primary goal is to monitor respiratory function, decrease secretions, and manage assisted ventilation. There is often an improvement in respiratory strength over time, and consideration for tracheostomy should be careful. Maintenance pulmonary therapy includes cough assist, breathe staking, etc. Pulmonary function testing includes vital capacity (<40% predict nocturnal hypoventilation), spirometry (>20% difference between sitting and supine vital capacity indicates diaphragmatic weakness and is a predictor of nocturnal hypoventilation). Other tests include peak cough flow, polysomnography, and blood gases. Pneumococcal and influenza vaccines are recommended, and palivizumab against RSV for children under two years of age.

Cardiology: arrhythmias, myopathies, and structural cardiac diseases can present with lethargy, dyspnea, pallor, palpitations, and syncope. Twice yearly assessment is required with closer follow-ups in symptomatic patients.

Gastroenterology: serial monitoring of nutrition and growth, feeding, GI motility (GERD, dysmotility, constipation), and oral care is recommended. Feeding tubes with or without Nissen fundoplication, laxatives, antacids, proton pump inhibitors, antiemetics, and probiotics are advisable to consider.

Malocclusion, teeth crowding, caries, and gingival hyperplasia (prolonged NPO) should prompt an orthodontist evaluation.

Orthopedics and Rehabilitation: conservative or surgical interventions are required to manage joint contractures, scoliosis, foot, and spine deformities. Bracing, serial splinting and assisting devices to include walkers, orthotics, scooters, and wheelchairs, might be required to facilitate standing/walking/sitting. Yearly evaluation is recommended, more frequent in younger children to assess motor development and function. Physical activity is essential as children will experience progressive improvements of proximal muscle strength.

Pain Management: Patients with CMD are prone to developing contractures and can lead to painful spasms and joint pain. Adequate management of pain is important to achieve a good quality of life.[27][28][29]

Surgical Care: pre-anesthesia assessment, prolonged postoperative monitoring, and combined procedures under single sedation are recommended as children at higher risk for complications. Avoidance of specific agents, including inhaled sedation (halothane), IV sedation (thiopentone), muscle relaxants (succinylcholine, vecuronium), neostigmine, and some chemotherapy, is essential. Propofol-induced pain can induce myotonia.[8]

Psychiatry: Patients with CMD with their disability are prone to develop depression and anxiety and must have a psychiatry/psychologist referral as part of multidisciplinary care.[30]

Every six months: dentistry assessment

Every year: ECG, 24-hour Holter, pulmonary function test, fasting glucose/HBA1C

Every two years: ophthalmologic exam

Surveillance:[3]

Differential Diagnosis

Congenital myopathies (multiminicore, nemaline, and centronuclear) [8]

Hereditary inclusion body myopathy

Limb-girdle muscular dystrophy types 2B (dysferlinopathy) and 2L

Differential diagnoses of congenital myotonic dystrophy include the following:

Antisense Oligonucleotides (AONs): work by degrading the CUG expansion, or by binding to CUG expansion to inhibit RNA sequestration and sites for abnormal MBNL binding.

Recombinant Adeno-associated viral (rAAV): stimulates overexpression of MBNL1, to prevent sequestration. Inhibition of CUG-BP1 activity via small molecules (pentamidine) or by inhibiting protein kinase C (involved in activating CUG-BP1) can also prevent sequestration.

Clustered regularly interspaced short palindromic repeats (CRISPR/Cas): cleave and degrade CUG mRNA expansion.

Others: agents to increase muscle anabolism, such as testosterone, creatine, dehydroepiandrosterone, and recombinant insulin-like growth factor (IGF-1), and myostatin inhibitors.

Pertinent Studies and Ongoing Trials

Prognosis

The mortality rate is up to 40% in the neonatal period due to respiratory diseases. The mean life expectancy is 45 years.[3][4]

Complications

Severe CDM will require intensive care mainly for feeding and respiratory support. Gastric/jejunum feeding tube and tracheostomy for mechanical ventilation are occasionally required.[3]

1. Congenital myotonic dystrophy (CMD) is a multisystem disease affecting many organs in the body. It is caused by a mutation in the DMPK gene.

2. Infants appear weak, and sometimes require help with breathing and feeding.

3. It is usually diagnosed by genetic testing for the targeted gene.

4. There is no cure, but multiple teams will follow the patient for symptoms management, surveillance, and family support.

5. Unfortunately, the mortality rate is up to 40% in the neonatal period secondary to respiratory failure.

Deterrence and Patient Education

1. Congenital myotonic dystrophy (CMD) is an autosomal dominant neuromuscular disorder with multisystem involvement. It is a subtype of myotonic dystrophy type 1. Features include severe hypotonia and generalized muscle weakness; myotonia is classically absent in infancy.

Severe CDM will require intensive care mainly for feeding and respiratory support. Gastric/jejunum feeding tube, and tracheostomy for mechanical ventilation, and splinting of talipes is occasionally commenced.

2. Mutation in the DMPK gene, located on chromosome 19q13.3, results in the expansion of DNA (CTG) repeats.

3. Targeted molecular genetic testing of the DMPK gene appears positive for a heterozygous pathogenic variant in nearly 100% of affected individuals.

4. The multidisciplinary team approach is critical for symptom management, surveillance, and family support.

5. The mortality rate is up to 40% in the neonatal period due to respiratory diseases. The mean life expectancy is 45 years.

Pearls and Other Issues

Enhancing Healthcare Team Outcomes

As discussed previously, a multidisciplinary team approach is critical for symptom management, surveillance, and family support. Consensus-based care recommendations for congenital and childhood-onset myotonic dystrophy type 1 published in 2019, and Consensus Statement on Standard of Care for Congenital Muscular Dystrophies, published in 2014 summarized the guidelines recommended inpatient care.[25][26]

Future clinical trials include:

1 Natural History: Trial Readiness and Endpoint Assessment in Congenital Myotonic Dystrophy (TREAT_CDM): children with CDM between ages 0 and 15 will be enrolled, with visits at baseline and one year to evaluate physical and cognitive function and quality of life, to extend understanding of disease progression.

2 Treatment: Efficacy and Safety of Tideglusib in Congenital Myotonic Dystrophy. Randomized, double-blind, placebo-controlled trials of tideglusib versus placebo in the treatment of children and adolescents 6 to 16 years of age with congenital DM1. The outcome is a change in Clinician-Completed Congenital DM1 Rating Scale (CDM1-RS) after 22 weeks.

References

# data[].attributes.attachment_link.description
Congenital myotonic dystrophy (CMD) is an autosomal dominant genetic disorder caused by trinucleotide repeat expansion of CTG (cytosine-thymine-guanine) in the DMPK (dystrophia myotonica protein kinase) gene on chromosome 19q 13.3.

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ERS Bronchiectasis in Children & Young People 2021

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ERS Bronchiectasis in Children & Young People 2021

# data[].attributes.attachment_link.readable_text
This post was created by DFTB in collaboration with Health Education England, Respiratory Surge in Children programme

As cases of bronchiolitis increase in the wake of COVID we wanted to visit some of the more pragmatic aspects of care. In this post, we are going to go over high flow oxygen.

What is high flow?

Horses, like babies, are obligate nasal breathers. As they gallop around the racecourse their massive lungs can draw in around 160 litres of air every minute. This can lead to exercise-induced pulmonary haemorrhage. In fact, the 'bleeding;' affects 95% of racing thoroughbreds. Tired of treating with horse frusemide (actually, the same as human frusemide, but probably more expensive) Blacker and Hedman (1988) developed a device to train horses, to condition their cardiorespiratory system to the high flows they would be exposed to.

In a case of horses for courses, the thought occurred to the engineers at Fisher and Paykel that if such a device could reduce the work of breathing for a horse, it might just work for something 120 times smaller.

Is it high flow an aerosol generating procedure (AGP)?

Optiflow™️/Airvo™️/heated humidified high flow nasal cannula oxygenation is an aerosol-generating procedure and, as such, should be performed in an appropriate environment with staff wearing the appropriate level of PPE. This also impacts where the treatment is started. It makes no sense to start the patient on therapy in the paediatric emergency department only to then switch it off to transfer them to either the ward or HDU. It is far more sensible to commence treatment in the setting where it is going to be continued.

The decision to initiate high flow therapy should be made by a senior decision maker.

Why do we use high flow?

There has been a great deal of debate over the evidence base for the superiority of high flow nasal cannula oxygen therapy over standard nasal cannula oxygen in cases of moderate-to-severe bronchiolitis. Anecdotally, as staff become more comfortable setting it up and using it, high flow is started earlier. This leads to an ' it works because I have seen it work' mentality. Trial the patient on nasal cannula oxygen first. If they remain hypoxic with oxygen saturations less than 90% then perhaps you should start them on high flow, but this is a decision that should be placed in the context of that child's acuity and background combined with the local system and availability of escalation personal and resource (see "Getting Started" section)

Humidification and heating (to 34°C) can reduce the damage to nasal mucosa caused by room temperature air. The increased ambient moisture in the respiratory tract can also help loosen stubborn mucus.

Standard nasal cannulae may not be able to match the higher inspiratory flow rates needed in the respiratory failure of bronchiolitis.

High flow may increase the functional residual capacity, or FRC, at the end of expiration, not due to increased PEEP, per se, but due to alveolar distension.

The increased inspired concentration of oxygen will reduce the dilution of entrained air.

There is some soft evidence (in animal models) that it can help wash out CO ₂ from the oropharyngeal dead space but if there are chest x-ray changes suggestive of some consolidation on the background of increased work of breathing it is probably worth starting high flow sooner rather than later.

High flow should NOT be started in patients with craniofacial abnormalities, recurrent apnoeas (consider intubation) or undrained pneumothoraces.

Getting started with high flow

We tend to base our estimate of the patient's needs on their oxygen saturations. If they are less than X we admit, and if they are greater than Y we send them home. We need to have a degree of flexibility in our guidelines based on a number of factors including pre-morbid conditions, how well the child looks and not just a magic number. Schuh et al (2014) showed that we tend to focus on the number, not the patient. When experimenters presented clinicians with artificially raised oxygen saturations, a lot fewer children were admitted. If we are not looking at the number but instead the duration of symptoms then we should heed the data from BIDS. The Bronchiolitis in Infancy Discharge Study (BIDS) found that whether we targeted sats of 90% or 94%, the cough still persisted for about 15 days.

If the patient improves there is little role for continuous pulse oximetry monitoring. Chi et al (2020) suggest it leads to an increased length of stay for no intrinsic patient benefit as staff and parents watch the monitor waiting for the correct number to pop up. It is much better to base weaning and discharge decisions around an assessment of effort and effect of breathing.

There is still a great degree of debate ongoing surrounding the benefits of high flow oxygen therapy with Kepreotes et al (2017) showing that the duration of supplemental therapy required was no different between the high flow and standard oxygen therapy groups. The more recent PARIS trial (2018) also compared standard oxygen therapy to high flow therapy. Whilst Franklin et al (2018) suggested an NNT of 9 to prevent one escalation of care (from standard O ₂ to high flow) there is an alternative reading of the data. If you start a patient on humidified high flow nasal cannula oxygen at the outset, 70% of the time it will be of no benefit to the patient. The trial was really a comparison of immediate high flow to rescue high flow therapy. Read Ally Munro's piece to dive a little deeper.

Monitoring during high flow

Once a patient requires high flow therapy it is worthwhile considering where this will take place. Should it be started in the paediatric emergency department? Can the patient be managed on the ward? Should they go to PICU? Some of these decisions may have already been made before a single patient even comes through the doors with many district general hospitals not having a PICU service. There seems to be a divide between what is acceptable practice in a tertiary centre and what is acceptable in a district general hospital. These decisions are often based on both staffing levels and staffing competence. Interestingly financial considerations may not come into it as a number of studies have shown that it is cheaper to run high flow in a ward-based environment than in a PICU/HDU (Kalburgi and Halley, 2020). As the need for supplemental oxygen therapy rises is it likely that a compromise will have to be reached. Bressan et al. (2013), in a pragmatic study involving 27 infants with moderate-to-severe bronchiolitis, recorded no adverse events when they were treated with high flow in a ward-based environment.

When patients with a common disease, such as bronchiolitis, present in numbers, it is easy to think of them as a homogenous entity. One of the big challenges is identifying the patient that has a purely respiratory compromise, and needs assistance, from children who are maybe septic or have a degree of fluid overload or myocarditis. It seems reasonable for patients who simply require mild to moderate respiratory support and have no red flags for deterioration to be managed by skilled nurses in a ward-based environment. There need to be clear track and trigger guidelines in place to support nursing staff in the event of clinical deterioration.

Tachypnoea is more of a problem than tachycardia. As the rate goes up there are more insensible losses. If you can increase the flow (and hence the volume delivered) then things tend to settle down.

All children on high flow can turn tachycardic and grumpy. It is hard to know if this is their normal unless you have seen them earlier in the admission. Likewise, tachypnoea is also very subjective. If you are unsure then this is a great opportunity for some shared decision making with the retrieval service using telehealth (or your mobile phone).
Dynamic assessment is the key. Assess, intervene, watch and wait, then reassess. Repeat as necessary.
Managing on high flow

All patients on high flow therapy should have a nasogastric tube inserted before commencement. This reduces the risk of gastric distension and subsequent diaphragmatic incursion on respiration. If the child cannot tolerate oral feeds then the NG can also be used to provide enteral nutrition.

Weaning high flow

There are two main ways to wean a patient off of high flow oxygen. We can either wean the flow down first then switch to nasal cannulae or we can wean the percentage of inspired oxygen first. Generally the older (and heavier) a child is, the faster they will get better. It's time to refresh some of our respiratory physiology and Poiseuille's law. Smaller airways are more likely to get gunked up with snot and mucus. This creates turbulent flow. This, in turn, leads to increased work of breathing. The same amount of mucus in a larger away contributes much less and so there is more laminar flow and reduced work of breathing.

The RCPCH National guidance for the management of children with bronchiolitis and lower respiratory tract infections during COVID-19 map out a rapid weaning plan. Essentially, there are two options.

Weaning the flow

Wean the flow rate down to 1l/kg then switch to standard nasal cannulae

Weaning the oxygen

Once on a FiO ₂ of 0.3 (30%) oxygen (regardless of flow rate flow) switch to standard nasal cannulae.

Deteriorating on high flow

Some children are more likely to fail high flow therapy than others, becoming either hypoxic or apnoeic. See the table below for some key risk factors.

The smaller, younger patient still has an immature breathing system. If Optiflow™️ is started at the right time the overwhelming majority get better - and go home. There will always, however, those that do not get better with CPAP. Flipping the switch from CPAP to BiPAP will offer more respiratory support. It can feel uncomfortable doing this if you have not done it before. Most PICU outreach services can provide training on how to swap modes. This may be enough to stave off the need for intubation, critical care retrieval and the subsequent filling of limited paediatric ICU beds.

Transport considerations

There may be times when transportation to a tertiary centre is required to provide ongoing care. This can be a real challenge when a patient is on high flow oxygen. Early discussions with the retrieval service can prevent delays down the track. We tend to think of a retrieval service in isolation, dealing with the patient in front of us. It is important to recognise that it is not just a simple matter of popping along in an ambulance and picking up a child and taking them down the road. Each case, or mission, can take eight hours, on average. Longer journeys of up to eighteen hours are not unheard of.

Moving the patient from a safe, warm building to another safe, warm building via a rattling metal box on wheels is not without risk. One also needs to consider the profound impact on the family of moving their child away from their home hospital to somewhere many hours away from where they may have no psycho-social support. Better training and better resources will improve family-centred care.

Power

Many ambulances only have a two-pin plug, rather than a mains plug, and so need a converter. These cost a few pounds but require PAT testing to make sure they are medically safe. Not all transport services have access and so the Optiflow™️ device cannot be plugged in.

Oxygen

An 18-month-old toddler with bronchiolitis weighs approximately 10kg in weight. At 2l/kg/minute they will go through 20 litres of oxygen a minute. A standard ambulance holds 2 D size (1600L) cylinders. The smaller C-size handheld cylinders hold just 450L. Either should be more than enough for a single trip by road, even if you are driving from West Cornwall Hospital to Caithness General Hospital.

If you don't have high flow, then what?

Healthcare is beset with the challenge of managing with finite resources. Whilst we might be able to cope with a few cases of bronchiolitis in any given year it is possible that demand for high flow outstrips availability. There are devices available that can, for very little cost, converts the dry oxygen from the wall to humidified (but not warmed) oxygen. When a baby is bunged up with copious secretions that will cause them to plug off their airways humidification of their supplemental oxygen is key. Even at higher flow rates ( 2l/kg/min), it is better to humidify the oxygen.

High flow vs low flow vs headbox - Ian Sinha looks at the evidence

We did a quick and dirty analysis looking at 8 studies ( 2122 infants)

In hypoxic infants, using high flow instead of low flow made no difference in terms of length of stay, the need for ICU admission or the need for mechanical ventilation. We can say this with a moderate to high degree of certainty though this is impaired by the lack of blinding, and differences in ICU admissions between the studies.

Risk of bias

Risk of bias summary

226/969 ( 23.3%) of infants randomised to low flow 'failed' and required escalation of therapy. It does not appear that high flow modifies the disease process.

There is no evidence, apart from one small study, comparing high flow to headbox oxygen so meaningful comparisons and conclusions cannot be inferred.

Low flow oxygen is sufficient in around 75% of infants. If care needs to be escalated because of hypoxemia then they are not at risk of worse outcomes than if they have been commenced on HFNC oxygen at the outset.
If there is a shortage of high flow delivery devices then humidify the standard wall oxygen.
The Bottom line
Unless a child is critically hypoxic or apnoeic start them on nasal cannula O₂ if their saturations are less than 90%.

High flow oxygen is safe for use in the ward environment in appropriate, low-risk patients

Upskilling staff to flick the switch to BiPAP may lessen the need for higher level care thus reducing the PICU workload

Talk to your retrieval service early, they may be able to guide you in order to optimise therapy
Selected references

Blackmer RH, Hedman JW. (1988). Method and apparatus for pulmonary and cardiovascular conditioning of racehorses and competition animals. US4722334A.

Bressan, S., Balzani, M., Krauss, B., Pettenazzo, A., Zanconato, S. and Baraldi, E., 2013. High-flow nasal cannula oxygen for bronchiolitis in a pediatric ward: a pilot study. European Journal of Pediatrics, 172(12), pp.1649-1656.

Chi KW, Coon ER, Destino L, Schroeder AR. Parental perspectives on continuous pulse oximetry use in bronchiolitis hospitalizations. Pediatrics. 2020 Aug 1;146(2)

Clayton, J.A., McKee, B., Slain, K.N., Rotta, A.T. and Shein, S.L., 2019. Outcomes of children with bronchiolitis treated with high-flow nasal cannula or noninvasive positive pressure ventilation. Pediatric Critical Care Medicine| Society of Critical Care Medicine, 20(2), pp.128-135.

Cunningham, S., Rodriguez, A., Adams, T., Boyd, K.A., Butcher, I., Enderby, B., MacLean, M., McCormick, J., Paton, J.Y., Wee, F. and Thomas, H., 2015. Oxygen saturation targets in infants with bronchiolitis (BIDS): a double-blind, randomised, equivalence trial. The Lancet, 386(9998), pp.1041

Durand, P., Guiddir, T., Kyheng, C., Blanc, F., Vignaud, O., Epaud, R., Dugelay, F., Breant, I., Badier, I., Degas-Bussière, V. and Phan, F., 2020. A Randomised Trial of High-Flow Nasal Cannula in Infants with Moderate Bronchiolitis. European Respiratory Journal.

Franklin, D., Babl, F.E., Schlapbach, L.J., Oakley, E., Craig, S., Neutze, J., Furyk, J., Fraser, J.F., Jones, M., Whitty, J.A. and Dalziel, S.R., 2018. A randomized trial of high-flow oxygen therapy in infants with bronchiolitis. New England Journal of Medicine, 378(12), pp.1121-1131.

Franklin, D., Babl, F.E., Gibbons, K., Pham, T.M., Hasan, N., Schlapbach, L.J., Oakley, E., Craig, S., Furyk, J., Neutze, J. and Moloney, S., 2019. Nasal high flow in room air for hypoxemic bronchiolitis infants. Frontiers in Pediatrics, 7, p.426.

Hodgson, K.A., Davis, P.G. and Owen, L.S., 2019. Nasal high flow therapy for neonates: current evidence and future directions. Journal of Paediatrics and Child Health, 55(3), pp.285-290.

Hosheh, O., Edwards, C.T. and Ramnarayan, P., 2020. A nationwide survey on the use of heated humidified high flow oxygen therapy on the paediatric wards in the UK: current practice and research priorities. BMC Pediatrics, 20(1), pp.1-9.

Jackson, T., Deibert, D., Wyatt, G., Durand-Moreau, Q., Adisesh, A., Khunti, K., Khunti, S., Smith, S., Chan, X.H.S., Ross, L. and Roberts, N., 2020. Classification of aerosol-generating procedures: a rapid systematic review. BMJ open respiratory research, 7(1), p.e000730.

Kalburgi, S. and Halley, T., 2020. High-flow nasal cannula use outside of the ICU setting. Pediatrics, 146(5).

Kawaguchi, A., Garros, D., Joffe, A., DeCaen, A., Thomas, N.J., Schibler, A., Pons-Odena, M., Udani, S., Takeuchi, M., Junior, J.C. and Ramnarayan, P., 2020. Variation in Practice Related to the Use of High Flow Nasal Cannula in Critically Ill Children. Pediatric Critical Care Medicine, 21(5), pp.e228-e

Leyenaar, J.K. and Ralston, S.L., 2020. Widespread adoption of low-value therapy: the case of bronchiolitis and high-flow oxygen. Pediatrics, 146(5).

Lin, J., Zhang, Y., Xiong, L., Liu, S., Gong, C. and Dai, J., 2019. High-flow nasal cannula therapy for children with bronchiolitis: a systematic review and meta-analysis. Archives of Disease in Childhood, 104(6), pp.564-576.

Lutman, D. and Petros, A.J., 2006. How many oxygen cylinders do you need to take on transport? A nomogram for cylinder size and duration. Emergency Medicine Journal, 23(9), pp.703-704.

Masarweh, K., Gur, M., Leiba, R., Bar-Yoseph, R., Toukan, Y., Nir, V., Gut, G., Ben-David, Y., Hakim, F. and Bentur, L., 2020. Factors predicting length of stay in bronchiolitis. Respiratory medicine, 161, p.105824.

Mayfield, S., Bogossian, F., O'Malley, L. and Schibler, A., 2014. High‐flow nasal cannula oxygen therapy for infants with bronchiolitis: Pilot study. Journal of Paediatrics and Child Health, 50(5), pp.373-378.

Milési, C., Essouri, S., Pouyau, R., Liet, J.M., Afanetti, M., Portefaix, A., Baleine, J., Durand, S., Combes, C., Douillard, A. and Cambonie, G., 2017. High flow nasal cannula (HFNC) versus nasal continuous positive airway pressure (nCPAP) for the initial respiratory management of acute viral bronchiolitis in young infants: a multicenter randomized controlled trial (TRAMONTANE study). Intensive Care Medicine, 43(2), pp.209-216.

Moreel, L. and Proesmans, M., 2020. High flow nasal cannula as respiratory support in treating infant bronchiolitis: a systematic review. European Journal of Pediatrics, pp.1-8.

O'Brien, S., Borland, M.L., Cotterell, E., Armstrong, D., Babl, F., Bauert, P., Brabyn, C., Garside, L., Haskell, L., Levitt, D. and McKay, N., 2019. Australasian bronchiolitis guideline. Journal of Paediatrics and Child Health, 55(1), pp.42

O'Brien, S., Craig, S., Babl, F.E., Borland, M.L., Oakley, E., Dalziel, S.R. and Paediatric Research in Emergency Departments International Collaborative (PREDICT) Network, Australasia, 2019. 'Rational use of high‐flow therapy in infants with bronchiolitis. What do the latest trials tell us?'A Paediatric Research in Emergency Departments International Collaborative perspective. Journal of Paediatrics and Child Health, 55(7), pp.746-752.

Principi T, Coates AL, Parkin PC, Stephens D, DaSilva Z, Schuh S. Effect of Oxygen Desaturations on Subsequent Medical Visits in Infants Discharged From the Emergency Department With Bronchiolitis. JAMA Pediatrics 2016;170(6):602-8.

Ralston, S.L., 2020. High-flow nasal cannula therapy for pediatric patients with bronchiolitis: time to put the horse back in the barn. JAMA Pediatrics, 174(7), pp.635-636.

Ramnarayan, P. and Schibler, A., 2017. Glass half empty or half full? The story of high-flow nasal cannula therapy in critically ill children.

Ramnarayan, P., Lister, P., Dominguez, T., Habibi, P., Edmonds, N., Canter, R.R., Wulff, J., Harrison, D.A., Mouncey, P.M., Peters, M.J. and United Kingdom Paediatric Intensive Care Society Study Group, 2018. FIRST-line support for Assistance in Breathing in Children (FIRST-ABC): a multicentre pilot randomised controlled trial of high-flow nasal cannula therapy versus continuous positive airway pressure in paediatric critical care. Critical Care, 22(1), p.144.

Schuh S, Freedman S, Coates A, et al. Effect of Oximetry on Hospitalization in Bronchiolitis: A Randomized Clinical Trial. JAMA. 2014;312(7):712-718. doi:10.1001/jama.2014.8637

Slain KN, Martinez-Schlurmann N, Shein SL, et al: Nutrition and high- flow nasal cannula respiratory support in children with bronchiolitis. Hosp Pediatr 2017; 7:256-262

Spentzas, T., Minarik, M., Patters, A.B., Vinson, B. and Stidham, G., 2009. Children with respiratory distress treated with high-flow nasal cannula. Journal of Intensive Care Medicine, 24(5), pp.323-328.

Vahlkvist, S., Jürgensen, L., La Cour, A., Markoew, S., Petersen, T.H. and Kofoed, P.E., 2020. High flow nasal cannula and continuous positive airway pressure therapy in treatment of viral bronchiolitis: a randomized clinical trial. European Journal of Pediatrics, 179(3), pp.513-518.

Weiler, T., Kamerkar, A., Hotz, J., Ross, P.A., Newth, C.J. and Khemani, R.G., 2017. The relationship between high flow nasal cannula flow rate and effort of breathing in children. The Journal of Pediatrics, 189, pp.66-71.

# data[].attributes.attachment_link.authors[].name
Alison Boast, Alasdair Munro + Henry Goldstein

# data[].attributes.attachment_link.title
High Flow Help - Don't Forget the Bubbles

# data[].attributes.attachment_link.description
As cases of bronchiolitis increase in the wake of COVID we wanted to visit some of the more pragmatic aspects of care. In this post, we are going to go over high flow oxygen. Horses, like babies, are obligate nasal breathers.

# data[].attributes.attachment_link.readable_text
This post was created by DFTB in collaboration with Health Education England, Respiratory Surge in Children programme

As cases of bronchiolitis increase in the wake of COVID we wanted to visit some of the more pragmatic aspects of care. In this post, we are going to go over high flow oxygen.

What is high flow?

Horses, like babies, are obligate nasal breathers. As they gallop around the racecourse their massive lungs can draw in around 160 litres of air every minute. This can lead to exercise-induced pulmonary haemorrhage. In fact, the 'bleeding;' affects 95% of racing thoroughbreds. Tired of treating with horse frusemide (actually, the same as human frusemide, but probably more expensive) Blacker and Hedman (1988) developed a device to train horses, to condition their cardiorespiratory system to the high flows they would be exposed to.

In a case of horses for courses, the thought occurred to the engineers at Fisher and Paykel that if such a device could reduce the work of breathing for a horse, it might just work for something 120 times smaller.

Is it high flow an aerosol generating procedure (AGP)?

Optiflow™️/Airvo™️/heated humidified high flow nasal cannula oxygenation is an aerosol-generating procedure and, as such, should be performed in an appropriate environment with staff wearing the appropriate level of PPE. This also impacts where the treatment is started. It makes no sense to start the patient on therapy in the paediatric emergency department only to then switch it off to transfer them to either the ward or HDU. It is far more sensible to commence treatment in the setting where it is going to be continued.

The decision to initiate high flow therapy should be made by a senior decision maker.

Why do we use high flow?

There has been a great deal of debate over the evidence base for the superiority of high flow nasal cannula oxygen therapy over standard nasal cannula oxygen in cases of moderate-to-severe bronchiolitis. Anecdotally, as staff become more comfortable setting it up and using it, high flow is started earlier. This leads to an ' it works because I have seen it work' mentality. Trial the patient on nasal cannula oxygen first. If they remain hypoxic with oxygen saturations less than 90% then perhaps you should start them on high flow, but this is a decision that should be placed in the context of that child's acuity and background combined with the local system and availability of escalation personal and resource (see "Getting Started" section)

Humidification and heating (to 34°C) can reduce the damage to nasal mucosa caused by room temperature air. The increased ambient moisture in the respiratory tract can also help loosen stubborn mucus.

Standard nasal cannulae may not be able to match the higher inspiratory flow rates needed in the respiratory failure of bronchiolitis.

High flow may increase the functional residual capacity, or FRC, at the end of expiration, not due to increased PEEP, per se, but due to alveolar distension.

The increased inspired concentration of oxygen will reduce the dilution of entrained air.

There is some soft evidence (in animal models) that it can help wash out CO ₂ from the oropharyngeal dead space but if there are chest x-ray changes suggestive of some consolidation on the background of increased work of breathing it is probably worth starting high flow sooner rather than later.

High flow should NOT be started in patients with craniofacial abnormalities, recurrent apnoeas (consider intubation) or undrained pneumothoraces.

Getting started with high flow

We tend to base our estimate of the patient's needs on their oxygen saturations. If they are less than X we admit, and if they are greater than Y we send them home. We need to have a degree of flexibility in our guidelines based on a number of factors including pre-morbid conditions, how well the child looks and not just a magic number. Schuh et al (2014) showed that we tend to focus on the number, not the patient. When experimenters presented clinicians with artificially raised oxygen saturations, a lot fewer children were admitted. If we are not looking at the number but instead the duration of symptoms then we should heed the data from BIDS. The Bronchiolitis in Infancy Discharge Study (BIDS) found that whether we targeted sats of 90% or 94%, the cough still persisted for about 15 days.

If the patient improves there is little role for continuous pulse oximetry monitoring. Chi et al (2020) suggest it leads to an increased length of stay for no intrinsic patient benefit as staff and parents watch the monitor waiting for the correct number to pop up. It is much better to base weaning and discharge decisions around an assessment of effort and effect of breathing.

There is still a great degree of debate ongoing surrounding the benefits of high flow oxygen therapy with Kepreotes et al (2017) showing that the duration of supplemental therapy required was no different between the high flow and standard oxygen therapy groups. The more recent PARIS trial (2018) also compared standard oxygen therapy to high flow therapy. Whilst Franklin et al (2018) suggested an NNT of 9 to prevent one escalation of care (from standard O ₂ to high flow) there is an alternative reading of the data. If you start a patient on humidified high flow nasal cannula oxygen at the outset, 70% of the time it will be of no benefit to the patient. The trial was really a comparison of immediate high flow to rescue high flow therapy. Read Ally Munro's piece to dive a little deeper.

Monitoring during high flow

Once a patient requires high flow therapy it is worthwhile considering where this will take place. Should it be started in the paediatric emergency department? Can the patient be managed on the ward? Should they go to PICU? Some of these decisions may have already been made before a single patient even comes through the doors with many district general hospitals not having a PICU service. There seems to be a divide between what is acceptable practice in a tertiary centre and what is acceptable in a district general hospital. These decisions are often based on both staffing levels and staffing competence. Interestingly financial considerations may not come into it as a number of studies have shown that it is cheaper to run high flow in a ward-based environment than in a PICU/HDU (Kalburgi and Halley, 2020). As the need for supplemental oxygen therapy rises is it likely that a compromise will have to be reached. Bressan et al. (2013), in a pragmatic study involving 27 infants with moderate-to-severe bronchiolitis, recorded no adverse events when they were treated with high flow in a ward-based environment.

When patients with a common disease, such as bronchiolitis, present in numbers, it is easy to think of them as a homogenous entity. One of the big challenges is identifying the patient that has a purely respiratory compromise, and needs assistance, from children who are maybe septic or have a degree of fluid overload or myocarditis. It seems reasonable for patients who simply require mild to moderate respiratory support and have no red flags for deterioration to be managed by skilled nurses in a ward-based environment. There need to be clear track and trigger guidelines in place to support nursing staff in the event of clinical deterioration.

Tachypnoea is more of a problem than tachycardia. As the rate goes up there are more insensible losses. If you can increase the flow (and hence the volume delivered) then things tend to settle down.

All children on high flow can turn tachycardic and grumpy. It is hard to know if this is their normal unless you have seen them earlier in the admission. Likewise, tachypnoea is also very subjective. If you are unsure then this is a great opportunity for some shared decision making with the retrieval service using telehealth (or your mobile phone).
Dynamic assessment is the key. Assess, intervene, watch and wait, then reassess. Repeat as necessary.
Managing on high flow

All patients on high flow therapy should have a nasogastric tube inserted before commencement. This reduces the risk of gastric distension and subsequent diaphragmatic incursion on respiration. If the child cannot tolerate oral feeds then the NG can also be used to provide enteral nutrition.

Weaning high flow

There are two main ways to wean a patient off of high flow oxygen. We can either wean the flow down first then switch to nasal cannulae or we can wean the percentage of inspired oxygen first. Generally the older (and heavier) a child is, the faster they will get better. It's time to refresh some of our respiratory physiology and Poiseuille's law. Smaller airways are more likely to get gunked up with snot and mucus. This creates turbulent flow. This, in turn, leads to increased work of breathing. The same amount of mucus in a larger away contributes much less and so there is more laminar flow and reduced work of breathing.

The RCPCH National guidance for the management of children with bronchiolitis and lower respiratory tract infections during COVID-19 map out a rapid weaning plan. Essentially, there are two options.

Weaning the flow

Wean the flow rate down to 1l/kg then switch to standard nasal cannulae

Weaning the oxygen

Once on a FiO ₂ of 0.3 (30%) oxygen (regardless of flow rate flow) switch to standard nasal cannulae.

Deteriorating on high flow

Some children are more likely to fail high flow therapy than others, becoming either hypoxic or apnoeic. See the table below for some key risk factors.

The smaller, younger patient still has an immature breathing system. If Optiflow™️ is started at the right time the overwhelming majority get better - and go home. There will always, however, those that do not get better with CPAP. Flipping the switch from CPAP to BiPAP will offer more respiratory support. It can feel uncomfortable doing this if you have not done it before. Most PICU outreach services can provide training on how to swap modes. This may be enough to stave off the need for intubation, critical care retrieval and the subsequent filling of limited paediatric ICU beds.

Transport considerations

There may be times when transportation to a tertiary centre is required to provide ongoing care. This can be a real challenge when a patient is on high flow oxygen. Early discussions with the retrieval service can prevent delays down the track. We tend to think of a retrieval service in isolation, dealing with the patient in front of us. It is important to recognise that it is not just a simple matter of popping along in an ambulance and picking up a child and taking them down the road. Each case, or mission, can take eight hours, on average. Longer journeys of up to eighteen hours are not unheard of.

Moving the patient from a safe, warm building to another safe, warm building via a rattling metal box on wheels is not without risk. One also needs to consider the profound impact on the family of moving their child away from their home hospital to somewhere many hours away from where they may have no psycho-social support. Better training and better resources will improve family-centred care.

Power

Many ambulances only have a two-pin plug, rather than a mains plug, and so need a converter. These cost a few pounds but require PAT testing to make sure they are medically safe. Not all transport services have access and so the Optiflow™️ device cannot be plugged in.

Oxygen

An 18-month-old toddler with bronchiolitis weighs approximately 10kg in weight. At 2l/kg/minute they will go through 20 litres of oxygen a minute. A standard ambulance holds 2 D size (1600L) cylinders. The smaller C-size handheld cylinders hold just 450L. Either should be more than enough for a single trip by road, even if you are driving from West Cornwall Hospital to Caithness General Hospital.

If you don't have high flow, then what?

Healthcare is beset with the challenge of managing with finite resources. Whilst we might be able to cope with a few cases of bronchiolitis in any given year it is possible that demand for high flow outstrips availability. There are devices available that can, for very little cost, converts the dry oxygen from the wall to humidified (but not warmed) oxygen. When a baby is bunged up with copious secretions that will cause them to plug off their airways humidification of their supplemental oxygen is key. Even at higher flow rates ( 2l/kg/min), it is better to humidify the oxygen.

High flow vs low flow vs headbox - Ian Sinha looks at the evidence

We did a quick and dirty analysis looking at 8 studies ( 2122 infants)

In hypoxic infants, using high flow instead of low flow made no difference in terms of length of stay, the need for ICU admission or the need for mechanical ventilation. We can say this with a moderate to high degree of certainty though this is impaired by the lack of blinding, and differences in ICU admissions between the studies.

Risk of bias

Risk of bias summary

226/969 ( 23.3%) of infants randomised to low flow 'failed' and required escalation of therapy. It does not appear that high flow modifies the disease process.

There is no evidence, apart from one small study, comparing high flow to headbox oxygen so meaningful comparisons and conclusions cannot be inferred.

Low flow oxygen is sufficient in around 75% of infants. If care needs to be escalated because of hypoxemia then they are not at risk of worse outcomes than if they have been commenced on HFNC oxygen at the outset.
If there is a shortage of high flow delivery devices then humidify the standard wall oxygen.
The Bottom line
Unless a child is critically hypoxic or apnoeic start them on nasal cannula O₂ if their saturations are less than 90%.

High flow oxygen is safe for use in the ward environment in appropriate, low-risk patients

Upskilling staff to flick the switch to BiPAP may lessen the need for higher level care thus reducing the PICU workload

Talk to your retrieval service early, they may be able to guide you in order to optimise therapy
Selected references

Blackmer RH, Hedman JW. (1988). Method and apparatus for pulmonary and cardiovascular conditioning of racehorses and competition animals. US4722334A.

Bressan, S., Balzani, M., Krauss, B., Pettenazzo, A., Zanconato, S. and Baraldi, E., 2013. High-flow nasal cannula oxygen for bronchiolitis in a pediatric ward: a pilot study. European Journal of Pediatrics, 172(12), pp.1649-1656.

Chi KW, Coon ER, Destino L, Schroeder AR. Parental perspectives on continuous pulse oximetry use in bronchiolitis hospitalizations. Pediatrics. 2020 Aug 1;146(2)

Clayton, J.A., McKee, B., Slain, K.N., Rotta, A.T. and Shein, S.L., 2019. Outcomes of children with bronchiolitis treated with high-flow nasal cannula or noninvasive positive pressure ventilation. Pediatric Critical Care Medicine| Society of Critical Care Medicine, 20(2), pp.128-135.

Cunningham, S., Rodriguez, A., Adams, T., Boyd, K.A., Butcher, I., Enderby, B., MacLean, M., McCormick, J., Paton, J.Y., Wee, F. and Thomas, H., 2015. Oxygen saturation targets in infants with bronchiolitis (BIDS): a double-blind, randomised, equivalence trial. The Lancet, 386(9998), pp.1041

Durand, P., Guiddir, T., Kyheng, C., Blanc, F., Vignaud, O., Epaud, R., Dugelay, F., Breant, I., Badier, I., Degas-Bussière, V. and Phan, F., 2020. A Randomised Trial of High-Flow Nasal Cannula in Infants with Moderate Bronchiolitis. European Respiratory Journal.

Franklin, D., Babl, F.E., Schlapbach, L.J., Oakley, E., Craig, S., Neutze, J., Furyk, J., Fraser, J.F., Jones, M., Whitty, J.A. and Dalziel, S.R., 2018. A randomized trial of high-flow oxygen therapy in infants with bronchiolitis. New England Journal of Medicine, 378(12), pp.1121-1131.

Franklin, D., Babl, F.E., Gibbons, K., Pham, T.M., Hasan, N., Schlapbach, L.J., Oakley, E., Craig, S., Furyk, J., Neutze, J. and Moloney, S., 2019. Nasal high flow in room air for hypoxemic bronchiolitis infants. Frontiers in Pediatrics, 7, p.426.

Hodgson, K.A., Davis, P.G. and Owen, L.S., 2019. Nasal high flow therapy for neonates: current evidence and future directions. Journal of Paediatrics and Child Health, 55(3), pp.285-290.

Hosheh, O., Edwards, C.T. and Ramnarayan, P., 2020. A nationwide survey on the use of heated humidified high flow oxygen therapy on the paediatric wards in the UK: current practice and research priorities. BMC Pediatrics, 20(1), pp.1-9.

Jackson, T., Deibert, D., Wyatt, G., Durand-Moreau, Q., Adisesh, A., Khunti, K., Khunti, S., Smith, S., Chan, X.H.S., Ross, L. and Roberts, N., 2020. Classification of aerosol-generating procedures: a rapid systematic review. BMJ open respiratory research, 7(1), p.e000730.

Kalburgi, S. and Halley, T., 2020. High-flow nasal cannula use outside of the ICU setting. Pediatrics, 146(5).

Kawaguchi, A., Garros, D., Joffe, A., DeCaen, A., Thomas, N.J., Schibler, A., Pons-Odena, M., Udani, S., Takeuchi, M., Junior, J.C. and Ramnarayan, P., 2020. Variation in Practice Related to the Use of High Flow Nasal Cannula in Critically Ill Children. Pediatric Critical Care Medicine, 21(5), pp.e228-e

Leyenaar, J.K. and Ralston, S.L., 2020. Widespread adoption of low-value therapy: the case of bronchiolitis and high-flow oxygen. Pediatrics, 146(5).

Lin, J., Zhang, Y., Xiong, L., Liu, S., Gong, C. and Dai, J., 2019. High-flow nasal cannula therapy for children with bronchiolitis: a systematic review and meta-analysis. Archives of Disease in Childhood, 104(6), pp.564-576.

Lutman, D. and Petros, A.J., 2006. How many oxygen cylinders do you need to take on transport? A nomogram for cylinder size and duration. Emergency Medicine Journal, 23(9), pp.703-704.

Masarweh, K., Gur, M., Leiba, R., Bar-Yoseph, R., Toukan, Y., Nir, V., Gut, G., Ben-David, Y., Hakim, F. and Bentur, L., 2020. Factors predicting length of stay in bronchiolitis. Respiratory medicine, 161, p.105824.

Mayfield, S., Bogossian, F., O'Malley, L. and Schibler, A., 2014. High‐flow nasal cannula oxygen therapy for infants with bronchiolitis: Pilot study. Journal of Paediatrics and Child Health, 50(5), pp.373-378.

Milési, C., Essouri, S., Pouyau, R., Liet, J.M., Afanetti, M., Portefaix, A., Baleine, J., Durand, S., Combes, C., Douillard, A. and Cambonie, G., 2017. High flow nasal cannula (HFNC) versus nasal continuous positive airway pressure (nCPAP) for the initial respiratory management of acute viral bronchiolitis in young infants: a multicenter randomized controlled trial (TRAMONTANE study). Intensive Care Medicine, 43(2), pp.209-216.

Moreel, L. and Proesmans, M., 2020. High flow nasal cannula as respiratory support in treating infant bronchiolitis: a systematic review. European Journal of Pediatrics, pp.1-8.

O'Brien, S., Borland, M.L., Cotterell, E., Armstrong, D., Babl, F., Bauert, P., Brabyn, C., Garside, L., Haskell, L., Levitt, D. and McKay, N., 2019. Australasian bronchiolitis guideline. Journal of Paediatrics and Child Health, 55(1), pp.42

O'Brien, S., Craig, S., Babl, F.E., Borland, M.L., Oakley, E., Dalziel, S.R. and Paediatric Research in Emergency Departments International Collaborative (PREDICT) Network, Australasia, 2019. 'Rational use of high‐flow therapy in infants with bronchiolitis. What do the latest trials tell us?'A Paediatric Research in Emergency Departments International Collaborative perspective. Journal of Paediatrics and Child Health, 55(7), pp.746-752.

Principi T, Coates AL, Parkin PC, Stephens D, DaSilva Z, Schuh S. Effect of Oxygen Desaturations on Subsequent Medical Visits in Infants Discharged From the Emergency Department With Bronchiolitis. JAMA Pediatrics 2016;170(6):602-8.

Ralston, S.L., 2020. High-flow nasal cannula therapy for pediatric patients with bronchiolitis: time to put the horse back in the barn. JAMA Pediatrics, 174(7), pp.635-636.

Ramnarayan, P. and Schibler, A., 2017. Glass half empty or half full? The story of high-flow nasal cannula therapy in critically ill children.

Ramnarayan, P., Lister, P., Dominguez, T., Habibi, P., Edmonds, N., Canter, R.R., Wulff, J., Harrison, D.A., Mouncey, P.M., Peters, M.J. and United Kingdom Paediatric Intensive Care Society Study Group, 2018. FIRST-line support for Assistance in Breathing in Children (FIRST-ABC): a multicentre pilot randomised controlled trial of high-flow nasal cannula therapy versus continuous positive airway pressure in paediatric critical care. Critical Care, 22(1), p.144.

Schuh S, Freedman S, Coates A, et al. Effect of Oximetry on Hospitalization in Bronchiolitis: A Randomized Clinical Trial. JAMA. 2014;312(7):712-718. doi:10.1001/jama.2014.8637

Slain KN, Martinez-Schlurmann N, Shein SL, et al: Nutrition and high- flow nasal cannula respiratory support in children with bronchiolitis. Hosp Pediatr 2017; 7:256-262

Spentzas, T., Minarik, M., Patters, A.B., Vinson, B. and Stidham, G., 2009. Children with respiratory distress treated with high-flow nasal cannula. Journal of Intensive Care Medicine, 24(5), pp.323-328.

Vahlkvist, S., Jürgensen, L., La Cour, A., Markoew, S., Petersen, T.H. and Kofoed, P.E., 2020. High flow nasal cannula and continuous positive airway pressure therapy in treatment of viral bronchiolitis: a randomized clinical trial. European Journal of Pediatrics, 179(3), pp.513-518.

Weiler, T., Kamerkar, A., Hotz, J., Ross, P.A., Newth, C.J. and Khemani, R.G., 2017. The relationship between high flow nasal cannula flow rate and effort of breathing in children. The Journal of Pediatrics, 189, pp.66-71.

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Alison Boast, Alasdair Munro + Henry Goldstein

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High Flow Help - Don't Forget the Bubbles

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As cases of bronchiolitis increase in the wake of COVID we wanted to visit some of the more pragmatic aspects of care. In this post, we are going to go over high flow oxygen. Horses, like babies, are obligate nasal breathers.

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NEW 298 Expenses Guide Claimant and Approver

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Abstract

Pulmonary function tests are fundamental to the diagnosis and monitoring of respiratory diseases. There is uncertainty around whether potentially infectious aerosols are produced during testing and there are limited data on mitigation strategies to reduce risk to staff. Healthy volunteers and patients with lung disease underwent standardised spirometry, peak flow and FE NO assessments. Aerosol number concentration was sampled using an aerodynamic particle sizer and an optical particle sizer. Measured aerosol concentrations were compared with breathing, speaking and voluntary coughing. Mitigation strategies included a standard viral filter and a full-face mask normally used for exercise testing (to mitigate induced coughing). 147 measures were collected from 33 healthy volunteers and 10 patients with lung disease. The aerosol number concentration was highest in coughs (1.45-1.61 particles/cm ³), followed by unfiltered peak flow (0.37-0.76 particles/cm ³). Addition of a viral filter to peak flow reduced aerosol emission by a factor of 10 without affecting the results. On average, coughs produced 22 times more aerosols than standard spirometry (with filter) in patients and 56 times more aerosols in healthy volunteers. FE NO measurement produced negligible aerosols. Cardiopulmonary exercise test (CPET) masks reduced aerosol emission when breathing, speaking and coughing significantly. Lung function testing produces less aerosols than voluntary coughing. CPET masks may be used to reduce aerosol emission from induced coughing. Standard viral filters are sufficiently effective to allow guidelines to remove lung function testing from the list of aerosol-generating procedures.

Introduction

Due to the pandemic, concerns about viral transmission by aerosols and droplets mean that many respiratory diagnostic services are being cancelled or delayed. 1 There is an urgent need to restart these vital diagnostic services and mitigate risks to patients and staff from viral transmission. However, there remains uncertainty around the role of lung function testing in the generation of aerosols and onward transmission risk.

A rapid systematic review identified seven sources that classified the aerosol-generating procedure (AGP) status of lung function tests. 2 Four of these defined lung function tests as an AGP, two defined them as a possible AGP and one source stated that these were not an AGP. All cited sources were guidelines, none of which referred to primary experimental data that could support these recommendations. Current advice from expert groups and guidance bodies is contradictory, leading to variation in clinical practice. 3-5 Previous experimental work has been performed outside an ultra-clean environment, which does not allowaccurate attribution of aerosol and can potentially misclassify it, does not conform to clinical standards, and does not include patients with lung disease.

In this study, we aimed to generate primary data on aerosol generation during lung function tests and assess mitigation strategies using highly sensitive technology in an ultra-clean, laminar flow theatre.

Methods

This study was performed as part of the AERosolisation And Transmission Of SARS-CoV-2 in Healthcare Settings (AERATOR) study to assess the risk of aerosolised transmission of SARS-CoV-2 in healthcare settings.

Results

Full results and patient demographics are found in online supplemental appendix S2. Correlation between the APS and OPS was extremely high (r>0.95), and therefore only APS results are reported in the text. In brief, the highest aerosol emission was generated during a voluntary cough, with the next highest in unfiltered peak flow ( table 1 and figure 1). Patients with lung disease generated higher aerosol concentrations than volunteers when breathing (0.29 vs 0.04 particles/cm ³, p<0.01) and speaking (0.20 vs 0.10 particles/cm ³, p=0.04), but not when coughing (1.45 vs 1.61 particles/cm ³, p>0.2).

Unfiltered peak flow produced approximately half the aerosol of voluntary coughing, but the addition of a filter reduced this by an order of magnitude in volunteers (0.76 vs 0.9 particles/cm ³, p<0.01) and patients (0.37 vs 0.01 particles/cm ³, p<0.01), with no clinically significant change in measured peak flow value ( online supplemental figure S3).

Filtered spirometry also produced little aerosol (0.11 particles/cm ³ in volunteers and 0.10 particles/cm ³ in patients), with voluntary cough producing on average 56 times more aerosol in volunteers (and 22 times more aerosol in patients). We could not elicit any aerosol emission from the FE NO device.

A potential mitigation strategy for induced coughing, the CPET mask, was tested in five volunteers, with formal results reported in online supplemental appendix S2. Briefly, large reductions in aerosol emission during breathing (0.02 vs <0.0001 particles/cm ³, p=0.08, paired t-test on log-transformed data for all comparisons), speaking (0.1 vs <0.001 particles/cm ³, p=0.06) and coughing (1.12 vs 0.06 particles/cm ³, p<0.01) were observed, although this did not meet a significance threshold due to the low number of participants.

Finally, we tested whether receiving nebulised salbutamol altered subsequent aerosol emission in patients and we identified no significant change ( online supplemental results and figures S4-S6).

Discussion

This study provides much-needed high-quality experimental data characterising aerosols generated during standard clinical lung function tests in volunteers and patients. The finding that spirometry, peak expiratory flow (with standard BVF) and exhaled nitric oxide testing do not generate significant aerosols (in comparison with cough) suggests there is likely limited additional risk associated with lung function testing outside of the potential to generate aerosols via coughing.

Peak flow testing without a filter does produce aerosols (although less than coughing). However, the addition of a filter reduces this aerosol concentration to negligible levels and renders the procedure non-aerosol-generating. Together this points to the effectiveness of standard CE-marked viral filters in reducing aerosol emission.

The study also identifies a potential effective mitigation measure (reusable filtered CPET mask) for aerosols generated by subjects who cough as a result of the procedure, with promising data showing large reductions in aerosol emission, although we caveat this is due to the small number of participants. Finally we provide reassurance that salbutamol nebulisation used as part of bronchodilator reversibility testing does not induce higher aerosol emission during subsequent testing. Taken together, we believe that this may allow for a significant increased diagnostic capacity through reduced need for air room changes between subjects.

This study has a number of strengths. First, we performed spirometry as following standard UK practice in an ultra-clean, laminar flow theatre with extremely low background aerosol concentration. This allows us to make confident conclusions about the source and level of aerosols produced. Second, we measured aerosol production from healthy volunteers and patients with a mixture of chronic lung conditions that were suspected to affect aerosol emissions.

There are some limitations to our study. We included patients with a mixture of small airways and suppurative lung conditions in our study, but the patient group was too small and heterogeneous to draw any definitive conclusions about the comparison between individual lung diseases. Common to all prior studies and for safety reasons, none of the subjects was known to be suffering from viral infections which have been shown to increase aerosol production. 7 Finally, the link between recorded aerosol concentration and risk of onward infection remains unknown, with the capture and quantification of infectious SARS-CoV-2 or other pathogens in exhaled aerosol remaining a considerable technical challenge at present.

There are three comparable studies that have examined this question. 8-10 First, Helgeson et al's 8 small-scale study identified aerosol generation during spirometry performed by five healthy volunteers. It detected aerosol production despite inclusion of viral filters, but excluded participants who coughed and only measured aerosols at a distance from the source, being unable to definitively identify the source. Greening et al 9 included 33 healthy volunteers who performed different respiratory manoeuvres outside of an ultra-clean environment using particles in exhaled air methodology. They identified cough as the major source of aerosols and found varied results with other lung function testing. However, the authors acknowledge that their pulmonary function tests (PFTs) did not meet the ERS/ATS spirometry criteria and 22 of the volunteers performed only tidal breathing. Finally, Li et al 10 performed lung function testing on 28 patients. Only one measure of aerosol (OPS) was performed during PFTs and for 30-60 min following the procedure after the patients and researchers had left the room. The paper concludes that PFTs should be considered an AGP; however, on examination of the presented data, measured aerosol levels remained steady or fell during the procedures. The peak aerosol production occurs when the patients moved away from the apparatus and breathed, spoke and coughed without a mask on. In our view, these data more likely reflect aerosol emission from normal respiratory activity such as coughing, rather than relating to the lung function testing, and highlight the need for measurement at the source of aerosol emission and an ultra-clean background.

Bringing all the data together, including our and others' evidence that aerosol is generated from normal respiratory activity, this paper suggests that the major risk in lung function testing remains the potential for infectious aerosols to be generated by coughing rather than in performing spirometry. Risk assessments should focus on the risk of infection to the patient, ventilation of the room and whether induced coughing can be mitigated, rather than on the type of lung function testing performed.

Conclusions

Spirometry (performed with a standard filter) and FE NO do not generate significant aerosol concentrations compared with coughs in healthy volunteers and patients with lung disease. Peak flow does generate aerosols, although a viral filter reduces this >10-fold. Reusable CPET masks with filters applied to subjects prior to testing may be a potential solution to mitigate aerosol emission from induced coughing before and after the procedure.

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Are aerosols generated during lung function testing in patients and healthy volunteers? Results from the AERATOR study

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Pulmonary function tests are fundamental to the diagnosis and monitoring of respiratory diseases. There is uncertainty around whether potentially infectious aerosols are produced during testing and there are limited data on mitigation strategies to reduce risk to staff. Healthy volunteers and patients with lung disease underwent standardised spirometry, peak flow and FENO assessments.

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Planned Teaching sessions for Wednesday mornings