Volume 152, No. 2122

Chenda Chheang, Stéphane Guinand, Christophe von Garnier, Claudio Sartori (Author)

New perspectives of biological therapy for severe asthma in adults and adolescents

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Severe asthma is associated with increased morbidity, mortality, healthcare costs and impaired quality of life. Asthma is no longer considered as a single entity but as a heterogeneous disease with different clinical presentations (phenotypes) and variable underlying mechanistic biological pathways (endotypes). Two different endotypes are based on the inflammatory Type 2 T-helper response: T2-high and T2-low. The understanding of these endotypes has revolutionised the management of severe asthma. Recent guidelines from the 2019 European Respiratory Society/American Thoracic Society (ERS/ATS) and Global Initiative for Asthma (GINA) 2021 specifically address the diagnosis and the management of severe asthma in adults, but less evidence exists for the paediatric population. Presently, five biologics for the treatment of severe asthma are approved, i.e., omalizumab (anti-IgE antibody), mepolizumab and reslizumab (anti-IL-5 antibody), benralizumab (anti-IL-5 receptor antibody) and dupilumab (anti-IL-4 receptor alpha antibody). This article reviews the pathological mechanisms of severe asthma, clinical biomarkers related to the T2-high endotype, and their use for the prediction of the severity of the disease and response to biological therapy. Furthermore, future developments of biologics for severe asthma are presented.

Fabienne N. Jaeger, Christoph Berger, Michael Buettcher, Sarah Depallens, Ulrich Heininger, Yvon Heller, Malte Kohns Vasconcelos, Bodil Leforestier, Nicole Pellaud, Christa Relly, Johannes Trück, Saskia von Overbeck Ottino, Noémie Wagner, Nicole Ritz (Author)

Paediatric refugees from Ukraine: guidance for health care providers

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BACKGROUND: With the invasion of Ukraine by the Russian Army in February 2022, refugees, the majority of whom are women and children, started fleeing the war to neighbouring countries. Even before the current escalation, the conflict in the eastern part of Ukraine has led to the internal displacement of more than 200,000 children, and many others have experienced attacks, e.g. on schools. This inevitably leads to limitations in health care delivery. During transit, overcrowding, poor shelter and vulnerability may further put refugees at increased risk for infectious diseases. This consensus document aims to provide information and guidance regarding health issues that paediatricians and general practitioners may face when caring for Ukrainian children.

METHODS: Members of the Migrant Health Reference Group of Paediatrics Switzerland and the Paediatric Infectious Disease Group in Switzerland developed this recommendation between March and April 2022 in a modified Delphi process.

RESULTS: A total of 50 recommendations were agreed on with a ≥80% consensus. These include the following topics: i) general aspects, including interpreter services, urgent health needs, personal history and general check-ups; ii) mental health, including how to search for signs of psychological distress without going into traumatic details; iii) vaccinations, including recommendations for evaluation and catch-up; iv) screening for tuberculosis, human immunodeficiency virus, and hepatitis B and C; and v) providing age-appropriate preventive and health service information.

CONCLUSION: This document provides current evidence and guidance when caring for paediatric refugees from Ukraine. The recommendations focus on Switzerland but may well be used in other countries. These are based on current evidence and may need to be adapted to individual situations and once further evidence becomes available.

Iza Lehmann, Arnaud Peytremann, Yolanda Mueller (Author)

Impact of the COVID-19 pandemic on adherence to infection prevention and control measures between 2019 and 2021 in Swiss sentinel private practices: repeated cross-sectional surveys

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AIMS OF THE STUDY: The COVID-19 pandemic has shown the importance of infection prevention and control (IPC) measures in health care settings, including primary care. We aimed to describe how it influenced adherence to infection prevention and control measures in private practices in the Swiss sentinel network (Sentinella).

METHOD: An online cross-sectional survey was sent to the 181 Sentinella practices in 2021 that included questions on the practice’s spatial organisation, staff habits and vaccination coverage, ventilation, mask wearing, hand hygiene, as well as triage and separation of patients with suspected infection. Results were compared with those of a 2019 survey conducted in the same setting.

RESULTS: We received 127 valid questionnaires (70.2% response rate). At the time of the study, SARS-CoV-2 vaccination was underway among physicians (51.3%). Between 2019 and 2021, an absence of specific recommendations on mask wearing for staff (55.7%) changed into a recommendation for continuous wearing (93.7%); hand hygiene improved, especially upon arrival at the practice (63.9% vs 85.8%; p <0.001) and before examining patients (74.6% vs 88.2%; p <0.010); impossibility of distancing symptomatic patients dropped (27.9% vs 3.9%, p <0.001); and ventilation and cleaning improved (p <0.001).

CONCLUSIONS: The COVID-19 pandemic led to important changes in adherence to the recommended IPC measures.

Eugénie  Gradoux , Stefano Di Bernardo, Sabrina Bressieux-Degueldre, Yvan Mivelaz, Tatiana Boulos Ksontini, Milan Prsa, Nicole Sekarski (Author)

Epidemiology of Kawasaki Disease in children in Switzerland: a national prospective cohort study

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AIM OF THE STUDY: Kawasaki disease is a febrile illness which can lead to significant coronary artery lesions. Its incidence varies among countries and is highest in Japan (330.2 children under 5 years old/100,000 per year). Since the epidemiology of Kawasaki disease in Switzerland is unknown, we conducted a national prospective data collection between 2013 and 2017 to describe its incidence, diagnosis, and treatment.

METHODS: We collected demographic and clinical data of the children under 17 years old hospitalised with Kawasaki disease in Switzerland between March 2013 and February 2017 using anonymous data collection forms with the help of the Swiss Paediatric Surveillance Unit (SPSU). We defined Kawasaki disease per the 2004 American Heart Association criteria: patients with ≥5 days of fever and ≥4 of the 5 main clinical features were included as complete Kawasaki disease and patients with ≥5 days of fever and <4 of the 5 main clinical features were included as incomplete Kawasaki disease. The incidence was calculated with the data of the Federal Statistical Office of Switzerland, considering permanent residents of the country. The different groups were compared by the unpaired student t-test for continuous variables and Pearson’s chi squared test for categorical variables, respectively.

RESULTS: We included 175 patients: 60% were boys, with a mean age of 38.2 months. The incidence of Kawasaki disease was 3.1/100,000 [95% CI 2.6–3.7] per year in children under 17 years of age and 8.4/100,000 [95% CI 6.7–10.2] per year in children under 5 years of age. The most frequent clinical signs were a rash (85.4%) and changes of the lips and oral/pharyngeal mucosa (83.4%). The diagnosis of Kawasaki disease was made at a mean of 7.3 days after the first symptom. Echocardiography was abnormal in 52.3%. The treatment with intravenous immunoglobulins (IVIG) and acetylsalicylic acid was administered in accordance with international guidelines. Subgroup analysis showed that children older than 5 years old had significantly more complete Kawasaki disease than the younger ones (78.8% vs 57.4%, p  = 0.021). Children with “extreme ages” (<1 year old and >8 years old) were diagnosed later (8.6 (±0.9) vs 7.0 (±0.3) days, p  = 0.0129), had longer duration of fever (9.8 (±0.9) vs 8.1 (±0.3) days, p = 0.013) and had more echocardiographic abnormalities (n = 26 (70.3%) vs n = 65 (47.5%), p  = 0.014) at diagnosis. One child died during the acute phase of the illness. 

CONCLUSIONS: The incidence of Kawasaki disease in Switzerland is in the lower range of other European countries.

Paola A. Rouge Elton, Patrick A. Schmitt, Mohamed Faouzi, Petra Zimmermann, Céline Ritter Schenk (Author)

Seroprevalence of SARS-CoV-2 antibodies and associated risk factors in children less than 6 years of age in the canton of Fribourg, Switzerland (COVPED study): a population-based cross-sectional study

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BACKGROUND: To date, few data are available about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence in young children and the role of early-life childcare arrangements in transmission of the virus. In this study, we assessed the SARS-CoV-2 seroprevalence in children less than 6 years of age in the canton of Fribourg and identified risk factors associated with seropositivity.

METHODS: The COVPED study is a population-based cross-sectional study in children less than 6 years of age living in the canton of Fribourg, Switzerland, who presented to a private paediatrician or the paediatric emergency department of the Fribourg Hospital during a 9-week period between 11 January and 14 March 2021. Immunoglobulin G antibodies against SARS-CoV-2 trimeric spike protein were measured in capillary blood samples using an in-house Luminex assay. A mean fluorescence intensity ratio of above 6 was considered as positive. Metadata was collected through electronic questionnaires. Logistic regression analysis was performed to assess the risk of seropositivity and associated factors.

RESULTS: A total of 871 children, with a median age of 33 months (range 6 days to 5 years 11 months) were included; 412 (47%) were female. Overall, 180 (21%, 95% confidence interval [CI] 18–24%) children were seropositive. Age as continuous variable was not associated with seropositivity risk, apart from a higher rate in children less than 3 months of age. Univariable analysis showed that female sex was associated with a lower seropositivity risk (unadjusted odds ratio [OR] 0.69, 95% CI 0.49–0.96; p = 0.03). Day-care attendance was also associated with a lower seropositivity risk (OR 0.67, 95% CI 0.47–0.95; p = 0.03), whereas all other childcare arrangements were not associated with seropositivity. No association was found between the number of children and adults present in extra-familial care and seropositivity. Multivariable analysis identified the number of household members above the age of 12 years being positive for SARS-CoV-2 as the main risk factor for seropositivity in children (adjusted odds ratio [aOR] 7.80, 95% CI 4.65–13.07; p <0.001 for one household member, aOR 22.07, 95% CI 13.49–36.11; p <0.001 for two household members and aOR 32.20, 95% CI 9.30–111.55; p <0.001 for three or more household members).

CONCLUSION: The number of household members tested positive for SARS-CoV-2 (PCR test) is the main exposure risk to seropositivity for children less than 6 years of age. But the family size is not associated with an increased risk of infection. In young children, extra-familial care does not increase the risk of becoming SARS-CoV-2 seropositive, neither does the number of contacts present in extra-familial care. As adults and children will be vaccinated and new virus variants will be circulating the risk of exposure for young children will likely change and needs further monitoring.

Jennifer Villers, Andre Henriques, Serafina Calarco, Markus Rognlien, Nicolas Mounet, James Devine, Gabriella Azzopardi, Philip Elson, Marco Andreini, Nicola Tarocco, Claudia Vassella, Olivia Keiser (Author)

SARS-CoV-2 aerosol transmission in schools: the effectiveness of different interventions

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BACKGROUND: Indoor aerosol transmission of SARS-CoV-2 has been widely recognised, especially in schools where children remain in closed indoor spaces and largely unvaccinated. Measures such as strategic natural ventilation and high efficiency particulate air (HEPA) filtration remain poorly implemented and mask mandates are often progressively lifted as vaccination rollout is enhanced.

METHODS: We adapted a previously developed aerosol transmission model to study the effect of interventions (natural ventilation, face masks, HEPA filtration and their combinations) on the concentration of virus particles in a classroom of 160 m³ containing one infectious individual. The cumulative dose of viruses absorbed by exposed occupants was calculated.

RESULTS: In the absence of interventions, the cumulative dose absorbed was 1.5 times higher in winter than in spring/summer, increasing chances of indoor airborne transmission in winter. However, natural ventilation was more effective in winter, leading to up to a 20-fold decrease in cumulative dose when six windows were fully open at all times. In winter, partly opening two windows all day or fully opening six windows at the end of each class was effective as well (2.7- to 3-fold decrease). In summer, good ventilation levels could be achieved through the opening of windows all day long (2- to 7-fold decrease depending on the number of windows open). Opening windows only during yard and lunch breaks had minimal effect (≤1.5-fold decrease). One HEPA filter was as effective as two windows partly open all day in winter (3-fold decrease) whereas two filters were more effective (5-fold decrease). Surgical face masks were very effective independently of the season (8-fold decrease). Combined interventions (i.e., natural ventilation, masks, and HEPA filtration) were the most effective (≥25-fold decrease) and remained highly effective in the presence of a super-spreader.

INTERPRETATION: Natural ventilation, face masks, and HEPA filtration are effective interventions to reduce SARS-CoV-2 aerosol transmission. These measures should be combined and complemented by additional interventions (e.g., physical distancing, hygiene, testing, contact tracing and vaccination) to maximise benefit.

Marco Previsdomini, Jacopo Colombo, Bernard Cerutti, Bernhard Gerber, Axel Hofmann, Alessandro F Chiesa, Andrea Saporito, Davide La Regina, Stefano Cafarotti, Miriam Patella, Andreas Perren (Author)

Dissemination of patient blood management practices in Swiss intensive care units: a cross-sectional survey

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BACKGROUND: Patient blood management (PBM) promotes the routine detection and treatment of anaemia before surgery, optimising the management of bleeding disorders, thus minimising iatrogenic blood loss and pre-empting allogeneic blood utilisation. PBM programmes have expanded from the elective surgical setting to nonsurgical patients, including those in intensive care units (ICUs), but their dissemination in a whole country is unknown.

METHODS: We performed a cross-sectional, anonymous survey (10 October 2018 to 13 March 2019) of all ordinary medical members of the Swiss Society of Intensive Care Medicine and the registered ICU nurses from the 77 certified adult Swiss ICUs. We analysed PBM-related interventions adopted in Swiss ICUs and related them to the spread of PBM in Swiss hospitals. We explored blood test ordering policies, blood-sparing strategies and red blood cell-related transfusion practices in ICUs.

RESULTS: A total of 115 medical doctors and 624 nurses (response rates 27% and 30%, respectively) completed the surveys. Hospitals had implemented a PBM programme according to 42% of physicians, more commonly in Switzerland’s German-speaking regions (Odds Ratio [OR] 3.39, 95% confidence interval [CI] 1.23–9.35; p = 0.018) and in hospitals with more than 500 beds (OR 3.91, 95% CI 1.48–10.4; p = 0.006). The PBM programmes targeted the detection and correction of anaemia before surgery (79%), minimising perioperative blood loss (94%) and optimising anaemia tolerance (98%). Laboratory tests were ordered in 70.4% by the intensivist during morning rounds; the nurses performed arterial blood gas analyses autonomously in 48.4%. Blood-sparing techniques were used by only 42.1% of nurses (263 of 624, missing: 6) and 47.0% of physicians (54 of 115). Approximately 60% of respondents used an ICU-specific transfusion guideline. The reported haemoglobin threshold for the nonbleeding ICU population was 70 g/l and, therefore, was at the lower limit of current guidelines.

CONCLUSIONS: Based on this survey, the estimated proportion of the intensivists working in hospitals with a PBM initiative is 42%, with significant variability between regions and hospitals of various sizes. The risk of iatrogenic anaemia is relevant due to liberal blood sample collection practices and the underuse of blood-sparing techniques. The reported transfusion threshold suggests excellent adherence to current international ICU-specific transfusion guidelines.

Petra Zimmermann, Anita Uka, Michael Buettcher, Yves Fougère, Margherita Plebani, Christa Relly, Hanna Schmid, Nicole Ritz (Author)

Neonates with SARS-CoV-2 infection: spectrum of disease from a prospective nationwide observational cohort study

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BACKGROUND: Coronavirus disease 2019 (COVID-19) can be more severe in infants than in older children. To date, only a few case series have reported data on neonates with COVID-19, including mostly asymptomatic neonates who were tested because of exposure to maternal SARS-CoV-2 infection. This study summarises nationwide epidemiological data, clinical characteristics, treatment and outcomes of neonates presenting with symptomatic SARS-CoV-2 infection.

METHODS: Data were prospectively collected through the Swiss Paediatric Surveillance Unit from hospitalised neonates with laboratory-confirmed SARS-CoV-2 infection (positive polymerase chain reaction on a respiratory sample) from 1 March 2020 to 31 September 2021. All 29 paediatric hospitals in Switzerland reported cases.

RESULTS: In total, 73 neonates were included; 7 (10%) were preterm. The median age at presentation was 17 days (interquartile range [IQR] 11–23); 40 (55%) were female. The majority of neonates (64, 88%) were admitted from home. Nine (12%) had a pre-existing medical condition. Overall, the most common symptom recorded was fever in 52 (71%), followed by rhinorrhoea or nasal congestion in 32 (44%) and respiratory distress in 19 (26%). Twenty (27%) neonates presented with fever without a source. Seven (10%) neonates were admitted to an intensive care unit (5 for respiratory failure and 2 for monitoring). One (1%) neonate required inotropic support. The median length of hospital stay in term neonates was 4 days (IQR 3–5). Two (3%) were treated with corticosteroids and 1 (1%) with remdesivir. In total, 60 (82%) neonates had contact with a known or suspected SARS-CoV-2 index case. All of the 71 neonates for whom data were available were discharged to their homes without symptoms.

CONCLUSION: In neonates, COVID-19 mainly presents with fever, and symptoms of upper and lower respiratory tract infection. The clinical course is mostly mild, requiring a short period of hospitalisation. COVID-19 needs to be added as a differential diagnosis in neonates who present with fever without a source. However, the presence of SARS-CoV-2 should not deter from the search for a serious bacterial infection. Further data from surveillance studies are needed to better understand COVID-19 in neonates, guide therapy and to evaluate whether the clinical spectrum is changing with new SARS-CoV-2 variants.

Rahel Baumgartner, Ursula Winterfeld, Alice Panchaud, Ana Paula Simões-Wüst (Author)

Queries on medication use during pregnancy: characterisation of the Swiss Teratogen Information Service database

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AIMS OF THE STUDY: Limited information on medication safety may result in concerns on how to treat pregnant and breast-feeding patients. The Swiss Teratogen Information Service (STIS) provides information to healthcare professionals about medications during pregnancy and breast feeding. Our objective was to describe the queries addressed to the STIS over the past two decades.

METHODS: The STIS maintains a database of queries on pregnancy outcomes after exposure to various substances, which may be a valuable source of information. We initially analysed the general characteristics of all queries. Thereafter, we focused on exposure to medications during singleton pregnancies and associated health-related aspects.

RESULTS: From 2000 to 2019, 7148 queries were entered into the database. An increasing number of queries was recorded over the study period, with an average of 357 queries entered into the database per year. Most of the enquirers were physicians; more specifically, gynaecologists/obstetricians (2389/7148; 33.4%) and psychiatrists (1007/7148; 14.1%). Two thirds (4747/7148; 66.4%) of the queries addressed medication intake during pregnancy; the next most frequent queries concerned planned medication in the context of pregnancy (928/7148; 13.0%) or medication use during breast-feeding (873/7148; 12.2%). In more than 50% (3611/7148) of cases, women were treated with more than one drug; altogether, 15193 medications (taken alone or in combination) were identified. The most frequent queries concerned medicines for the nervous system (ATC group N, n = 7042), with selective serotonin reuptake inhibitors (n = 1271) in the leading position, followed by benzodiazepine derivatives (n = 1102) and other antidepressants (n = 780). The next most frequently mentioned drug classes were anti-infectives for systemic use (J, n = 1586) and drugs for the alimentary tract and metabolism (A, n = 1205). Analysis of follow-up information on cases of medication exposure during singleton pregnancies (n = 2672) revealed an offspring malformation rate of 4.2%. The organ system most often affected was the musculoskeletal system, followed by the circulatory system; congenital malformations of the nervous system and chromosomal abnormalities were also seen. The three most frequently documented congenital diagnoses were malformations of cardiac septa, the brain and major arteries.

CONCLUSIONS: Healthcare professionals often have concerns regarding the treatment of pregnant women with medication, and require professional counselling in this area. A variety of drugs are mentioned in queries addressed to the STIS, of which psycholeptics and psychoanaleptics are the most frequent. Proper guidelines on their use during pregnancy appear particularly urgent.

François R. Girardin, Alexandar Tzankov, Giuseppe Pantaleo, Françoise Livio, Gilbert Greub (Author)

Multifocal lymphadenopathies with polyclonal reactions primed after EBV infection in a mRNA-1273 vaccine recipient

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We report a case of recurrent tender, multifocal lymphadenopathies associated with B-symptoms, clinically mimicking lymphoma in a mRNA-1273 vaccine recipient after a recent Epstein-Barr virus (EBV) infection.

In the lymph node biopsy, monocytoid B-cell hyperplasia, TH2 (GATA3+) predominance, and hyperplasia of interferon-gamma-producing plasmacytoid dendritic cells were observed along with sustained neutralising antibody production against SARS-CoV-2 wild-type and five variants. High titres of anti-S antibodies and neutralising antibodies were observed, excepted for variant B.1.529** (omicron) and B.1.351** (beta), due to several mutations in the spike protein, including the E484K mutation.

We postulated that EBV acted as an immunological enhancer with the mRNA-1273 vaccine, inducing a sustained inflammatory response over several weeks. However, the polyclonal nature of the lymphadenopathy with polytypic plasmacytosis and pseudo-tumoural reaction cell hyperplasia were associated with failure to mount acute phase responses.