COVID-19: immunopathology, pathophysiological mechanisms, and treatment options.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread globally despite the worldwide implementation of preventive measures to combat the disease. Although most COVID-19 cases are characterised by a mild, self-limiting disease course, a considerable subset of patients develop a more severe condition, varying from pneumonia and acute respiratory distress syndrome (ARDS) to multi-organ failure (MOF). Progression of COVID-19 is thought to occur as a result of a complex interplay between multiple pathophysiological mechanisms, all of which may orchestrate SARS-CoV-2 infection and contribute to organ-specific tissue damage. In this respect, dissecting currently available knowledge of COVID-19 immunopathogenesis is crucially important, not only to improve our understanding of its pathophysiology but also to fuel the rationale of both novel and repurposed treatment modalities. Various immune-mediated pathways during SARS-CoV-2 infection are relevant in this context, which relate to innate immunity, adaptive immunity, and autoimmunity. Pathological findings in tissue specimens of patients with COVID-19 provide valuable information with regard to our understanding of pathophysiology as well as the development of evidence-based treatment regimens. This review provides an updated overview of the main pathological changes observed in COVID-19 within the most commonly affected organ systems, with special emphasis on immunopathology. Current management strategies for COVID-19 include supportive care and the use of repurposed or symptomatic drugs, such as dexamethasone, remdesivir, and anticoagulants. Ultimately, prevention is key to combat COVID-19, and this requires appropriate measures to attenuate its spread and, above all, the development and implementation of effective vaccines. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Validation of an Instrument for Real-Time Assessment of Neonatal Intubation Skills: A Randomized Controlled Simulation Study.

OBJECTIVE: This study aimed to evaluate the construct validity and reliability of real-time assessment of a previously developed neonatal intubation scoring instrument (NISI). STUDY DESIGN: We performed a randomized controlled simulation study at a simulation-based research and training facility. Twenty-four clinicians experienced in neonatal intubation ("experts") and 11 medical students ("novices") performed two identical elective intubations on a neonatal patient simulator. Subjects were randomly assigned to either the intervention group, receiving predefined feedback between the two intubations, or the control group, receiving no feedback. Using the previously developed NISI, all intubations were assessed, both in real time and remotely on video. Construct validity was evaluated by (1) comparing the intubation performances, expressed as percentage scores, with and without feedback, and (2) correlating the intubation performances with the subjects' level of experience. The intrarater reliability, expressed as intraclass correlation coefficient (ICC), of real-time assessment compared with video-based assessment was determined. RESULTS: The intervention group contained 18 subjects, the control group 17. Background characteristics and baseline intubation scores were comparable in both groups. The median (IQR) change in percentage scores between the first and second intubation was significantly different between the intervention and control group (11.6% [4.7-22.8%] vs. 1.4% [0.0-5.7%], respectively; p = 0.013). The 95% CI for this 10.2% difference was 2.2 to 21.4%. The subjects' experience level correlated significantly with their percentage scores (Spearman's R = 0.70; p <0.01). ICC's were 0.95 (95% CI: 0.89-0.97) and 0.94 (95% CI: 0.89-0.97) for the first and second intubation, respectively. CONCLUSION: Our NISI has construct validity and is reliable for real-time assessment. KEY POINTS: · Our neonatal intubation scoring instrument has construct validity.. · Our instrument can be reliably employed to assess neonatal intubation skills directly in real time.. · It is suitable for formative assessment, i.e., providing direct feedback during procedural training..

Healthcare professionals' knowledge of the systematic ABCDE approach: a cross-sectional study.

BACKGROUND: The Airway, Breathing, Circulation, Disability and Exposure (ABCDE) approach is a universal, priority-based approach for the assessment and treatment of critically ill patients. Although the ABCDE approach is widely recommended, adherence in practice appears to be suboptimal. The cause of this non-compliance is unknown. As knowledge is a prerequisite for adherence, the aim of this study was to assess healthcare professionals' knowledge of the ABCDE approach. METHODS: A cross-sectional study was conducted at the Radboud University Medical Center, the Netherlands. A digital multiple-choice assessment tool of the ABCDE approach was developed by an expert panel through a mini-Delphi method and validated by performing test item statistics and an expert-novice comparison. The validated test was sent to healthcare professionals (nurses, residents and medical specialists) of the participating departments: Anaesthesiology, Paediatrics, Emergency Department and the Neonatal, Paediatric and Adult Intensive Care Units. Primary outcome was the test score, reflecting individual level of knowledge. Descriptive statistics, regression analysis and ANOVA were used. RESULTS: Test validation showed a Cronbach's alpha of 0.71 and an expert-novice comparison of 91.9% (standard deviation (SD) 9.1) and 72.4% (15.2) respectively (p < 0.001). Of 954 eligible participants, 240 filled out the questionnaire. The mean (SD) test score (% of correct answers) was 80.1% (12.2). Nurses had significantly lower scores (74.9% (10.9)) than residents (92.3% (7.5)) and medical specialists (88.0% (8.6)) (p < 0.001). The Neonatal Intensive Care Unit (75.9% (12.6)) and Adult Intensive Care Unit (77.4% (11.2)) had significantly lower scores than Paediatric Intensive Care Unit (85.6% (10.6)), Emergency Department (85.5% (10.4)) and Anaesthesiology (85.3% (10.6)) (p < 0.05). Younger participants scored higher than older participants (-0.30% (-0.46;-0.15) in test score/year increase in age). CONCLUSION: Scores of a validated knowledge test regarding the ABCDE approach vary among healthcare professionals caring for critically ill patients. Type of department, profession category and age had a significant influence on the test score. Further research should relate theoretical knowledge level to clinical practice. Tailored interventions to increase ABCDE-related knowledge are recommended.

Validation of an Assessment Instrument for Pediatric Basic Life Support.

OBJECTIVES: To develop a valid and reliable instrument for the assessment of pediatric basic life support (PBLS). METHODS: An assessment instrument for PBLS was developed, based on 3 existing scoring systems and the European Resuscitation Council PBLS guideline. We tested if experienced PBLS instructors performed better than medical students on a standard PBLS examination on a low-fidelity pediatric manikin (construct validity). To pass the examination, 15 penalty points or less were required. The examinations were videotaped. One researcher assessed all videos once, and approximately half of them twice (intrarater reliability). A second researcher independently assessed part of the videos (interrater reliability). The time needed to assess 1 examination was determined. RESULTS: Face and content validity were established, because PBLS experts reached consensus on the instrument and because the instrument incorporated all items of the European Resuscitation Council algorithm. Of the 157 medical students that were scored, 98 (62.4%) passed the examination. Fourteen PBLS instructors were scored; all passed (100%). Pass rate (62.4% vs 100%) and median penalty points (15 [interquartile range, 10-22.5] vs 7.5 [interquartile range, 1.25-10]) were significantly different between students and instructors (P = 0.005 and <0.001, respectively). Reassessment demonstrated a κ for intrarater reliability of 0.62 (95% confidence interval, 0.45-0.81) (substantial agreement); κ for interrater reliability was 0.51 (95% confidence interval, 0.09-0.93) (moderate agreement). It took approximately 3 minutes to assess 1 videotaped examination. CONCLUSIONS: Our instrument for the (video-based) assessment of PBLS is valid and sufficiently reliable. It is also designed to be practical, time-efficient, and applicable in various settings, including resource limited.

Adherence to the ABCDE approach in relation to the method of instruction: a randomized controlled simulation study.

BACKGROUND: The Airway, Breathing, Circulation, Disability, and Exposure (ABCDE) approach is widely recommended and taught in many resuscitation courses. This study assessed the adherence to the ABCDE algorithm and whether this was affected by the instruction method used to teach this approach. METHODS: Randomized controlled trial in which simulation was used as investigational method. Between June 2017 and January 2018, neonatal healthcare providers routinely participated in simulated neonatal advanced life support (NALS) scenarios, using a high-fidelity manikin. They were randomly assigned to a video-based instruction (intervention group) or a conventional lecture (control group) as the method of instruction. One blinded researcher evaluated the adherence to the ABCDE approach on video with an assessment tool specifically designed and tested for this study. The primary outcomes were: 1) the overall adherence and 2) the between-group difference in individual adherence to the ABCDE approach, both expressed as a percentage score. Secondary outcomes were: 1) the scores of each profession category (nurses, neonatal ward clinicians, fellows/neonatologists) and 2) the scores for the separate domains (A, B, C, D, and E) of the algorithm. RESULTS: Seventy-two participants were assessed. Overall mean (SD) percentage score (i.e. overall adherence) was 31.5% (19.0). The video-based instruction group (28 participants) adhered better to the ABCDE approach than the lecture group (44 participants), with mean (SD) scores of 38.8% (18.7) and 27.8% (18.2), respectively (p = 0.026). The difference in adherence between both groups could mainly be attributed to differences in the adherence to domain B (p = 0.023) and C (p = 0.007). Neonatal ward clinicians (39.9% (18.2)) showed better adherence than nurses (25.0% (15.2)), independent of the study group (p = 0.010). CONCLUSIONS: Overall adherence to the ABCDE algorithm was rather low. Video-based instruction resulted in better adherence to the ABCDE approach during NALS training than lecturing. TRIAL REGISTRATION: ISRCTN registry, trial ID ISRCTN95998973 , retrospectively registered on October 13th, 2020.

Neonatal resuscitation guideline adherence: simulation study and framework for improvement.

We wanted to assess newborn life support (NLS) knowledge and guideline adherence, and provide strategies to improve (neonatal) resuscitation guideline adherence. Pediatricians completed 17 multiple-choice questions (MCQ). They performed a simulated NLS scenario, using a high-fidelity manikin. The literature was systematically searched for publications regarding guideline adherence. Forty-six pediatricians participated: 45 completed the MCQ, 34 performed the scenario. Seventy-one percent (median, IQR 56-82) of the MCQ were answered correctly. Fifty-six percent performed inflation breaths ≤ 60 s, 24% delivered inflation breaths of 2-3 s, and 85% used adequate inspiratory pressures. Airway patency was ensured 83% (IQR 76-92) of the time. Median events/min, compression rate, and percentage of effective compressions were 138/min (IQR 130-145), 120/min (IQR 114-120), and 38% (IQR 24-48), respectively. Other adherence percentages were temperature management 50%, auscultation of initial heart rate 100%, pulse oximeter use 94%, oxygen increase 74%, and correct epinephrine dose 82%. Ten publications were identified and used for our framework. The framework may inspire clinicians, educators, researchers, and guideline developers in their attempt to improve resuscitation guideline adherence. It contains many feasible strategies to enhance professionals' knowledge, skills, self-efficacy, and team performance, as well as recommendations regarding equipment, environment, and guideline development/dissemination.Conclusion: NLS guideline adherence among pediatricians needs improvement. Our framework is meant to promote resuscitation guideline adherence. What is Known: • Inadequate newborn life support (NLS) may contribute to (long-term) pulmonary and cerebral damage. • Video-based assessment of neonatal resuscitations has shown that deviations from the NLS guideline occur frequently; this assessment method has its audiovisual shortcomings. What is New: • The resuscitation quality metrics provided by our high-fidelity manikin suggest that the adherence of Dutch general pediatricians to the NLS guideline is suboptimal. • We constructed a comprehensive framework, containing multiple strategies to improve (neonatal) resuscitation guideline adherence.

Retention of knowledge and skills in pediatric basic life support amongst pediatricians.

Retention of resuscitation skills is usually assessed at a predefined moment, which enables participants to prepare themselves, possibly introducing bias. In this multicenter study, we evaluated the retention of knowledge and skills in pediatric basic life support (PBLS) amongst 58 pediatricians and pediatric residents with an unannounced examination. Practical PBLS skills were assessed with a validated scoring instrument, theoretical knowledge with a 10-item multiple-choice test (MCQ). Participants self-assessed their PBLS capabilities using five-point Likert scales. Background data were collected with a questionnaire. Of our participants, 21% passed the practical PBLS exam: 29% failed on compressions/ventilations, 31% on other parts of the algorithm, 19% on both. Sixty-nine percent passed the theoretical test. Participants who more recently completed a PBLS course performed significantly better on the MCQ (p = 0.03). This association was less clear-cut for performance on the practical exam (p = 0.11). Older, attending pediatricians with more years of experience in pediatrics performed less well than their younger colleagues (p < 0.05). Fifty-one percent of the participants considered themselves competent in PBLS. No correlation was found between self-assessed PBLS capabilities and actual performance on the practical exam (p = 0.25). CONCLUSION: Retention of PBLS skills appears to be poor amongst pediatricians and residents, whereas PBLS knowledge is retained somewhat better. What is Known: • Pediatricians and pediatric residents are not always competent in pediatric basic life support (PBLS) in daily practice. Poor retention of skills supposedly accounts for this incompetence. Without regular exposure, resuscitation skills usually deteriorate within 3 to 6 months after training. • Examination of resuscitation skills usually takes place after training. Also, in most studies evaluating retention of skills, participants are tested at a predefined moment. Inasmuch as participants are able to prepare themselves, these assessments do not reflect the ad hoc resuscitation capabilities of pediatricians and residents. What is New: • In this study, pediatricians and pediatric residents had to complete an unannounced PBLS exam at variable time intervals from last certification. Retention of PBLS skills was rather poor (pass rate 21%). • The PBLS skills of older, attending pediatricians with many working years in pediatrics appeared to be inferior to those of their younger colleagues.

Training practices in neonatal and paediatric life support: A survey among healthcare professionals working in paediatrics.

AIM: To evaluate neonatal and paediatric life support training practices across Europe. METHODS: We conducted a descriptive study. Paediatric residents, general paediatricians, and subspecialists were surveyed to assess how paediatric basic and advanced life support (PBLS/PALS) and neonatal life support (NLS) are practically arranged and utilised throughout Europe. A mini-Delphi approach was used for survey development. Eligible professionals in general and university hospitals received a web link to the survey. RESULTS: 498 respondents from 16 countries were included. A large majority of responses came from the Netherlands (n = 393) and Belgium (n = 42). Therefore, analysis was based on these responses. PBLS was more frequently offered than PALS and NLS, though not to all professionals caring for children. For PBLS, PALS, and NLS, official recertification varied between 35-75%. Approximately 80-90% had read the latest guidelines, at least partially. Sixty to seventy percent felt capable of instant PALS, 75-90% considered themselves able to perform PBLS and NLS instantly. Not reading the guidelines and less confidence about instant resuscitation seemed to occur more often in the lower and higher age/experience groups compared to the intermediate age/experience groups. A quarter of the respondents <30 years did not feel prepared for instant PALS. General paediatricians appeared to feel most capable of instant resuscitation. General and university hospitals had rather similar training practices and facilities. Manikins were predominantly low-fidelity, especially in general hospitals. Barriers to course participation were high costs, lack of time, the non-compulsory status, remote location, and unavailability of courses. CONCLUSION: Although most paediatric professionals receive life support training, guideline reading, recertification, training utilisation, and resuscitation preparedness require improvement. Barriers to course participation should be addressed.

A healthy, female chimera with 46,XX/46,XY karyotype.

We report a healthy and unambiguously female newborn, whose phenotypic sex contradicted the expected male sex based on previously performed prenatal cytogenetic analysis. Both 46,XX and 46,XY cells were detected in a villus sample, the former having been attributed to maternal cell contamination. Postnatal karyotyping in peripheral lymphocytes confirmed the presence of two cell lines, one 46,XX (70%) and one 46,XY (30%). After exclusion of alternative explanations for the observed genotype, a diagnosis of chimerism was made. Chimeras containing cell lines of opposite sex usually feature ovotesticular development with associated genital ambiguity. To account for the normal female appearance of our patient, we postulate the exclusive involvement of 46,XX cells in gonad formation.

Appraisal of a scoring instrument for training and testing neonatal intubation skills.

OBJECTIVE: To determine the validity, reliability, feasibility and applicability of a neonatal intubation scoring instrument. DESIGN: Prospective observational study. SETTING: Simulation-based research and training centre (Center for Advanced Pediatric and Perinatal Education), California, USA. SUBJECTS: Forty clinicians qualified for neonatal intubation. INTERVENTIONS: Videotaped elective intubations on a neonatal patient simulator were scored by two independent raters. One rater scored the intubations twice. We scored the preparation of equipment and premedication, intubation performance, tube position/fixation, communication, number of attempts, duration and successfulness of the procedure. MAIN OUTCOME MEASURES: Intraclass correlation coefficients (ICC) were calculated for intrarater and inter-rater reliability. Kappa coefficients for individual items and mean kappa coefficients for all items combined were calculated. Construct validity was assessed with one-way analysis of variance using the hypothesis that experienced clinicians score higher than less experienced clinicians. The approximate time to score one intubation and the instrument's applicability in another setting were evaluated. RESULTS: ICCs for intrarater and inter-rater reliability were 0.99 (95% CI 0.98 to 0.99) and 0.89 (95% CI 0.35 to 0.96), and mean kappa coefficients were 0.93 (95% CI 0.85 to 1.01) and 0.71 (95% CI 0.56 to 0.92), respectively. There were no differences between the more and less experienced clinicians regarding preparation, performance, communication and total scores. The experienced group scored higher only on tube position/fixation (p=0.02). Scoring one intubation took approximately 15 min. Our instrument, developed in The Netherlands, could be readily applied in the USA. CONCLUSIONS: Our scoring instrument for simulated neonatal intubations appears to be reliable, feasible and applicable in another centre. Construct validity could not be established.

Adapted ECMO criteria for newborns with persistent pulmonary hypertension after inhaled nitric oxide and/or high-frequency oscillatory ventilation.

PURPOSE: Early prediction of extracorporeal membrane oxygenation (ECMO) requirement in term newborns with persistent pulmonary hypertension (PPHN), partially responding to inhaled nitric oxide (iNO) and/or high-frequency oscillatory ventilation (HFOV), based on oxygenation parameters. METHODS: This was a retrospective cohort study in 53 partial responders from among 133 term newborns with PPHN born between 2002 and 2007. Alveolar-to-arterial oxygen gradient (AaDO2) values were determined in these 53 partial responders during the initial 72 h of iNO and/or HFOV treatment and compared between newborns who ultimately did (n = 11) and did not (n = 42) need ECMO. RESULTS: Over 72 h, partial responders not requiring ECMO showed a more profound AaDO2 decrease than those who needed ECMO (median decline 242.5 mmHg, IQR 144 to 353 mmHg, vs. 35 mmHg, IQR -15 to 123 mmHg; p = 0.0007). A decline of <123 mmHg over 72 h predicted the need for ECMO (sensitivity 82 %, specificity 79 %). At 72 h, AaDO2 was significantly lower in partial responders without the need for ECMO than in those who did need ECMO (median 369 mmHg, IQR 258 to 478 mmHg, vs. 570 mmHg IQR 455 to 590 mmHg; p = 0.0008). An AaDO2 >561 mmHg at 72 h predicted the need for ECMO (sensitivity 64 %, specificity 95 %, positive predictive value 78 %). CONCLUSIONS: In term newborns with PPHN partially responding to iNO and/or HFOV, oxygenation-based prediction of the need for ECMO appears to be possible after 72 h. ECMO centers are encouraged to develop their own prediction model in order to prevent both lung damage and unnecessary ECMO runs.

Long-term subcutaneous protein C replacement in neonatal severe protein C deficiency.

We describe here the case of a boy who presented 2 days after birth with purpura fulminans on his feet and scalp. Laboratory investigations revealed signs of disseminated intravascular coagulation. An underlying coagulation disorder was suspected, and therapy with recombinant tissue plasminogen activator, fresh-frozen plasma, and unfractionated heparin was started. On the basis of plasma protein C activity and antigen levels of 0.02 and 0.03 IU/mL, respectively, after administration of fresh-frozen plasma, a diagnosis of severe protein C deficiency was established, and therapy with intravenous protein C concentrate (Ceprotin [Baxter, Deerfield, IL]) was started. Because of difficulties with venous access, we switched to subcutaneous administration after 6 weeks. The precise dosing schedule for subcutaneously administered protein C concentrate is unknown. In the literature, a trough level of protein C activity at >0.25 IU/mL is recommended to prevent recurrent thrombosis. During 1 year of follow-up our patient frequently had protein C activity levels at <0.25 IU/mL. Clinically, however, there was no recurrent thrombosis, and we kept the dosage unchanged. This report highlights 2 important points: (1) subcutaneously administered protein C concentrate is effective in treating severe protein C deficiency; and (2) in accordance with previous studies, after the acute phase trough levels of protein C activity at >0.25 IU/mL may not be necessary to prevent recurrent thrombosis. However, further research on the dosing, efficacy, and safety of protein C concentrate for prophylaxis and treatment of severe protein C deficiency is needed.

A large extra-abdominal prevesical pseudo-cyst in a newborn with posterior urethral valves.

A male newborn is described, in whom a large extra-abdominal prevesical pseudo-cyst as well as prune-belly features were present, both of which were supposedly secondary to posterior urethral valves. It is postulated that the subvesical obstruction caused pressure build-up in the urinary tract, followed by fetal bladder rupture. The resultant urinoma migrated extra-abdominally. Distension of the urinary tract, bilateral cryptorchidism and abdominal wall laxity contributed to a prune-belly phenotype.

Exercise performance and activity level in children with transposition of the great arteries treated by the arterial switch operation.

The exercise capacity of children after arterial switch for transposition of the great arteries (TGA) is known to be at the lower limit of normal. We aimed to ascertain whether this results from compromised hemodynamics or deconditioning. A total of 17 children with TGA (12 male and 5 female children; age 12.1 + or - 2.0 years) treated with the arterial switch operation were compared with 20 age-matched controls (13 male and 7 female children; age 12.8 + or - 2.4 years) regarding their peak exercise capacity, peak workload, and peak heart rate, as assessed by cycle ergometry. The children's physical activity level was monitored for a 7-day period using a pedometer and diary, and a questionnaire was used to assess physical activity participation and overprotection. The results demonstrated that TGA children showed a significantly reduced peak exercise capacity (47.4 + or - 6.4 vs 41.1 + or - 6.6 ml/kg/min; p <0.05), maximal workload (3.7 + or - 0.5 vs 3.1 + or - 0.6 W/kg; p <0.01), and maximal heart rate (189 + or - 9 vs 180 + or - 14 beats/min; p <0.05) compared to the controls. No significant differences were found in the physical activity pattern or overprotection. In conclusion, given the comparable physical activity level, but reduced exercise capacity in the TGA children, these children most likely fall short in their exercise performance because of restrictive hemodynamics rather than deconditioning from reduced daily life activity.

Exercise capacity and participation of children with a ventricular septal defect.

Existing data on exercise performance in children with a ventricular septal defect (VSD) are scarce and inconclusive. We aimed to elucidate whether and why exercise capacity and physical activity level are decreased in children with VSD. Children 9 to 17 years of age with a surgically (operated, n = 13) or conservatively (unoperated, n = 14) managed VSD were compared with healthy peers (controls, n = 15) regarding (1) anthropometric and spirometric measurements; (2) cycle ergometric performance in terms of peak oxygen uptake, peak heart rate, and peak workload; and (3) mean daily energy expenditure. All subjects completed a questionnaire on physical activity participation, overprotection, and self-perceived fitness and health. Anthropometric variables were comparable among groups, whereas lung function at rest was mildly decreased in the 2 VSD subgroups. Exercise testing succeeded in all 42 subjects; valid results were obtained in 39. Weight- and body fat-adjusted peak oxygen uptake, peak workload, and energy expenditure were not significantly different among groups. Peak heart rate emerged as significantly lower in operated subjects, which was not attributable to poorer effort. Physical fitness and general health were rated comparably among groups, whereas participation in sports was markedly lower in children with VSD. Discouragement from engaging in (strenuous) exercise occurred equally infrequently in children with VSD and controls. In conclusion, children with patent or surgically closed VSDs have a normal exercise capacity, despite a mild chronotropic limitation in the latter. Previous cardiac surgery did not influence these children's exercise performance. These children consider themselves healthy, they exhibit a normal habitual physical activity level, and they are not withheld from (strenuous) exercise.