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Early-life viral infection can have profound effects on the developing lung and immune systems, both important in asthma development. For decades, research has aimed to establish whether there is a causal link between these viral infections as an exposure and asthma later in childhood. Establishing causality will remain important, but new insights regarding early-life viral infection as an exposure, the recognition of asthma as a heterogeneous outcome, and the shared genetic susceptibility to both suggest a refocus from answering the theoretical question of causality toward additional pragmatic approaches focusing on improving patient outcomes across the spectrum of respiratory disease. This Clinical Commentary reviews the evidence on the consequences of early-life viral infection and aims to look beyond the question of causality, suggesting a research agenda specifically aimed at what matters for human development, and for the quality of life of current and future patients with wheezing disorders.

Contains fulltext : 287860.pdf (Publisher’s version ) (Open Access) Dolutegravir 50 mg is registered for use in children weighing 20-40 kg. This approval is based on data from an African paediatric cohort, and no pharmacokinetic data was available from children outside of Africa. This study provides further evidence of the effective use of dolutegravir 50 mg in children weighing 20 to 40 kg by showing that concentration data gathered in clinical practice shows adequate concentration levels in Dutch children without a safety signal.

SARS-CoV-2 Omicron variants BA.1 and BA.2 seem to show reduced clinical severity. We classified 172 COVID-19 Omicron patient admissions. 66.2% of patients were admitted with primary or admission-contributing COVID-19. We therefore must be careful to base healthcare and public health decisions on the total number of hospitalized COVID-19 patients alone.

Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade. Using cells from patients and newly generated mouse models, we uncovered ELF4-mutant macrophages having hyperinflammatory responses to a range of innate stimuli. In mouse macrophages, Elf4 both sustained the expression of anti-inflammatory genes, such as Il1rn, and limited the upregulation of inflammation amplifiers, including S100A8, Lcn2, Trem1 and neutrophil chemoattractants. Blockade of Trem1 reversed inflammation and intestine pathology after in vivo lipopolysaccharide challenge in mice carrying patient-derived variants in Elf4. Thus, ELF4 restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory disorders such as IBD.

IFN–gamma receptor (IFNGR) signaling via STAT1 is crucial in the defense against intracellular pathogens. Defects in this pathway enhance the susceptibility to infection by otherwise weak pathogenic mycobacteria, resulting in a primary immunodeficiency called mendelian susceptibility to mycobacterial disease (MSMD). Here we describe three patients with MSMD caused by variants in the IFNGR1 or STAT1 genes. All three patients presented with disseminated non-tuberculous mycobacterial infections caused by M. avium , M. persicum or M. bovis BCG respectively. Whole-exome sequencing (WES) was used as the first line diagnostic approach, however in all patients additional analysis was crucial to make the definite diagnosis. In Patient 1, only one heterozygous autosomal recessive variant p.(Val63Gly) in the IFNGR1 gene was identified. Patient 2 was compound heterozygous for the pathogenic null p.(Val68Lysfs*6) variant and the hypomorphic p.(Ile37Thr) variant in IFNGR1. In Patient 3 a novel variant in the STAT1 gene c.1379A>T, p.(Asn460Ile) was identified. Additional genetic analysis identified a second novel complex Alu-insertion in the IFNGR1 gene in Patient 1. Functional analysis showed that Patients 1 and 2 had reduced expression of IFNGR1. All patients had reduced phosphorylation of STAT1 and absent induction of SOCS1 mRNA after IFN-γ stimulation. While STAT1 phosphorylation was normal after IFN–α stimulation in Patient 1 and 2, it was mildly reduced in Patient 3. We conclude that functional assays are crucial to assess the extent of IFNGR signaling defects when new combinations of bi-allelic or non-conclusive genetic variants are found, which is important in the determination of clinical treatment.

Although fatigue is a common symptom in adult patients with Primary Immunodeficiencies (PID), data in pediatric patients are limited. The goal of this study is to estimate the prevalence and impact of fatigue in children with PID as reported by patients, parents and health-care providers. A retrospective single center observational study was performed. Prevalence of fatigue was measured by reviewing medical charts of 54 children in our department who are on immunoglobulin substitution therapy. Both prevalence and impact were also measured by the PedsQL-Multidimensional Fatigue Scale (MFS). This comprises age-appropriate questionnaire for self-report in patients aged 5-18 years and parent proxy-reports for patients aged 2-18 years. General, cognitive, sleep-rest fatigue was measured and a total fatigue score was calculated. Means, standard deviation and Z-scores were calculated using age-specific reference values. Intraclass correlation coefficients (ICC) were calculated for comparison of scores provided by parents vs children’s self-reported scores.Both chart review data and PedsQL-MFS showed fatigue rates of 65%. Pediatric PID patients of all ages had significantly lower scores on all subscales and total score of the PedsQL-MFS compared to healthy children. General fatigue was the most affected subscale in PID patients; indicating fatigue of these patients is mainly physical. Seventy-four % of PID patients had a Z-score lower than -1 on the General fatigue subscale indicating severe fatigue. Child-parent concordance varied between 0.24 and 0.93. Our results show high prevalence and severity of fatigue in children with PID, addressing the importance of this issue in our patient care.

Mycoplasma pneumoniae is a common cause of respiratory tract infections (RTI's), especially in children. While severe M. pneumoniae infections are generally treated with antibiotics, the diagnosis as well as treatment of these infections should be reconsidered in the light of recent clinical findings. First, M. pneumoniae was found to be carried in the upper respiratory tract of a relatively high percentage of healthy, asymptomatic children. Clearly, this complicates the diagnosis of a suspected M. pneumoniae RTI and, thus, the decision when to initiate treatment. A complication in the treatment of these infections is that data on the efficacy of antibiotic treatment of M. pneumoniae RTI's are sparse and derived exclusively from comparative studies. A recent Cochrane review concluded that there is insufficient evidence about the efficacy of antibiotics for M. pneumoniae lower respiratory tract infections (LRTI) in children. Due to side effects associated with the use of tetracyclines and quinolones in children, only macrolides can be used to treat M. pneumoniae infections in young patients. The general applicability of macrolides, however, is currently threatened by the worldwide increase in macrolide-resistant M. pneumoniae strains. Finally, limited evidence is available that corticosteroids might have an additional benefit in the treatment of M. pneumoniae infections. In this review, the current issues related to the diagnosis and treatment of M. pneumoniae infections will be discussed.

Contains fulltext : 142513.pdf (Publisher’s version ) (Closed access) INTRODUCTION: Adherence to highly active antiretroviral therapy is required to obtain an optimal long term virologic response rate of HIV-1-infected children. Plasma concentrations of protease inhibitors (PIs) outside the limits of the reference values indicate nonadherence to antiretroviral therapy in adults. We studied during a 2-year follow-up period routinely taken plasma protease inhibitor concentrations to assess adherence to antiretroviral therapy in HIV-1-infected children. METHODS: In 40 children (ages 3 months to 18 years) blood samples were taken at regular outpatient visits every 12 weeks after the start of highly active antiretroviral therapy and analyzed for plasma concentrations of indinavir or nelfinavir by high performance liquid chromatography and for plasma HIV-1 RNA load. The percentage of samples fulfilling the criteria for adherence was assessed for each child by three methods. For each sample a concentration ratio was calculated by dividing the concentration in that sample by the time-adjusted population value. According to Method 1 concentration ratios below or above concentration ratio limits (CORALs) of population data obtained in adults were highly indicative of nonadherence. Because many children have high PI levels, Method 2 evaluated plasma samples of PIs with only the lower CORAL. According to Method 3 only children with plasma samples below the limit of quantification (0.04 mg/l) were considered noncompliant. Differences in adherence rate between virologic responders and virologic nonresponders and between adherence rates and the two protease inhibitors were analyzed. The cumulative incidence of HIV-1 RNA levels >500 copies/ml in children was calculated. RESULTS: Thirty-one children started treatment with indinavir, and nine children started treatment with nelfinavir. The median adherence rates for indinavir as determined by methods 1, 2 and 3 were 54% [interquartile range (IQR), 25 to 69%], 67% (IQR 50 to 92%) and 80% (IQR 63 to 100%), respectively. For nelfinavir median adherence rates of 60% (IQR 39 to 75%), 100% (IQR 67 to 100%) and 100% (IQR 100 to 100%) were observed. Adherence rates calculated with Method 2 were significantly higher in virologic responders ( = 0.04). Adherence rates calculated with Methods 2 and 3 were significantly lower in children using indinavir compared with those using nelfinavir ( = 0.02 and = 0.02, respectively). CONCLUSION: Calculation of adherence rates using the lower limit of CORALs of indinavir or nelfinavir in children may be a useful measurement for the assessment of nonadherence to antiretroviral therapy in children.