Pulmonary function and long-term respiratory symptoms in children and adolescents after COVID-19

$\bf Background:$ Persistent respiratory symptoms after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in adults are frequent, and there can be long-term impairment of pulmonary function. To date, only preliminary evidence is available on persistent respiratory sequelae of SARS-CoV-2 in children and adolescents. Our objective was to examine the long-term effects of symptomatic and asymptomatic SARS-CoV-2 infections on pulmonary function in this age group in a single-center, controlled, prospective study. $\bf Methods:$ Participants with serological or polymerase chain reaction-based evidence of SARS-CoV-2 infection were recruited from a population-based study of seroconversion rates. Multiple-breath washout (MBW), body plethysmography, and diffusion capacity testing were performed for children and adolescents. Participants were interviewed about their symptoms during the acute phase of infection and long-lasting symptoms. Cases were compared with SARS-CoV-2 seronegative controls from the same population-based study with and without history of respiratory infection within 6 months prior to assessment. Primary endpoints were differences in pulmonary function, including diffusion capacity and MBW, between participants with and without evidence of SARS-CoV-2 infection. Secondary endpoints included correlation between lung function and long-lasting symptoms as well as disease severity. $\bf Findings:$ In total, 73 seropositive children and adolescents (5–18 years) were recruited after an average of 2.6 months (range 0.4–6.0) following SARS-CoV-2 infection. Among 19 patients (27.1%) who complained of persistent or newly emerged symptoms since SARS-CoV-2, 8 (11.4%) reported respiratory symptoms. No significant differences were detected in frequency of abnormal pulmonary function when comparing cases with 45 controls, including 14 (31.1%) with a history of previous infection (SARS-CoV-2: 12, 16.4%; controls: 12, 27.7%; odds ratio 0.54, 95% confidence interval 0.22–1.34). Only two patients with persistent respiratory symptoms showed abnormal pulmonary function. Multivariate analysis revealed reduced forced vital capacity ($\it p$ = 0.012) in patients with severe SARS-CoV-2 infection. $\bf Interpretation:$ Pulmonary function is rarely impaired in children and adolescents after SARS-CoV-2 infection, except from those with severe infection, and did not differ between SARS-CoV-2 and other previous infections, suggesting that SARS-CoV-2 is not more likely to cause pulmonary sequelae than other infections. The discrepancy between persisting respiratory symptoms and normal pulmonary function suggests a different underlying pathology such as dysfunctional breathing

Somatosensory abnormalities after infection with SARS-CoV-2

$\bf Background:$ Long-term neurological complaints after SARS-CoV-2 infection occur in 4–66% of children and adolescents. Controlled studies on the integrity of the peripheral nerve system are scarce. Therefore, we examined the somatosensory function in children and adolescents after SARS-CoV-2 infection in a case-control study compared with age-matched individuals. $\textbf {Materials and Methods:}$ Eighty-one subjects after SARS-CoV-2 infection ($\it n$ = 44 female, 11.4 $\pm$ 3.5 years, $\it n$ = 75 SARS-CoV-2 seropositive, $\it n$ = 6 PCR positive during infection and SARS-CoV-2 seronegative at the time point of study inclusion, $\it n$ = 47 asymptomatic infection) were compared to 38 controls without SARS-CoV-2 infection (26 female, 10.3 $\pm$ 3.4 years, $\it n$ = 15 with other infection within last 6 months). After standardised interviews and neurological examinations, large fibre (tactile and vibration detection thresholds) and small fibre (cold and warm detection thresholds, paradoxical heat sensation) functions were assessed on both feet following a validated protocol. After z-transformation of all values, all participants were compared to published reference values regarding the number of abnormal results. Additionally, the mean for all sensory parameters values of both study groups were compared to an ideal healthy population (with $\it z$-value 0 $\pm$ 1), as well as with each other, as previously described. Statistical analyses: $\it t$-test, Chi-squared test, and binominal test. $\bf Findings:$ None of the controls, but 27 of the 81 patients (33%, $\it p$ < 0.001) reported persistent complaints 2.7 $\pm$ 1.9 (0.8–8.5) months after SARS-CoV-2 infection, most often reduced exercise capacity (16%), fatigue (13%), pain (9%), or paraesthesia (6%). Reflex deficits or paresis were missing, but somatosensory profiles showed significantly increased detection thresholds for thermal (especially warm) and vibration stimuli compared to controls. Approximately 36% of the patients after SARS-CoV-2, but none of the controls revealed an abnormal sensory loss in at least one parameter ($\it p$ < 0.01). Sensory loss was characterised in 26% by large and 12% by small fibre dysfunction, the latter appearing more frequently in children with prior symptomatic SARS-CoV-2 infection. Myalgia/paraesthesia was indicative of somatosensory dysfunction. In all eight re-examined children, the nerve function recovered after 2–4 months. $\bf Interpretation:$ This study provides evidence that in a subgroup of children and adolescents previously infected with SARS-CoV-2, regardless of their complaints, the function of large or small nerve fibres is presumably reversibly impaired

Painful cutaneous electrical stimulation vs. heat pain as test stimuli in conditioned pain modulation

Different paradigms can assess the effect of conditioned pain modulation (CPM). The aim of the present study was to compare heat pain, as an often used test stimulus (TS), to painful cutaneous electrical stimulation (PCES), having the advantage of the additional recording of PCES-related evoked potentials. In 28 healthy subjects we applied heat and PCES at the dominant hand as test stimulus (TS) to compare the CPM-effect elicited by hand immersion into cold water (10 °C) as conditioning stimulus (CS). Subjects rated the pain intensity of TS at baseline, during and 5 min after CS application and additionally of CS, on a numerical rating scale (NRS) (0–100). The "early" (during CS–before CS) and 'late' (after CS–before CS) CPM-effects were analyzed. Parallel to the PCES, the related evoked potentials were recorded via Cz to evaluate any changes in PCES-amplitudes. CS reduced significantly the pain intensity of both PCES and heat pain as TS. On a group level, the CPM-effect did not differ significantly between both paradigms. Both early and late CPM-effect based on PCES correlated significantly with the CS pain intensity ($\it r$ = −0.630 and −0.503, respectively), whereas using heat pain the correlation was not significant. We found a significant reduction of PCES-amplitudes during CS, but this did not correlate with the PCES-induced pain intensity. Correlation with the CS painfulness $\it r$ = −0.464) did not achieve the significance level after Bonferroni correction. The extent of the CPM effects was similar in both testing paradigms at group level, despite intraindividual differences. Future studies should further elicit the exact mechanisms explaining the modality of these specific differences

Distraction by a cognitive task has a higher impact on electrophysiological measures compared with conditioned pain modulation

$\bf Background$ Conditioned pain modulation (CPM) evaluates the effect of a painful conditioning stimulus (CS) on a painful test stimulus (TS). Using painful cutaneous electrical stimulation (PCES) as TS and painful cold water as CS, the pain relief was paralleled by a decrease in evoked potentials (PCES-EPs). We now aimed to compare the effect of CPM with cognitive distraction on PCES-induced pain and PCES-EP amplitudes. $\bf Methods$ PCES was performed using surface electrodes inducing a painful sensation of 60 (NRS 0–100) on one hand. In a crossover design healthy subjects (included: n = 38, analyzed: n = 23) immersed the contralateral hand into 10 °C cold water (CS) for CPM evaluation and performed the 1-back task for cognitive distraction. Before and during the CS and 1-back task, respectively, subjects rated the pain intensity of PCES and simultaneously cortical evoked potentials were recorded. $\bf Results$ Both CPM and cognitive distraction significantly reduced PCES-EP amplitudes (CPM: 27.6 $\pm$ 12.0 $\mu$V to 20.2 $\pm$ 9.5 $\mu$V, cognitive distraction: 30.3 $\pm$ 14.2 $\mu$V to 13.6 $\pm$ 5.2 $\mu$V, p < 0.001) and PCES-induced pain (on a 0–100 numerical rating scale: CPM: 58 $\pm$ 4 to 41.1 $\pm$ 12.3, cognitive distraction: 58.3 $\pm$ 4.4 to 38.0 $\pm$ 13.0, p < 0.001), though the changes in pain intensity and PCES-amplitude did not correlate. The changes of the PCES-EP amplitudes during cognitive distraction were more pronounced than during CPM (p = 0.001). $\bf Conclusions$ CPM and cognitive distraction reduced the PCES-induced pain to a similar extent. The more pronounced decrease of PCES-EP amplitudes after distraction by a cognitive task implies that both conditions might not represent the general pain modulatory capacity of individuals, but may underlie different neuronal mechanisms with the final common pathway of perceived pain reduction