Distinct clinical parameters were associated with shorter spontaneous resolution in children with non-tuberculous mycobacterial lymphadenitis.

AIM: Non-tuberculous mycobacteria (NTM) lymphadenitis typically resolves spontaneously, yet factors influencing the duration remain explored. We aimed to identify clinical parameters associated with shorter spontaneous resolution. METHODS: This cohort study included children with NTM lymphadenitis from 1 January 2015 to 1 March 2021 at Copenhagen University Hospital. Time-to-event analysis assessed clinical parameters associated with the duration of NTM lymphadenitis. RESULTS: Sixty children (57% boys) with a median age of 24 months (range 11-84) were included; 13 (22%) received primary surgery, 13 (22%) underwent surgery after a wait-and-see period and 34 (57%) received no intervention. In children without intervention, the median duration was 10 months (range 2-25). Faster resolution was associated with parental-reported lymph node enlargement within 2 weeks (HR 2.3, 95% CI 1.0-5.0; p = 0.044), abscess on ultrasound examination (HR 3.3, 95% CI 1.5-7.3; p = 0.003) and skin discoloration and/or perforation within 3 months of onset (HR 4.3, 95% CI 1.3-14.4; p = 0.017 and HR 3.7, 95% CI 1.5-9.1; p = 0.005). CONCLUSION: Knowledge of predictors for shorter spontaneous resolution of NTM lymphadenitis, such as rapid initial lymph node enlargement, abscess on ultrasound examination, and skin discoloration and/or perforation within 3 months of disease onset, may guide clinical management decisions concerning surgery versus a conservative approach.

Central Venous Oxygen Saturation in Children With Cancer.

OBJECTIVE: Central venous saturation (ScvO2) can guide resuscitation of children with septic shock. The normal range of ScvO2 is typically considered as 0.70-0.80, but has not been established in children with cancer. Children with cancer are particularly prone to develop sepsis due to their immunosuppressive therapy, and usually have a permanent central venous catheter, making ScvO2 readily available. We aimed to investigate normal values of ScvO2 in clinically stable children with cancer, and the association between ScvO2, hemoglobin, and lactate. METHODS: We conducted a prospective clinical study at the outpatient clinic of a tertiary pediatric hematology/oncology unit. Blood samples were collected from stable children aged 0-17.9 years who were treated for cancer between January 1 and November 30, 2019, during their routine outpatient clinic visits. RESULTS: A total of 183 blood samples were collected from 68 patients (24 girls and 44 boys). The predicted mean level of ScvO2 with a 95% confidence interval was 0.67 (0.56-0.78). The ScvO2 value was below the expected lower normal limit of 0.70 in 126 (69%) of the samples and in 48 patients (71%) at least once. ScvO2 was significantly associated with hemoglobin (ß1 = 0.012 per g/L hemoglobin, P < 0.001), but not with age, sex, underlying diagnosis, or lactate. CONCLUSIONS: The study revealed that a substantial portion of clinically stable childhood cancer patients exhibited ScvO2 levels below the typical reference value of 0.70, suggesting that these children may have inherently lower baseline ScvO2 levels. This should be kept in mind when evaluating children with cancer for septic shock, emphasizing the importance of tailored assessments in this population. Further understanding of baseline ScvO2 abnormalities may be helpful if ScvO2 is used to guide resuscitation.

Host RNA Expression Signatures in Young Infants with Urinary Tract Infection: A Prospective Study.

Early diagnosis of infections in young infants remains a clinical challenge. Young infants are particularly vulnerable to infection, and it is often difficult to clinically distinguish between bacterial and viral infections. Urinary tract infection (UTI) is the most common bacterial infection in young infants, and the incidence of associated bacteremia has decreased in the recent decades. Host RNA expression signatures have shown great promise for distinguishing bacterial from viral infections in young infants. This prospective study included 121 young infants admitted to four pediatric emergency care departments in the capital region of Denmark due to symptoms of infection. We collected whole blood samples and performed differential gene expression analysis. Further, we tested the classification performance of a two-gene host RNA expression signature approaching clinical implementation. Several genes were differentially expressed between young infants with UTI without bacteremia and viral infection. However, limited immunological response was detected in UTI without bacteremia compared to a more pronounced response in viral infection. The performance of the two-gene signature was limited, especially in cases of UTI without bloodstream involvement. Our results indicate a need for further investigation and consideration of UTI in young infants before implementing host RNA expression signatures in clinical practice.

Vaccination timeliness of preterm infants hospitalised in a neonatal intensive care unit in Denmark.

AIM: In Denmark, preterm infants are recommended to receive childhood vaccinations without correction for gestational age. This study aimed to describe the timeliness of the Danish Childhood Vaccination Program in preterm infants during the first 13 months of life and to evaluate possible determinants of delay. METHODS: This retrospective cohort study included preterm infants admitted to a level III neonatal intensive care unit between October 2019 and October 2020. Clinical data were retrieved from medical records and the Danish Vaccination Register. Timely vaccination was defined corresponding to chronological age of 3-, 5- and 12 months, within a time interval of 30 days before to 29 days after the expected date. RESULTS: Analyses included 365 infants. Timely vaccination occurred in 91%, 83% and 67% of preterm infants for the first, second and third vaccination, respectively, and timeliness was highest if born before gestational age 28 weeks. Gestational age 28-31 + 6 weeks and delayed former vaccinations negatively influenced the timeliness of the following vaccinations. CONCLUSION: Most preterm infants received the first vaccination timely; however, timeliness decreased with each subsequent vaccination. Efforts to improve timeliness should focus on counselling healthcare personnel and parents to follow the recommendations for the first and the following vaccinations.

Lactate as a Screening Tool for Critical Illness in a Pediatric Emergency Department.

OBJECTIVES: Lactate has in some pediatric emergency departments (PEDs) gained acceptance as a screening tool for critical illness, with cut-off values of 2.0 to 2.5 mmol/L. We aimed to investigate if lactate could predict the need of acute resuscitation in patients in a PED. PATIENTS AND METHODS: This retrospective observational cohort study included patients aged 0 to 17 years admitted to the PED at Copenhagen University Hospital in Denmark from January 1, 2019 to January 1, 2021. Patients were included if they had lactate measured as part of their routine blood sampling because of acute PED evaluation. Area under the receiver operating characteristic (ROC) curve (AUC) was calculated to assess the ability of lactate to predict the need of acute resuscitation. In patients without need of acute resuscitation, we calculated the lactate upper limit as the 95th percentile, and significant predictors were included in a multiple linear regression model. RESULTS: A total of 1355 children were included. Fourteen (1%) children with a need of acute resuscitation had a median lactate of 1.7 mmol/L (interquartile range, 1.4-2.3) versus 1.6 mmol/L (interquartile range, 1.3-2.1) in children without need of resuscitation ( P > 0.05). The AUC for lactate to predict acute resuscitation was 0.56 (95% confidence interval, 0.54-0.59). In children without need of acute resuscitation, the 95th percentile of lactate was 3.2 mmol/L, and 392 (29.8%) had lactate greater than 2.0 mmol/L. Increasing age and venous sampling were associated with lower lactate. Lactate was not associated with sex, pediatric early warning score, or duration of hospital admission. The 95th percentile of lactate after inhaled beta-2-agonists was 5.0 mmol/L. CONCLUSIONS: In children evaluated in a PED, lactate achieved a low AUC, suggesting a poor ability of predicting acute resuscitation. In children without need of acute resuscitation, the 95th percentile for lactate was 3.2 mmol/L, higher than the generally accepted cut-off values. This is important to recognize to avoid concern in otherwise clinically stable children. Our data did not support the use of lactate as a screening tool for early recognition of critical illness in a PED.

A Protocol for Low-Input RNA-Sequencing of Patients with Febrile Neutropenia Captures Relevant Immunological Information.

Improved methods are needed for diagnosing infectious diseases in children with cancer. Most children have fever for other reasons than bacterial infection and are exposed to unnecessary antibiotics and hospital admission. Recent research has shown that host whole blood RNA transcriptomic signatures can distinguish bacterial infection from other causes of fever. Implementation of this method in clinics could change the diagnostic approach for children with cancer and suspected infection. However, extracting sufficient mRNA to perform transcriptome profiling by standard methods is challenging due to the patient's low white blood cell (WBC) counts. In this prospective cohort study, we succeeded in sequencing 95% of samples from children with leukaemia and suspected infection by using a low-input protocol. This could be a solution to the issue of obtaining sufficient RNA for sequencing from patients with low white blood cell counts. Further studies are required to determine whether the captured immune gene signatures are clinically valid and thus useful to clinicians as a diagnostic tool for patients with cancer and suspected infection.

Invasive group A streptococcal infections in children and adolescents in Denmark during 2022-23 compared with 2016-17 to 2021-22: a nationwide, multicentre, population-based cohort study.

BACKGROUND: A historic increase in paediatric invasive group A streptococcal (iGAS) infections was reported globally in 2022. iGAS infections can lead to severe manifestations (eg, pleural empyema, necrotising fasciitis, toxic shock syndrome, osteomyelitis, septic arthritis, and meningitis). We aimed to compare the incidence and severity of iGAS infections overall, for distinct clinical phenotypes, and for GAS emm variants in Denmark in 2022-23 with reference to the previous six seasons (ie, 2016-17, 2017-18, 2018-19, 2019-20, 2020-21, and 2021-22). METHODS: In this nationwide, multicentre, population-based cohort study, we included all children and adolescents in Denmark aged 0-17 years with a positive culture of GAS or GAS confirmed through PCR-based methods from otherwise sterile sites in 2022-23 and the previous six seasons from 2016-17 to 2021-22. For all seven seasons, data were obtained from week 21 to week 20 of the next year. Patients at all 18 paediatric hospital departments in Denmark were identified through the Danish Microbiology Database, in which iGAS isolates from sterile sites are prospectively registered, including emm typing. We obtained electronic medical health records for each patient admitted with a diagnosis of iGAS. We calculated the incidence of iGAS per 1 000 000 inhabitants aged 0-17 years in each season from week 21 to week 20 of the next year and the risk ratios (RRs) for incidence of iGAS, distinct disease manifestations, and emm variants in 2022-23 versus the three pre-COVID-19 seasons in 2016-17, 2017-18, and 2018-19 using Fisher's exact test and Pearson's χ2 test. FINDINGS: Among the Danish population of 1 152 000 children and adolescents aged 0-17 years, 174 with iGAS disease were included. 76 children and adolescents with iGAS during 2022-23 were identified; 31 (41%) of 76 were female and 45 (59%) were male. 98 children and adolescents with iGAS during 2016-17 to 2021-22 were identified; 41 (42%) of 98 were female and 57 (58%) were male. There was an increase in incidence of iGAS from mean 22·6 (95% CI 14·7-33·1) per 1 000 000 children and adolescents during 2016-17 to 2018-19 to 66·0 (52·0-82·6) per 1 000 000 during 2023-23 (RR 2·9, 95% CI 1·9-4·6; p<0·0001). During the COVID-19 pandemic in 2019-20, 2020-21, and 2021-22, the mean incidence of iGAS was 6·1 (95% CI 2·4-12·5) per 1 000 000 children and adolescents. In 2022-23, there was a 9·5-fold increase in emm-12 (95% CI 2·2-40·8; p=0·0002) and a 2·7-fold increase in emm-1 (1·3-5·5; p=0·0037). The most common clinical manifestations of iGAS in 2022-23 were soft-tissue infections, which increased by 4·5-fold (1·9-10·9; p=0·0003), and complicated pneumonia with parapneumonic effusion, which increased by 4·0-fold (1·4-11·4; p=0·0059), both compared with the three pre-COVID-19 seasons. Overall, there was no increased severity of iGAS in 2022-23 compared with the previous six seasons as measured by median duration of hospital stay (8 days, IQR 4-14 vs 9 days, 5-15; p=0·39), paediatric intensive care unit (PICU) admission (17 [22%] of 76 vs 17 [17%] of 98; p=0·53), duration of stay in PICU (4 days, IQR 2-10 vs 4 days, 2-11; p=0·84), or mortality (three [4%] of 76 vs three [3%] of 98; p=1·00). In 2022-23, there was a 3·6-fold (95% CI 1·8-7·3; p=0·0001) increase in children with a preceding upper respiratory tract infection and a 4·6-fold (1·5-14·1; p=0·0034) increase in children with a preceding varicella-zoster infection, both compared with the three pre-COVID-19 seasons. INTERPRETATION: In Denmark, the incidence of paediatric iGAS increased in 2022-23 compared with the three pre-COVID-19 seasons of 2016-17, 2017-18, and 2018-19. However, the course of iGAS disease in children and adolescents in 2022-23 was not more severe than in previous seasons. The high morbidity across all seasons highlights iGAS as a major invasive bacterial infection in children and adolescents. FUNDING: Innovation Fund Denmark.

Proteomic profiling reveals diagnostic signatures and pathogenic insights in multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a severe disease that emerged during the COVID-19 pandemic. Although recognized as an immune-mediated condition, the pathogenesis remains unresolved. Furthermore, the absence of a diagnostic test can lead to delayed immunotherapy. Using state-of-the-art mass-spectrometry proteomics, assisted by artificial intelligence (AI), we aimed to identify a diagnostic signature for MIS-C and to gain insights into disease mechanisms. We identified a highly specific 4-protein diagnostic signature in children with MIS-C. Furthermore, we identified seven clusters that differed between MIS-C and controls, indicating an interplay between apolipoproteins, immune response proteins, coagulation factors, platelet function, and the complement cascade. These intricate protein patterns indicated MIS-C as an immunometabolic condition with global hypercoagulability. Our findings emphasize the potential of AI-assisted proteomics as a powerful and unbiased tool for assessing disease pathogenesis and suggesting avenues for future interventions and impact on pediatric disease trajectories through early diagnosis.

Herpes simplex virus infection among neonates suspected of invasive bacterial infection: a population-based cohort study.

OBJECTIVE: To estimate the incidence of neonatal herpes simplex virus (HSV) infection and the number of neonates with suspected invasive bacterial infection (IBI) needed to treat (NNT) with acyclovir to ensure prompt treatment of invasive HSV infections. DESIGN: A nationwide population-based cohort study. SETTING: All neonatal and paediatric emergency departments in Denmark from 1 January 2010 to 31 December 2019. PATIENTS: Neonates aged 0-28 days with HSV infection. MAIN OUTCOME MEASURES: The main outcome measures were incidence and NNT. The NNT was calculated based on neonates with invasive HSV infection whose onset symptoms resembled IBI and the estimated number of Danish neonates who received antibiotics for suspected IBI. RESULTS: Fifty-four neonates with HSV infection were identified, that is, an incidence of 9 per 100 000 live births. Twenty presented with symptoms resembling IBI, all within the first 14 days of life. Of 18 (78%) neonates, 14 had elevated C reactive protein, 14 of 19 (74%) had elevated alanine aminotransferase and 11 of 17 (65%) had thrombocytopaenia. The estimated NNTs with empiric acyclovir at postnatal ages 0-3, 4-7 and 8-14 days were 1139 (95% CI 523 to 3103), 168 (95% CI 101 to 726) and 117 (95% CI 48 to 198), respectively. CONCLUSIONS: The incidence of neonatal HSV infection was higher than in previous decades; however, the estimated NNT with empiric acyclovir was high. Therefore, we propose not to treat all neonates suspected of IBI with empiric acyclovir, as current European guidelines suggest. However, HSV should be considered in neonates with signs of infection, especially after the third postnatal day and in neonates with high alanine aminotransferases and thrombocytopaenia.

Hospital admissions and need for mechanical ventilation in children with respiratory syncytial virus before and during the COVID-19 pandemic: a Danish nationwide cohort study.

BACKGROUND: The incidence of respiratory syncytial virus (RSV) increased in several countries after the relaxation of COVID-19 restrictions. We aimed to investigate the age-related risk of RSV-associated hospital admissions and need for mechanical ventilation during the RSV resurgence in summer and autumn 2021 compared with the four RSV seasons preceding the COVID-19 pandemic. We also aimed to describe the clinical complications necessitating mechanical ventilation. METHODS: This population-based cohort study included patients aged 0-17 years admitted to hospital with RSV in Denmark during the RSV resurgence in summer and autumn 2021, and the four pre-COVID-19 RSV seasons (2016-17, 2017-18, 2018-19, and 2019-20). We retrieved data on RSV-associated hospital admissions from the Danish National Patient Registry and demographic and clinical details of children who received mechanical ventilation through prospective real-time data collection in 2021-22 and retrospective data collection for the 2016-17 to 2019-20 RSV seasons from all eight paediatric and neonatal intensive care units in Denmark. Risk factors for severe RSV disease were as defined as age younger than 3 months or severe comorbidities. We calculated the risk of RSV-associated hospital admissions per 100 000 population in each RSV season from week 21 to week 20 of the following year. We also calculated the risk rate of receiving mechanical ventilation per 100 000 population and 1000 RSV-associated hospital admissions during each RSV season from week 21 to week 20 of the following year. We calculated risk ratios (RRs) for hospital admission and mechanical ventilation by dividing the risk rate of hospital admission and mechanical ventilation in 2021-22 by annual mean risk rates in the four pre-COVID-19 RSV epidemics (2016-17 to 2019-20). We compared RRs using Fisher's exact test. We compared complications leading to intubation between children with and without risk factors for severe RSV disease. The study is registered at ClinicalTrials.gov, NCT05186597. FINDINGS: Among 310 423 Danish children aged younger than 5 years, the mean number of RSV-associated hospital admissions increased from 1477 (SD 226) in the 2016-17 to 2019-20 RSV seasons to 3000 in the 2021-22 RSV season (RR 2·0 [95% CI 1·9-2·1]). 54 children with RSV received mechanical ventilation in 2021-22 compared with 15-28 annually in the 2016-17 to 2019-20 RSV seasons (2·3 [1·6-3·3]). The highest increase in hospital admissions and need for mechanical ventilation occurred among children aged 24-59 months (4·1 [3·6-4·7] for hospital admission; 4·6 [1·7-12·6] for mechanical ventilation). Among children admitted to hospital, the risk of mechanical ventilation was similar in 2021-22 and the four pre-COVID-19 seasons (risk rate 14·3 per 1000 RSV-associated hospital admissions [95% CI 10·4-19·3] vs 12·9 [10·1-16·1]; RR 1·1 [95% CI 0·8-1·6]). Across all RSV seasons studied, among children younger than 3 months or those with severe comorbidities, respiratory failure due to bronchiolitis led to mechanical ventilation in 69 (79%) of 87 children. Of 46 children with no risk factors for severe RSV, 40 (87%) received mechanical ventilation due to additional complications, including neurological (n=16; 35%), cardiac (n=1; 2%), and pulmonary complications (n=23; 50%; eg, wheeze responsive to bronchodilator therapy, severe bacterial co-infections, and pneumothorax). INTERPRETATION: In Denmark, RSV disease did not seem to be more severe for the individual child during the RSV resurgence in 2021 following relaxation of COVID-19 restrictions. However, hospital admissions were higher among older children, possibly due to a postponed first RSV infection or no recent reinfection. Older children without risk factors for severe RSV disease had atypical complications that led to intubation. If new RSV-preventive interventions for healthy infants delay first RSV infection, a higher number of older children might be admitted to hospital due to atypical clinical phenotypes, rather than classical bronchiolitis. FUNDING: National Ministry of Higher Education and Science and the Innovation Fund Denmark.

Switch from intravenous-to-oral antibiotics in neonatal probable and proven early-onset infection: a prospective population-based real-life multicentre cohort study.

OBJECTIVE: To evaluate the implementation of switch from intravenous-to-oral antibiotic therapy with amoxicillin in neonates with early-onset infection (EOI). DESIGN, SETTING AND PATIENTS: A population-based multicentre cohort study. All term-born neonates with EOI were prospectively included between 1 December 2018 to 30 November 2020. INTERVENTION: Intravenous-to-oral switch antibiotic therapy in clinically stable neonates. MAIN OUTCOME MEASURES: The primary outcome was readmission due to infection. Secondary outcomes were days of hospitalisation and antibiotic use in the pre-implementation versus post implementation period. RESULTS: During 2 years, 835 neonates commenced antibiotics for EOI (1.5% (95% CI 1.4% to 1.6%)) of all term live births). Of those, 554 (66%) underwent a full course of treatment. There were 23 episodes of culture-proven infection (0.42 per 1000 term live births (95% CI 0.27 to 0.63)). A total of 478 of 531 (90%) neonates with probable infection underwent switch therapy. None was readmitted due to infection. The median duration of hospitalisation was 3.0 days (IQR 2.5-3.5) and 7.4 days (IQR 7.0-7.5) in the switch and intravenous therapy groups, respectively. According to antibiotic surveillance data, 1.2% underwent a full course of treatment following implementation of oral switch therapy (2019-2020), compared with 1.2% before (2017-2018). CONCLUSION: In clinical practice, switch therapy was safe and used in 9 of 10 neonates with probable EOI. Knowledge of the safety of antibiotic de-escalation is important as home-based oral therapy ameliorates the treatment burden for neonates, caregivers and healthcare systems. Despite the ease of oral administration, implementation of switch therapy did not increase the overall use of antibiotics.

[Herpes simplex virus infection in newborns].

Neonatal herpes simplex disease (HSV) is a rare but life-threatening infection associated with high rates of morbidity and mortality. Recent studies indicate that the incidence rate has continued to rise over the past decades, while the mortality remains unchanged. Early clinical suspicion of HSV and parenteral antiviral treatment of acute disease is essential for the prognosis. The subsequent use of suppressive therapy with oral acyclovir has further enhanced the long-term prognosis. This review presents evidence of risk factors, clinical presentation, prevention, and management of HSV in newborns.

Language barriers and use of interpreters in two Danish paediatric emergency units.

INTRODUCTION: Paediatric consultations require safe and unambiguous communication. For children and adolescents of foreign ethnic and language backgrounds, professional interpretation may be crucial to avoid misunderstandings and malpractice. Knowledge about language barriers in paediatric consultations in the Danish healthcare is sparse. METHODS: The study was based on questionnaires completed by medical professionals at two paediatric emergency units in Copenhagen from March through June 2018. Questionnaire A, completed by doctors, addressed all patients aged 0-18 years regardless of the parents' first language and, if foreign, the presence of language barriers, whether clinical management was affected and use of professional interpretation. All doctors and nurses were asked to complete questionnaire B addressing their knowledge, experiences and practices with language barriers in their clinical work. RESULTS: Language barriers were present in 37% of 136 non-native-Danish consultations. In 44% of these, clinical management was affected. Professional interpretation was not used in any consultations. Almost half of the medical professionals reported insufficient communication opportunities with non-native-Danish-speaking patients (48%). CONCLUSIONS: Language barriers frequently affected communication and clinical decision-making in the two Danish paediatric emergency units studied. Even so, professional interpretation was not used. Further studies are needed to explore whether language is a barrier to equal health. FUNDING: none. TRIAL REGISTRATION: not relevant.