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.

Pertussis epidemic in Denmark, August 2023 to February 2024.

We report a record high pertussis epidemic in Denmark since August 2023. Highest incidence was in adolescents, while peak incidence in infants was lower vs previous epidemics in 2019 and 2016. Among infants aged 0-2 months, over half (29/48) were hospitalised and one infant died, underlining the disease severity in the youngest. To protect infants, pertussis vaccination in pregnant women was introduced in January 2024 in the national vaccination programme. Improved vaccination surveillance in pregnant women is being implemented.

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.

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.

Unexplained fever in children-Benefits and challenges of FDG-PET/CT.

AIM: To explore [fluorine-18]-fluoro-2-deoxy-d-glucose positron-emission-tomography/computed tomography (18 FDG-PET/CT) in patients where standard investigations were non-diagnostic. METHODS: We reviewed medical records of previously healthy children who had 18 FDG-PET/CT performed at Copenhagen University Hospital in 2015-2020 due to unexplained fever. RESULTS: Thirty-five of 819 paediatric 18 FDG-PET/CT were performed due to unexplained fever. The final diagnoses were malignancy (11%), infections (23%), inflammatory diseases (43%) and miscellaneous (26%). 18 FDG-PET/CT was diagnostic in six cases with Takayasu's arteritis, tuberculosis, Langerhans cell histiocytosis and Ewing sarcoma. Sixteen cases had focal 18 FDG-uptake, but 18 FDG-PET/CT could only differentiate malignancy, infection and inflammation in three cases. In six cases with inflammatory diseases and no focal signs, PET/CT was normal except increased non-specific 18 FDG-uptake in bone marrow and spleen in five cases. One case was false positive (suspicion of appendicitis) and two false negative (leukaemia and inflammatory disease). CONCLUSION: 18 FDG-PET/CT was diagnostic, or contributed to the diagnosis, in several children with unexplained fever referred to a tertiary centre. Challenges comprised (i) only increased non-specific 18 FDG-uptake in bone marrow and spleen in half of cases with inflammatory diseases, (ii) no differentiation between complicated infections, malignancy and inflammation in most cases with focal processes and (iii) a small risk of false positive and false negative results.

Left ventricular thrombus in multisystem inflammatory syndrome in children associated with COVID-19.

A 17-year-old adolescent with severe multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease-2019 developed reduced left ventricular function and left ventricular thrombus. With treatment, his condition improved and the thrombus was dissolved. This case illustrates the risk of severe intra-cardiac thrombotic complications in patients with MIS-C.

The right antibiotic for the right neonate? A prospective observational cohort study at a district hospital in Pemba, Tanzania.

BACKGROUND: The highest neonatal mortality is in Sub-Saharan Africa, where neonatal sepsis accounts for approximately 50%. At Pemba Island, Tanzania, we examined the use of prophylactic antibiotics in neonates and related it to WHO guidelines and compared clinical signs of infection with the use of antibiotic treatment; furthermore, we aimed to investigate all use of antibiotic treatment in the neonatal period. METHOD: This prospective observational cohort study was performed from 1 January 2022 to 15 April 2022 at a district hospital on Pemba Island, Tanzania. Women admitted in early established or active labour, and their neonates, were eligible for inclusion. We used questionnaires for mother and health worker and examined the neonates 2 h after birth. Follow-up was made at discharge or at 18 h of life, and days 7 and 28. RESULTS: We included 209 women and their 214 neonates. The neonatal mortality was 5 of 214 (23 per 1000 live births). According to WHO guidelines 29 (13.6%) had ≥ 1 risk factor for infection. Of these, three (10.3%) received prophylactic antibiotic treatment; only one (3.4%) received the correct antibiotic drug recommended in guidelines. Thirty-nine (18.2%) neonates had ≥ 1 clinical indicator of infection and 19 (48.7%) of these received antibiotic treatment. A total of 30 (14.0%) neonates received antibiotics during the study period. Twenty-three (76.7%) were treated with peroral antibiotics. CONCLUSION: Adherence to WHO guidelines for prophylactic antibiotic treatment to prevent neonatal infection was low. Further, only half of neonates with clinical signs of infection received antibiotics.

Antibiotics for hospital-acquired pneumonia in neonates and children.

BACKGROUND: Hospital-acquired pneumonia is one of the most common hospital-acquired infections in children worldwide. Most of our understanding of hospital-acquired pneumonia in children is derived from adult studies. To our knowledge, no systematic review with meta-analysis has assessed the benefits and harms of different antibiotic regimens in neonates and children with hospital-acquired pneumonia. OBJECTIVES: To assess the beneficial and harmful effects of different antibiotic regimens for hospital-acquired pneumonia in neonates and children. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, three other databases, and two trial registers to February 2021, together with reference checking, citation searching, and contact with study authors to identify additional studies. SELECTION CRITERIA: We included randomised clinical trials comparing one antibiotic regimen with any other antibiotic regimen for hospital-acquired pneumonia in neonates and children. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We assessed the certainty of the evidence using the GRADE approach. Our primary outcomes were all-cause mortality and serious adverse events; our secondary outcomes were health-related quality of life, pneumonia-related mortality, non-serious adverse events, and treatment failure. Our primary time point of interest was at maximum follow-up. MAIN RESULTS: We included four randomised clinical trials (84 participants). We assessed all trials as having high risk of bias. We did not conduct any meta-analyses, as the included trials did not compare similar antibiotic regimens. Each of the four trials assessed a different comparison, as follows: cefepime versus ceftazidime; linezolid versus vancomycin; meropenem versus cefotaxime; and ceftobiprole versus cephalosporin. Only one trial reported our primary outcomes of all-cause mortality and serious adverse events. Three trials reported our secondary outcome of treatment failure. Two trials primarily included community-acquired pneumonia and hospitalised children with bacterial infections, hence the children with hospital-acquired pneumonia constituted subgroups of the total sample sizes. Where outcomes were reported, the certainty of the evidence was very low for each of the comparisons. We are unable to draw meaningful conclusions from the numerical results. None of the included trials assessed health-related quality of life, pneumonia-related mortality, or non-serious adverse events. AUTHORS' CONCLUSIONS: The relative beneficial and harmful effects of different antibiotic regimens remain unclear due to the very low certainty of the available evidence. The current evidence is insufficient to support any antibiotic regimen being superior to another. Randomised clinical trials assessing different antibiotic regimens for hospital-acquired pneumonia in children and neonates are warranted.

Antibody response to vaccination after haematopoietic cell transplantation in children using a reduced dose schedule-A retrospective cohort study.

Children receiving HCT loose protective immunity to vaccines received pre-HCT. Therefore, revaccination post-HCT is of major importance. In Denmark, a vaccination schedule with fewer doses post-HCT has been used, including two doses for diphtheria, tetanus, polio, measles, mumps, and rubella, and one dose only for Haemophilus influenzae type B. The background for this was the presumption that post-HCT immunization constituted booster vaccination of donor immunity. Our objective was to evaluate the proportion of children protected after the scheduled vaccination programme. A nationwide retrospective cohort study of all children who have received an HCT in Denmark during 1994-2012. Antibody levels were analysed in blood samples drawn before and after vaccination, and the probability of achieving protection after the scheduled immunization programme was estimated. A total of 198 children were included. The protection post-immunization was as follows: diphtheria 75.3%, tetanus 89.1%, polio 97.7%, and Haemophilus influenzae type B 94.8%. For diphtheria and tetanus, the probability of achieving protection increased to 93.8% and 97.3%, respectively, after a third dose. For measles, mumps, and rubella, the probability of achieving protection was 89.4%, 80.9%, and 94.2%, respectively. In conclusion, our findings support a more extensive vaccination schedule including three doses for diphtheria and tetanus which are in line with current international guidelines.

Meropenem to Children With Febrile Neutropenia Induces Monoresistant Pseudomonas aeruginosa.

Antimicrobial resistance in Pseudomonas aeruginosa is a threat to children with cancer. We explored the association between P. aeruginosa resistance and previous antibiotic exposure. All children with cancer and P. aeruginosa bacteremia in 2007 to 2016 in Denmark, a country with an overall resistance rate of ∼3%, were included. Twenty percent (10/49) of isolates from children previously exposed to meropenem were meropenem nonsusceptible. The only significant risk factor of meropenem nonsusceptibility was previous meropenem therapy (P=0.03). On the basis of these results, we suggest that meropenem should be reserved as a last resort for children with febrile neutropenia in countries with low antimicrobial resistance.

Infectious diseases detected by screening after arrival to Denmark in internationally adopted children.

AIM: To show the prevalence of selected infectious diseases among internationally adopted children (IAC) in Denmark. BACKGROUND: Each year approximately 200 IAC arrive in Denmark. These are at increased risk of infectious diseases rarely seen in Danish children. Studies from the 1990s showed that 60% of IAC had infectious diseases and that the majority of these were undetected without screening. METHODS: The study is a prospective study of medical records from children seen in the adoption clinic at Copenhagen University Hospital in the period 2009-2013. Screening was done for hepatitis A (HAV), B (HBV) and C (HCV), syphilis, HIV, tuberculosis (TB) and intestinal parasites. RESULTS: In 245 IAC tested, 2% had evidence of recent HAV infection, 3% with HBV and one child with HCV, and no cases of HIV were found. One child had antibodies against syphilis (anti-Trpa AB positivity), and 2% were latently infected with tuberculosis. We found 30% infected with pathogenic intestinal parasites. Only 46% had serologic evidence of immunisation against HBV. CONCLUSION: The prevalence of infections in IAC was lower than previously reported but compared to the general population, a higher prevalence of intestinal parasites, hepatitis and tuberculosis was found. We recommend that IAC are offered screening shortly after arrival.

Pediatric toxic epidermal necrolysis treated successfully with infliximab.

Successful management of toxic epidermal necrolysis (TEN) with tumor necrosis factor-α inhibitors has been described in adults. We present a case of a 7-year-old boy with infection-associated TEN, diagnosed by typical clinical and histopathological features, most likely caused by Mycoplasma pneumoniae. Treatment with a single dose of infliximab 5 mg/kg intravenously on day 5 after the onset of symptoms was followed by cessation of all blister formation over 3 days and complete resolution within a week. Sequelae were mild, consisting of postinflammatory hyperpigmentation and dry eyes.

OK-432 Treatment of Early Fetal Chylothorax: Pregnancy Outcome and Long-Term Follow-Up of 14 Cases.

BACKGROUND: The treatment options for fetal chylothorax include thoracocentesis, thoracoamniotic shunting, and pleurodesis using OK-432. Knowledge on the long-term outcomes after treatment with OK-432 is limited. OBJECTIVE: The aim of this study was to assess the long-term outcomes of children treated in utero with OK-432. METHODS: We performed follow-up on pregnancies and children treated in utero with OK-432 between 2003 and 2009 at Copenhagen University Hospital Rigshospitalet for pleural effusions at gestational age (GA) 16+0-21+6 weeks. Anamnestic information, physical examination, pulmonary function test, neuropediatric examination, and intelligence testing using the Wechsler Intelligence Scale were used for evaluation. RESULTS: Fourteen cases, all chylothorax, were treated with OK-432. None had preterm premature rupture of membranes (PPROM), and the median GA at delivery was 38+5 (24+4-41+5) weeks. Twelve children were eligible for follow-up. The median age at follow-up was 11.4 (7.8-13.8) years. Pulmonary function was normal in all children and the mean full-scale IQ did not differ from that of normal children. Four children had a diagnosed medical condition, attention deficit disorder, or genetic syndrome. The remaining children had normal follow-up. CONCLUSION: Children treated with OK-432 have comparable survival rates and long-term neurodevelopmental outcomes to those treated with thoracoamniotic shunts. There seems to be a lower risk of procedure-related PPROM.

Staphylococcus aureus Bacteremia in Children Aged 5-18 Years-Risk Factors in the New Millennium.

OBJECTIVES: To assess the association between comorbidities and Staphylococcus aureus bacteremia in children aged 5-18 years, thus, in children with a matured immune system. Further, we aimed to identify presumably healthy children acquiring bacteremia. STUDY DESIGN: By cross-linking nationwide registries, we consecutively included all children born from 1995 onward at their 5-year birthday or date of immigration during 2000-2015. We examined incidence rate ratios (IRR) between preselected exposures and microbiologically verified S aureus bacteremia (reference = children without exposure) using Poisson regression models. RESULTS: We followed 1 109 169 children in 2000-2015 during which 307 children (incidence rate: 3.7 per 100 000 person-years) acquired S aureus bacteremia (methicillin-resistant S aureus = 8; 2.6%). Children without known comorbidities or recent contact with the healthcare system comprised 37.1% of infected children. The highest IRRs were observed in children undergoing dialysis or plasmapheresis (IRR = 367.2 [95% CI) = 188.5-715.3]), children with organ transplantation (IRR = 149.5 [95% CI = 73.9-302.2]), and children with cancer (IRR = 102.9 [95% CI = 74.4-142.2]). Positive associations also were observed in children with chromosomal anomalies (IRR = 7.16 [95% CI = 2.96-17.34]), atopic dermatitis (IRR = 4.89 [95% CI = 3.11-7.69]), congenital heart disease (IRR = 3.14 [95% CI = 1.92-5.11]), and in children undergoing surgery (IRR = 3.34 [95% CI = 2.59-4.28]). Neither premature birth nor parental socioeconomic status was associated with increased disease rates. CONCLUSIONS: S aureus bacteremia is uncommon in children between 5 and 18 years of age. Risk factors known from the adult population, such as dialysis, plasmapheresis, organ transplantation, and cancer, were associated with the highest relative rates. However, prematurity and parental socioeconomic status were not associated with increased rates. Approximately one-third of infected children were presumably healthy.

Successful Treatment of Rhino-Orbital-Cerebral Mucormycosis in a Child With Leukemia.

Rhino-orbital-cerebral mucormycosis (ROCM) is a rare fulminant opportunistic fungal infection that despite relevant treatment has high mortality. We present a case of a 3-year-old girl with acute lymphoblastic leukemia and ROCM, who was treated successfully with excessive surgery, systemic antifungal treatment with amphotericin B (AmB), posaconazole, and terbinafine as well as hyperbaric oxygen. Surgery included, beside extracranial and intracranial removal of infected areas, endoscopic sinus and skull base surgery with local AmB installation and in addition placement of an Ommaya reservoir for 114 intrathecal administrations of AmB. In addition, we review the literature of ROCM in pediatric patients with hematological diseases.

Hepatotoxicity During Maintenance Therapy and Prognosis in Children With Acute Lymphoblastic Leukemia.

Hepatotoxicity is a known toxicity to treatment of childhood acute lymphoblastic leukemia. Hepatotoxicity occurs during maintenance therapy and is caused by metabolites of 6-Mercaptopurine (6 MP) and Methotrexate (MTX). Our objective was to investigate the association between alanine aminotransferases (ALAT) levels and relapse rate. We included 385 patients enrolled in the NOPHO ALL-92 protocol. Data on ALAT levels, 6 MP and MTX doses, cytotoxic MTX/6 MP metabolites, and thiopurine methyltransferase (TPMT) activity were prospectively registered. In total, 91% of the patients had a mean ALAT (mALAT) level above upper normal limit (40 IU/L) and ALAT levels were positively correlated to 6 MP doses (rs=0.31; P<0.001). In total, 47 patients suffered a relapse, no difference in mALAT levels were found in these compared with nonrelapse patients (median, 107 vs. 98 IU/L; P=0.39). mALAT levels in patients classified as TPMT high activity (TPMT) were higher than in TPMT low-activity patients (median, 103 vs. 82 IU/L; P=0.03). In a Cox regression model risk of relapse was not associated with ALAT levels (P=0.56). ALAT levels increased 2.7%/month during the last year of maintenance therapy (P<0.001). In conclusion, elevated ALAT levels are associated with TPMT and may indicate treatment adherence in these patients. If liver function is normal, elevated ALAT levels should not indicate treatment adaptation.