The considerable impact of the SARS-CoV-2 pandemic and COVID-19 on the UK National Mycology Reference Laboratory activities and workload.

Starting late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating global pandemic of coronavirus-19 disease (COVID-19) with ∼179 million cases and ∼3.9 million deaths to date. COVID-19 ranges from asymptomatic infection to severe illness with acute respiratory distress requiring critical care in up to 40% of hospitalized patients. Numerous reports have identified COVID-19-associated pulmonary aspergillosis (CAPA) as an important infective complication of COVID-19. In the UK, the pandemic has had unprecedented impacts on the National Health Service (NHS'): each wave of infections required hospitals to reconfigure for large surges in patients requiring intensive care, to the detriment of most aspects of non-COVID care including planned operations, outpatient appointments, general practitioner consultations and referrals. The UK National Mycology Reference Laboratory (MRL) offers a comprehensive service for the diagnosis and management of fungal disease nationwide, with a test portfolio that includes: diagnosis of allergies to fungal and other respiratory allergens; diagnosis of superficial and invasive/systemic fungal infections using traditional mycological, serological and molecular approaches; identification and susceptibility testing of the causative fungi; therapeutic drug monitoring of patients receiving antifungal therapy. Here, we describe the impact of the first 14 months of the COVID-19 pandemic on MRL activities. Changes to MRL workload closely mirrored many of the NHS-wide challenges, with marked reductions in 'elective' mycological activities unrelated to the pandemic and dramatic surges in tests that contributed to the diagnosis and management of COVID-19-related secondary fungal infections, in particular CAPA and candidemia in COVID-19 patients in intensive care. LAY SUMMARY: The COVID-19 pandemic has had an unprecedented impact on the UK National Health Service, with hospitals forced to repeatedly reconfigure to prepare for large surges in COVID-19 patients. Here we describe the impact of the first 14 months of the UK pandemic on the workload of the National Mycology Reference Laboratory.

COVID-19-Associated Invasive Aspergillosis: Data from the UK National Mycology Reference Laboratory.

COVID-19-associated pulmonary aspergillosis (CAPA) was recently reported as a potential infective complication affecting critically ill patients with acute respiratory distress syndrome following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with incidence rates varying from 8 to 33% depending on the study. However, definitive diagnosis of CAPA is challenging. Standardized diagnostic algorithms and definitions are lacking, clinicians are reticent to perform aerosol-generating bronchoalveolar lavages for galactomannan testing and microscopic and cultural examination, and questions surround the diagnostic sensitivity of different serum biomarkers. Between 11 March and 14 July 2020, the UK National Mycology Reference Laboratory received 1,267 serum and respiratory samples from 719 critically ill UK patients with COVID-19 and suspected pulmonary aspergillosis. The laboratory also received 46 isolates of Aspergillus fumigatus from COVID-19 patients (including three that exhibited environmental triazole resistance). Diagnostic tests performed included 1,000 (1-3)-ß-d-glucan and 516 galactomannan tests on serum samples. The results of this extensive testing are presented here. For a subset of 61 patients, respiratory specimens (bronchoalveolar lavage specimens, tracheal aspirates, and sputum samples) in addition to serum samples were submitted and subjected to galactomannan testing, Aspergillus-specific PCR, and microscopy and culture. The incidence of probable/proven and possible CAPA in this subset of patients was approximately 5% and 15%, respectively. Overall, our results highlight the challenges in biomarker-driven diagnosis of CAPA, especially when only limited clinical samples are available for testing, and the importance of a multimodal diagnostic approach involving regular and repeat testing of both serum and respiratory samples.

3D ultrasound to quantify lateral hip displacement in children with cerebral palsy: a validation study.

AIM: To assess the validity of a new index, lateral head coverage (LHC), for describing hip dysplasia in a population of children with cerebral palsy (CP). METHOD: LHC is derived from 3D ultrasound assessment. Twenty-two children (15 males, seven females; age 4-15y) with CP undergoing routine hip surveillance were recruited prospectively for the study. Each participant had both a planar radiograph acquired as part of their routine care and a 3D ultrasound assessment within 2 months. Reimer's migration percentage (RMP) and LHC were measured by the same assessor, and the correlation between them calculated using Pearson's correlation coefficient. The repeatability of LHC was investigated with three assessors, analysing each of 10 images three times. Inter- and intra-assessor variation was quantified using intraclass correlation coefficients. RESULTS: LHC was strongly correlated with RMP (Spearman's rank correlation coefficient=-0.86, p<0.001). LHC had similar inter-assessor reliability to that reported for RMP (intraclass correlation coefficient=0.97 and intra-assessor intraclass correlation coefficient=0.98). INTERPRETATION: This is an initial validation of the use of 3D ultrasound in monitoring hip development in children with CP. LHC is comparable with RMP in estimating hip dysplasia with similar levels of reliability that are reported for RMP.

Investigating the impact of measurement uncertainty in the radiographic surveillance of hip displacement in cerebral palsy: A Monte Carlo simulation.

Hip surveillance programmes have greatly improved the management of hip dysplasia in children with cerebral palsy. Reimer's migration percentage is the most common index for quantifying hip dysplasia from planar radiographs. However, measurement uncertainty could undermine the diagnostic accuracy. A Monte Carlo simulation was created to investigate the impact of measurement error on decision making in hip surveillance programmes. The simulation was designed to mimic the annual surveillance of children with cerebral palsy (Gross Motor Functional Classification System levels III-V) between 2 and 8 years of age. Simulation parameters for the natural history of hip dysplasia and measurement error were derived from published data. At each measurement interval, the influence of uncertainty in the measurement of Reimer's migration percentage on decision-making was investigated. The probability of a child being indicated for intervention in error during the course of the simulation was relatively high, particularly in the highest functioning cohort where the positive predictive value of Reimer's migration percentage was at best 70% and at worse less than 20%. Including a rate of progression term within the decision-making algorithm had a negative effect on positive predictive power. This simulation suggests that hip surveillance programmes are sensitive to detecting genuine hip dysplasia but can have poor positive predictive power, potentially resulting in unnecessary indication for intervention.

Selective motor control and gross motor function in bilateral spastic cerebral palsy.

AIM: To investigate the relationship between selective motor control (SMC), muscle volume, and spasticity with gross motor function in adolescents and young adults with bilateral spastic cerebral palsy (CP). METHOD: Eleven male participants with CP (mean age 15y 7mo, standard deviation 3y 6mo, range 12y 1mo-23y 1mo) in Gross Motor Function Classification System (GMFCS) levels I to IV took part in this cross-sectional study. Magnetic resonance imaging (MRI) of both lower limbs of all participants were acquired, from which 18 muscles were manually segmented and muscle volume calculated by a single assessor. Muscle volumes were normalized to body mass and averaged between limbs for each individual. SMC was assessed using Selective Control Assessment of the Lower Extremity (SCALE). Spasticity was assessed using the Modified Ashworth Scale (MAS), and gross motor functional ability was assessed using the Gross Motor Function Measure (GMFM-66). RESULTS: GMFM-66 was strongly positively correlated to SCALE (r=0.901, p≤0.001) and lower limb muscle volume normalized to body mass (r=0.750, p=0.008). MAS was significantly correlated with GMFM-66 (r=-0.691, p=0.018). INTERPRETATION: SMC is a major factor influencing gross motor function in individuals with CP. Lower limb muscle volume and spasticity also influence gross motor function. WHAT THIS PAPER ADDS: Selective motor control is a major factor of gross motor function in adolescents and young adults with bilateral cerebral palsy (CP). Gross motor function is related to muscle size and level of spasticity in adolescents and young adults with bilateral CP.

The relationship between lower limb muscle volume and body mass in ambulant individuals with bilateral cerebral palsy.

BACKGROUND: Individuals with cerebral palsy have smaller muscle volumes normalised to body mass than their typically developing peers. The aim of this study is to investigate the relationship between lower limb muscle volume and body mass in young people with bilateral cerebral palsy and their typically developing peers. METHODS: Twenty-five participants with bilateral cerebral palsy (aged 14.7±3.0 years, GMFCS level I-III) and 25 of their typically developing peers (aged 16.8±3.3 years) took part in this study. None of the participants had undergone orthopaedic surgery, botulinum toxin injections, or serial casting in the previous year. All participants underwent magnetic resonance imaging of both lower limbs. Nine major muscles of each lower limb were individually manually segmented and the muscle volumes calculated. RESULTS: Body mass and total lower limb muscle volume were significantly linearly related in both the cerebral palsy (R2 = 0.75, p<0.001) and typically developing (R2 = 0.77, p<0.001) groups. The slope of the relationship between muscle volume and body mass was significantly shallower in the cerebral palsy group compared to the typically developing group (p=0.007). CONCLUSIONS: This cross-sectional study suggests that the increase in size of lower limb muscles relative to body mass is reduced in adolescents and young adults with cerebral palsy. Longitudinal studies are required to further investigate altered muscle growth trajectories in this group and their impact on long-term mobility.

Selective motor control correlates with gait abnormality in children with cerebral palsy.

Children with bilateral cerebral palsy (CP) commonly have limited selective motor control (SMC). This affects their ability to complete functional tasks. The impact of impaired SMC on walking has yet to be fully understood. Measures of SMC have been shown to correlate with specific characteristics of gait, however the impact of SMC on overall gait pattern has not been reported. This study explored SMC data collected as part of routine gait analysis in children with bilateral CP. As part of their clinical assessment, SMC was measured with the Selective Control Assessment of the Lower Extremities (SCALE) in 194 patients with bilateral cerebral palsy attending for clinical gait analysis at a single centre. Their summed SCALE score was compared with overall gait impairment, as measured by Gait Profile Score (GPS). Score on SCALE showed a significant negative correlation with GPS (rs=-0.603, p<0.001). Cerebral injuries in CP result in damage to the motor tracts responsible for SMC. Our results indicate that this damage is also associated with changes in the development of walking pattern in children with CP.

Intramuscular fat in ambulant young adults with bilateral spastic cerebral palsy.

BACKGROUND: It is known that individuals with bilateral spastic cerebral palsy (BSCP) have small and weak muscles. However, no studies to date have investigated intramuscular fat infiltration in this group. The objective of this study is to determine whether adults with BSCP have greater adiposity in and around their skeletal muscles than their typically developing (TD) peers as this may have significant functional and cardio-metabolic implications for this patient group. METHODS: 10 young adults with BSCP (7 male, mean age 22.5 years, Gross Motor Function Classification System (GMFCS) levels I-III), and 10 TD young adults (6 male, mean age 22.8 years) took part in this study. 11 cm sections of the left leg of all subjects were imaged using multi-echo gradient echo chemical shift imaging (mDixon). Percentage intermuscular fat (IMAT), intramuscular fat (IntraMF) and a subcutaneous fat to muscle volume ratio (SF/M) were calculated. RESULTS: IntraMF was higher with BSCP for all muscles (p = 0.001-0.013) and was significantly different between GMFCS levels (p < 0.001), with GMFCS level III having the highest IntraMF content. IMAT was also higher with BSCP p < 0.001). No significant difference was observed in SF/M between groups. CONCLUSION: Young adults with BSCP have increased intermuscular and intramuscular fat compared to their TD peers. The relationship between these findings and potential cardio-metabolic and functional sequelae are yet to be investigated.

Bone strength is related to muscle volume in ambulant individuals with bilateral spastic cerebral palsy.

OBJECTIVE: The aim of this study is to investigate how bone strength in the distal femur and proximal tibia are related to local muscle volume in ambulant individuals with bilateral spastic cerebral palsy (CP). METHODS: Twenty-seven participants with CP (mean age: 14.6±2.9years; Gross Motor Function Classification System (GMFCS) levels I-III) and twenty-two typically developing (TD) peers (mean age: 16.7±3.3years) took part in this study. Periosteal and medullary diameter in the distal femur and cortical bone cross-sectional area (CSA) and thickness (CT) in the distal femur and proximal tibia were measured along with nine lower limb muscle volumes using MRI. Additionally, the polar section modulus (Zp) and buckling ratio (BR) were calculated to estimate bone bending strength and compressional bone stability respectively in the distal femur. The relationships of all measured parameters with muscle volume, height, age, body mass, gender, and subject group were investigated using a generalized linear model (GZLM). RESULTS: In the distal femur, Zp was significantly positively related to thigh muscle volume (p=0.007), and height (p=0.026) but not significantly related to subject group (p=0.076) or body mass (p=0.098). BR was not significantly different between groups and was not related to any of the variables tested. Cortical bone CSA was significantly lower in the CP group at both the distal femur (p=0.002) and proximal tibia (p=0.009). It was also positively associated with thigh muscle volume (p<0.001) at the distal femur, and with subject height (p=0.005) at the proximal tibia. CONCLUSIONS: Bending and compressional strength of the femur, estimated from Zp and cortical bone CSA respectively, is associated with reduced thigh muscle volume. Increasing muscle volume by strength training may have a positive effect on bone mechanics in individuals with CP.

Lower limb muscle volumes in bilateral spastic cerebral palsy.

AIM: Muscle weakness is a feature of individuals with spastic cerebral palsy (SCP) but there are few reports in the literature of muscle volume in this group. This study compares muscle volumes in adolescents and young adults with SCP with those of their typically developing (TD) peers. DESIGN: Measurements of the volumes of nine major lower limb muscles in 19 independently ambulant subjects with SCP (mean age 14.2 years (sd 2.7), 11 male, GMFCS I (n=5); GMFCS II (n=14)), 19 TD subjects (mean age 16.5 years (sd 3.0), 11 male) were made using magnetic resonance imaging. RESULTS: Lower limb muscles were smaller in the SCP group (p≤0.023 in all muscles) than the TD group with the exception of the vastii (lateralis+intermedius; p=0.868) and gluteus maximus (p=0.056). Average muscle volume deficit was 27.9%. Muscle volume deficits were significantly greater for distal muscles than proximal muscles (p<0.001). CONCLUSIONS: Reduced muscle size in adolescence and the natural history of sarcopenia in adulthood may contribute to the early loss of mobility of adults with SCP.

Could muscle deformity in children with spastic cerebral palsy be related to an impairment of muscle growth and altered adaptation?

Skeletal muscle deformity is common in children with spastic cerebral palsy (CP), but the underlying mechanisms are unclear. This review explores some possible factors which may influence the development of muscle deformity in CP. Normal muscle function and growth appear to depend on the interaction of neuronal, endocrinal, nutritional, and mechanical factors, and also on the development of an appropriate balance between muscle protein synthesis and degradation, and between the development of contractile and non-contractile components. In this context, the changes seen in muscle in children with CP are reviewed and discussed. It is suggested that the development of muscle deformity in children with CP may be related to a multifactorial impairment of muscle growth, on which adaptation of the extracellular matrix due to altered loading may be imposed.

Continuous postural management and the prevention of deformity in children with cerebral palsy: an appraisal.

Continuous postural management programmes are commonly used for children with cerebral palsy (CP) in Gross Motor Function Classification System levels IV and V, with the aim of preventing musculoskeletal deformity. There is a lack of evidence to support their use in this capacity and a possibility that children with CP who are most likely to develop deformity may be least able to comply with a continuous postural management programme. The implications for the child and family of such a programme in terms of increased demands and potential discomfort are discussed within the framework of the International Classification of Functioning, Disability and Health. A shift in focus in the use of postural management from an emphasis on body structure towards the environment and participation of the child with CP is suggested.

Increases in muscle volume after plantarflexor strength training in children with spastic cerebral palsy.

Children with spastic cerebral palsy (CP) have small, weak muscles. However, change in muscle size due to resistance training in this group is unknown. We investigated the effect of plantarflexor strengthening on muscle volume, gait, and function in 13 ambulant children with spastic CP (seven males, six females; mean age 10 y 11 mo, SD 3 y 0 mo, range 6 y 11 mo-16 y 11 mo; eight with diplegia, five with hemiplegia; Gross Motor Function Classification System level I, six; level II, five; level III, two). Assessments were performed before training, 5 and 10 weeks into training, and at a 3-month follow-up. Medial and lateral gastrocnemius volumes were computed from three-dimensional ultrasound images. The number of unilateral heel raises able to be achieved on each side was assessed. Function was measured using three-dimensional gait analysis, the 'timed up and go' test, the Gillette Functional Assessment Questionnaire, and the Functional Mobility Scale. Training involved heel raises or Thera-Band resistance, 4 times a week for 10 weeks. Medial and lateral gastrocnemius volumes increased by 17 and 14% at week 5 (p=0.03, p=0.028). This increase was maintained at week 10 and follow-up (medial gastrocnemius p=0.001, p<0.001; lateral gastrocnemius p=0.006, p=0.007). Heel raises (mean number) increased by week 5 (p=0.002). This was maintained at week 10 and follow-up (p<0.001; p<0.001). No significant change in measured function was observed. Muscle volume increased in response to training in children with spastic CP. The role of progressive strength training in maintaining long-term function is discussed.

Can clinical gait analysis guide the management of ambulant children with bilateral spastic cerebral palsy?

BACKGROUND: The role of clinical gait analysis in the management of ambulant children with bilateral spastic cerebral palsy (BSCP) is controversial. We hypothesized that gait analysis would allow us to differentiate between children with BSCP who would benefit from surgical intervention and those in whom surgery was not indicated. METHODS: We reviewed the outcome in 3 groups of children with BSCP referred for treatment recommendations based on gait analysis by looking at changes in the popliteal angle (PA), Gillette Gait Index (GGI), and minimum knee flexion in single support (MKFS) on a subsequent gait analysis. We identified 15 children in whom surgical intervention was not thought to be needed (SNR group) and 15 children who had multilevel surgery recommended but not performed (SND group). We randomly selected and reviewed 15 children referred during the study period who had multilevel surgery recommended and performed following gait analysis (OP group) for comparison. RESULTS: The initial PA, MKFS, and GGI were greater in the OP and SND groups compared with the SNR group. Popliteal angle did not change between analyses in the SNR and SND groups and decreased in the OP group (P = 0.004). Minimum knee flexion in single support remained similar between analyses in the SNR group, increased in the SND group (P < 0.0001), and decreased in the OP group (P < 0.0001). The GGI remained similar in the SNR and SND groups but decreased in the OP group (P = 0.0002). The number of children in the SND group showing an increase of more than 10% in the GGI between analyses (8/15) was greater than that in the OP group (0/15) (P = 0.0022). The PA, MKFS, and GGI contributed significantly to the treatment recommendations (P = 0.0013, P = 0.0045, P = 0.0054, respectively), which were not affected by age and Gross Motor Functional Classification System level. CONCLUSIONS: Gait analysis helped us to distinguish children with BSCP who would benefit from surgery from those in whom nonoperative management was appropriate, and its routine clinical use is encouraged in the management of these children. LEVEL OF EVIDENCE: Level III, retrospective comparative study.