Working group summary of the 2023 full update of the Finnish national guidelines for paediatric lower respiratory tract infections.

AIM: The first evidence-based Finnish guidelines for paediatric lower respiratory tract infections (LRTIs) were published in 2014 and completely updated in 2023. This paper, by the interdisciplinary working group that developed the 2023 guidelines, summarises the main recommendations. METHODS: The 2023 guidelines were produced after a systematic review. Strong evidence was at least two separate, high-quality studies, moderate evidence was at least one high-quality study and weak evidence was at least one satisfactory study. The authors have now summarised the key points. RESULTS: There was strong evidence that antitussives and beta-sympathomimetics were not effective for bronchitis-related cough and that laryngitis should be treated with oral corticosteroids, with adrenaline inhalations added in severe cases. Also, that amoxicillin for 5 days provided sufficient treatment for paediatric community-acquired pneumonia and that children with apparent viral pneumonia could be observed without antimicrobial therapy. There was moderate evidence that corticosteroids or inhaled agents were not effective for bronchiolitis and that administering salbutamol with a holding chamber could relieve symptoms of wheezing bronchitis. Also, pertussis should be considered for unvaccinated infants with coughs. CONCLUSION: The 2023 guidelines aim to improve acute evidence-based treatment of LRTIs, through appropriate antibiotics, inhaled drugs, corticosteroids, radiology and laboratory testing.

Pneumonia, wheezing and asthma were more common in children after thymectomy due to open-heart surgery.

AIM: This nationwide study evaluated the clinical impact that an early thymectomy, during congenital heart defect (CHD) surgery, had on the health of children and adolescents. METHODS: The subjects were patients aged 1-15 years who had undergone CHD surgery at the University Children's Hospital, Helsinki, where all CHD surgery in Finland is carried out, from 2006 to 2018. The parents or the cases and population-based controls, matched for sex, age and hospital district, completed electronic questionnaires. We excluded those with low birth weights or a known immunodeficiency. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were calculated for prespecified outcomes. RESULTS: We received responses relating to 260/450 (58%) cases and 1403/4500 (31%) controls and excluded 73 cases with persistent cardiac or respiratory complaints after surgery. The CHD group reported more recurrent hospitalisations due to infections (aOR 6.3, 95% CI 3.0-13) than the controls and more pneumonia episodes (aOR 3.5, 95% CI 2.1-5.6), asthma (aOR 2.5, 95% CI 1.5-4.1) and wheezing (aOR 2.1, 95% CI 1.5-2.9). CONCLUSION: Hospitalisation due to infections, pneumonia, wheezing and asthma was more common in children after a thymectomy due to open-heart surgery than population-based controls, underlining the importance of immunological follow-ups.

Mycoplasma pneumoniae may cause dyspnoea and hospitalisations in young healthy adults.

Polymerase chain reaction (PCR)-based diagnostics for Mycoplasma pneumoniae (M. pneumoniae) from the respiratory tract has become widely available, but the interpretation of the results remains unclear. M. pneumoniae has been suggested to cause mainly mild and self-limiting infections or asymptomatic carriage. However, systematic analyses of the association between PCR results and clinical findings are scarce. This study aimed to clarify the clinical features of PCR-positive M. pneumoniae infections in a hospital setting. We reviewed 103 PCR-positive patients cared for in a university hospital during a 3-year period. Data on age, sex, health condition, acute symptoms, other pathogens found, laboratory and X-ray results and treatments were collected. Over 85% of the patients had a triad of typical symptoms: fever, cough and shortness of breath. Symptoms in the upper respiratory tract were rare. In 91% of the cases, M. pneumoniae was the only pathogen found. The highest incidence was found in the age group of 30-40 years, and 68% of the patients did not have any underlying diseases. Most patients were initially empirically treated with beta-lactam antibiotics and needed 2-4 changes in their treatment. Only 6% were discharged without an antibiotic effective against M. pneumoniae. This study shows that M. pneumoniae often led to hospitalisation and that patients needed appropriate antimicrobial treatment to recover. Mixed infections were rare, and situations that could be interpreted as carriage did not occur.

IL17F rs763780 single nucleotide polymorphism is associated with asthma after bronchiolitis in infancy.

AIM: Interleukin-17F (IL-17F) is involved with asthma. The aim of this study was to evaluate the association of IL17F polymorphisms with childhood asthma after bronchiolitis in infancy. METHODS: We invited 166 children who were hospitalised for bronchiolitis at younger than 6 months of age to follow-up visits at 5-7 years and 11-13 years of ages. Asthma and allergy diagnoses, asthma-presumptive symptoms and use of inhaled corticosteroids (ICSs) were registered. Blood samples were available for IL17F rs763780 (T/C), rs11465553 (C/T) and rs7741835 (C/T) determinations in 165 cases. RESULTS: The presence of IL17F rs11465553 and rs7741835 variations showed no significant associations with any asthma or allergy outcome at either 5-7 years or 11-13 years of ages. Instead, children with the variant IL17F rs763780 genotype had used more often ICSs between the follow-up visits from 5-7 to 11-13 years (adjusted OR 3.58) than those with the wild genotype. Children with the variant IL17F rs763780 genotype reported more often doctor-diagnosed atopic dermatitis (adjusted OR 2.71) at 11-13 years of age than those with the wild genotype. CONCLUSION: This prospective long-term follow-up study provided preliminary evidence on the association of the IL17F rs763780 polymorphism with asthma at school age after bronchiolitis in infancy.

Multi-inflammatory syndrome and Kawasaki disease in children during the COVID-19 pandemic: A nationwide register-based study and time series analysis.

AIM: We investigated whether the ongoing COVID-19 pandemic was associated with the occurrence of Kawasaki disease or with multi-inflammatory syndrome in children (MIS-C). METHODS: This national Finnish register-based study was based on laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, MIS-C and Kawasaki disease cases. We performed a time series analysis on the occurrence of Kawasaki disease in 2016-2020. RESULTS: In 2020, there were 5170 laboratory-confirmed COVID-19 cases in children under 18 years of age and five fulfilled the MIS-C case definition. The occurrence of MIS-C was 0.97 per 1000 (95% confidence interval: 0.31-2.26) laboratory-confirmed SARS-CoV-2 infections in children. Our time series analysis showed that Kawasaki disease cases decreased during the COVID-19 pandemic. The seasonally adjusted incidence rate ratio was 0.49 (95% confidence interval: 0.32-0.74) when it was compared to pre-pandemic levels. This coincided with a reduced occurrence of respiratory infections, due to social distancing in the population. CONCLUSION: This nationwide register-based study found that MIS-C was a rare complication of the SARS-CoV-2 infection. The occurrence of Kawasaki disease and respiratory infections decreased during the pandemic. This suggests that transmissible microbes may play an important role in Kawasaki disease and social distancing may have a protective effect.

Toll-like receptor 10 rs4129009 gene polymorphism is associated with post-bronchiolitis lung function in adolescence.

AIM: The aim was to evaluate the association of polymorphisms in the Toll-like receptor (TLR) 2 subfamily encoding genes with lung function by spirometry at 10-13 years of age in children who had been hospitalised for bronchiolitis at <6 months of age. METHODS: In a prospective cohort of 166 former bronchiolitis patients, 138 returned a structured questionnaire and 89 attended a clinical follow-up visit including spirometry before and after bronchodilation at 10-13 years of age. Data on polymorphisms of the TLR1, TLR2, TLR6 and TLR10 genes were available from 81-82 children. RESULTS: In the TLR10 rs4129009, the wild (AA) genotype was associated with lower FEV1/FVC before (92.4 vs 97.4, P = .002) and after (95.5 vs 98.6, P = .011) bronchodilator administration, compared to those with the variant genotype. When the TLR10 rs4129009 and TLR2 rs5743708 genotypes, and the TLR10 rs4129009 and TLR1 rs5743618 genotypes, respectively, were analysed as combined, both baseline and post-bronchodilator FEV1/FVC were lowest in the subjects with the wild (AA) genotype of the TLR10 rs4129009. CONCLUSION: In this post-bronchiolitis follow-up, lung function in children with the variant TLR10 rs4129009 genotype with potentially altered TLR10 function was superior to lung function in those with the wild genotype.

Prospective study confirms that bronchiolitis in early infancy increases the risk of reduced lung function at 10-13 years of age.

AIM: This study evaluated children hospitalised for bronchiolitis at less than six months of age to see if they had reduced lung function in early adolescence. METHODS: We have prospectively followed 166 children hospitalised for infant bronchiolitis in 2001-2004 at Tampere University Hospital, Finland. At 10-13 years of age, flow-volume spirometry was measured in 89 cases and 108 controls without infant bronchiolitis from the local population register. Parameters of flow-volume spirometry before and after bronchodilation were analysed. RESULTS: Forced expiratory volume in one second/forced vital capacity (FEV1/FVC) after bronchodilation was lower in cases than controls. FEV1 was pathological - under the 5th percentile of the national references - in 25% of cases and 12% of controls (p = 0.020) before bronchodilation and in 18% of cases and 5% of controls (p = 0.003) after bronchodilation. FEV1/FVC was pathological in 25% of cases and 13% of controls (p = 0.034) before bronchodilation. Logistic regression, adjusted for current asthma and maternal smoking, showed that infant bronchiolitis was associated with pathological FEV1 before (odds ratio 2.4) and after (odds ratio 4.4) bronchodilation. The result was similar for positive respiratory syncytial virus cases. CONCLUSION: Reduced FEV1 after bronchodilation was found in early adolescence after infant bronchiolitis, suggesting irreversible bronchial obstruction.

Interleukin-10 gene polymorphism rs1800896 is associated with post-bronchiolitis asthma at 11-13 years of age.

AIM: Interleukin-10 (IL-10) is an anti-inflammatory cytokine that is involved with bronchiolitis and asthma. We evaluated associations between four IL-10 polymorphisms, namely rs1800871, rs1800872, rs1800890 and rs1800896, and post-bronchiolitis asthma in young adolescents. METHODS: The cohort consisted of 125 children hospitalised for bronchiolitis at Tampere University Hospital, Finland, in 2000-2004, at less than six months of age. At 11-13 years, asthma diagnoses and asthma-presumptive symptoms, allergic rhinitis and use of inhaled corticosteroids (ICS) were registered. Data on the four polymorphisms and their genotypes, haplotypes and allele frequencies were analysed in relation to asthma, allergic rhinitis and asthma medication. RESULTS: The variant IL-10 rs1800896 genotype was associated with less persistent asthma at five to seven and 11-13 years of age (4.3 versus 15.2%, p = 0.04) than the wild genotype and less ICS use during the previous 12 months (5.4 versus 18.2%, p = 0.03), as was the variant allele G. Allele A was associated with more persistent asthma and ICS use. The significant differences between the variant and wild genotypes were lost in adjusted logistic regression, but the direction of the association remained. CONCLUSION: IL-10 rs1800896 gene polymorphism was associated with post-bronchiolitis asthma at 11-13 years of age in children hospitalised for bronchiolitis at less than six months of age.

Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders.

BACKGROUND: Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos-XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT). METHODS: Data from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used. RESULTS: Fifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5-552 months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC (P = .006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 [46%] vs 12/21 [57%], P = .45). Median follow-up was 35 months (range, 2-168 months). No secondary malignancies were reported during 15 years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved. CONCLUSION: RIC HCT resolves DNA repair disorder-associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.

Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections.

Background Combined immunodeficiencies are marked by inborn errors of T-cell immunity in which the T cells that are present are quantitatively or functionally deficient. Impaired humoral immunity is also common. Patients have severe infections, autoimmunity, or both. The specific molecular, cellular, and clinical features of many types of combined immunodeficiencies remain unknown. Methods We performed genetic and cellular immunologic studies involving five unrelated children with early-onset invasive bacterial and viral infections, lymphopenia, and defective T-cell, B-cell, and natural killer (NK)-cell responses. Two patients died early in childhood; after allogeneic hematopoietic stem-cell transplantation, the other three had normalization of T-cell function and clinical improvement. Results We identified biallelic mutations in the dedicator of cytokinesis 2 gene (DOCK2) in these five patients. RAC1 activation was impaired in the T cells. Chemokine-induced migration and actin polymerization were defective in the T cells, B cells, and NK cells. NK-cell degranulation was also affected. Interferon-α and interferon-λ production by peripheral-blood mononuclear cells was diminished after viral infection. Moreover, in DOCK2-deficient fibroblasts, viral replication was increased and virus-induced cell death was enhanced; these conditions were normalized by treatment with interferon alfa-2b or after expression of wild-type DOCK2. Conclusions Autosomal recessive DOCK2 deficiency is a new mendelian disorder with pleiotropic defects of hematopoietic and nonhematopoietic immunity. Children with clinical features of combined immunodeficiencies, especially with early-onset, invasive infections, may have this condition. (Supported by the National Institutes of Health and others.).

Toll-like receptor 1 and 10 gene polymorphisms are linked to postbronchiolitis asthma in adolescence.

AIM: Toll-like receptors (TLR) are innate immunity molecules and our previous studies found that TLR1 gene polymorphism was associated with postbronchiolitis asthma at one to six years of age, as was TLR10 at five to seven years of age. This study examined any associations at 11-13 years of age. METHODS: This prospective follow-up study was part of an ongoing evaluation of children admitted to Tampere University Hospital, Finland, for bronchiolitis in 2001-2004 at less than six months of age. We evaluated the association of TLR1 rs5743618 and TLR10 rs4129009 polymorphisms with asthma and asthma medication in 125 children aged 11-13 years. RESULTS: Associations were measured as adjusted odd ratios (aOR) with 95% confidence intervals (95% CI). The variant TLR1 rs5743618 (aOR 4.04, 95% CI 0.99-13.01) and TLR10 rs4129009 (aOR 7.02, 95% CI 1.56-31.53) genotypes increased the risk of needing inhaled corticosteroids (ICSs) at 11-13 years of age. The variant TLR10 genotype (aOR 7.69, 95% CI 1.35-43.95) increased the risk of persistent asthma continuing from five to seven years of age until 11-13 years of age. The results were similar when the combined genotypes were analysed. [Correction added on 3 October 2017, after online publication: The data in the variant TRL1 rs5743618 genotype were incorrect and have been corrected in this version.] CONCLUSION: Polymorphisms in both the TLR1 and TLR10 genes may increase the risk of asthma at 11-13 years after infant bronchiolitis.

Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes.

BACKGROUND: The nuclear factor κ light-chain enhancer of activated B cells (NF-κB) signaling pathway is a key regulator of immune responses. Accordingly, mutations in several NF-κB pathway genes cause immunodeficiency. OBJECTIVE: We sought to identify the cause of disease in 3 unrelated Finnish kindreds with variable symptoms of immunodeficiency and autoinflammation. METHODS: We applied genetic linkage analysis and next-generation sequencing and functional analyses of NFKB1 and its mutated alleles. RESULTS: In all affected subjects we detected novel heterozygous variants in NFKB1, encoding for p50/p105. Symptoms in variant carriers differed depending on the mutation. Patients harboring a p.I553M variant presented with antibody deficiency, infection susceptibility, and multiorgan autoimmunity. Patients with a p.H67R substitution had antibody deficiency and experienced autoinflammatory episodes, including aphthae, gastrointestinal disease, febrile attacks, and small-vessel vasculitis characteristic of Behçet disease. Patients with a p.R157X stop-gain experienced hyperinflammatory responses to surgery and showed enhanced inflammasome activation. In functional analyses the p.R157X variant caused proteasome-dependent degradation of both the truncated and wild-type proteins, leading to a dramatic loss of p50/p105. The p.H67R variant reduced nuclear entry of p50 and showed decreased transcriptional activity in luciferase reporter assays. The p.I553M mutation in turn showed no change in p50 function but exhibited reduced p105 phosphorylation and stability. Affinity purification mass spectrometry also demonstrated that both missense variants led to altered protein-protein interactions. CONCLUSION: Our findings broaden the scope of phenotypes caused by mutations in NFKB1 and suggest that a subset of autoinflammatory diseases, such as Behçet disease, can be caused by rare monogenic variants in genes of the NF-κB pathway.

IL-17A gene polymorphism rs2275913 is associated with the development of asthma after bronchiolitis in infancy.

BACKGROUND: Interleukin-17 (IL-17A) is a mainly pro-inflammatory cytokine, and IL-17 signaling implicates in the development of allergic asthma. The polymorphism rs2275913 in the promoter region of the IL-17A gene has in previous studies been associated with asthma susceptibility. The objective was to evaluate the association between IL-17A rs2275913 (-197G>A) polymorphism and post-bronchiolitis asthma and/or allergic rhinitis in a prospective 11-13 years post-bronchiolitis follow-up. METHODS: 166 previously healthy full-term infants, hospitalized for bronchiolitis at age less than 6 months, were invited to follow-up visits at the ages of 5-7 years and 11-13 years. Asthma diagnoses and presumptive symptoms, allergic rhinitis and use of inhaled corticosteroids (ICS) were registered. Blood samples for IL-17A rs2275913 (-197G>A) polymorphism were obtained during hospitalization or at the 5-7 years control visit. RESULTS: There were no significant differences between children with the wild GG and variant GA or AA genotype in the severity of bronchiolitis during hospitalization or in the outcomes until the age 5-7 years. At 11-13 years of age, children with the variant GA or AA genotype had significantly less often current asthma, use of ICSs during last 12 months or allergic rhinitis than those with the wild GG genotype. The ICS use during last 12 months retained the statistical significance in adjusted analyses (adjusted OR 0.25), whereas current asthma and allergic rhinitis marginally lost it. CONCLUSIONS: The IL-17A rs2275913 (-197G>A) polymorphism decreased the risk of post-bronchiolitis asthma at 11-13 years of age, but not earlier in life, in the present prospective, long-term follow-up study.

Healthcare costs doubled when children had urinary tract infections caused by extended-spectrum ß-lactamase-producing bacteria.

AIM: The impact of the emergence of antimicrobial resistant organisms has rarely been studied in children, including the healthcare costs of urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase (ESBL)-producing bacteria. We evaluated the effect of ESBL on UTI healthcare costs and risk factors for paediatric UTIs. METHODS: This retrospective case-control study covered 2005-2014 and focused on children below 16 years of age treated in a University hospital: 22 children with UTIs caused by ESBL-producing bacteria and 56 ESBL-negative UTI controls. RESULTS: The median healthcare costs were 3929 Euros for the 22 ESBL patients and 1705 Euros for the 56 controls (p = 0.015). The mean and standard deviation length of hospital stay was 7.4 (5.9) days for the ESBL group and 3.6 (2.3) days for the controls (p = 0.007), and the figures for antibiotic treatment were 12.3 (5.5) days versus 5.8 (3.0) days (p < 0.001), respectively. The odd ratios for ESBL were underlying disease (6.63, p = 0.013), previous hospitalisation (6.07, p = 0.009) and antibiotic prophylaxis (5.20, p = 0.035). CONCLUSION: Healthcare costs more than doubled when children had ESBL-related UTIs, mainly due to their increased length of stay. Effective oral antibiotics are urgently needed to treat paediatric infections caused by ESBL-producing bacteria.

Dysregulation of adaptive immune responses in complement C3-deficient patients.

In addition to its effector functions, complement is an important regulator of adaptive immune responses. Murine studies suggest that complement modulates helper T-cell differentiation, and Th1 responses in particular are impaired in the absence of functional complement. Here, we have studied humoral responses to toxoid vaccines in eight patients with C3 deficiency, representing more than 25% of all the known patients worldwide. Serum cytokine levels were also studied. The patients developed normal Ig responses to tetanus and diphtheria toxoids, but IgE levels were low. The pattern of antigen-specific IgG subclasses was abnormal, with increased Th1-related IgG3 responses, low IgG2, and almost completely undetectable IgG4. The patients also had increased amounts of Th1-related cytokines IL-12p70 and IL-21, and these showed a positive correlation with IgG3 levels. Our results confirm that complement modulates Th differentiation, but reveal a more nuanced outcome than previously reported. Since IgG4 has been linked to tolerogenic responses, the data also suggest that in the absence of functional complement at least some aspects of systemic tolerance are impaired.

Audits show that specialist paediatric training programmes are sensitive to medical, staffing and economic changes.

AIM: In Finland, specialist paediatrics training is led by university hospitals, but half of it is carried out in regional central hospitals. We audited the training provided by four regional central hospitals in the tertiary care area covered by Tampere University Hospital, in 2003, 2008 and 2015. METHODS: The audits comprised hospital visits and discussions with the chief doctor of the paediatric clinic, the trainees and the specialists who trained them. A modified version of the European Union of Medical Specialists 1997 protocol was used, and the key areas that performed poorly in the audits were followed up. RESULTS: In 2008 and 2015, most of the key follow-up issues had improved, but two main areas in need of further development were identified in 2015. These were that educational objectives should be clarified, and their implementation systemically followed up, and that trainees should spend more time working in outpatient settings. CONCLUSION: Since 2003, a marked improvement had taken place in the paediatric training provided by regional central hospitals, partly because of the increase in paediatric specialist resources. This study underlines the importance of repeat audits and the need for co-opera-tion between the university hospital and regional hospitals, including regular visits.

Following up infant bronchiolitis patients provided new evidence for and against the united airway disease hypothesis.

AIM: The united airway disease (UAD) hypothesis suggests that allergic rhinitis and asthma develop together. We evaluated the evidence for and against the UAD hypothesis at five to seven years of age after hospitalisation for bronchiolitis at less than six months. METHODS: This study used prospective follow-up data for 102 children hospitalised for bronchiolitis under the age of six months. We included the presence of previous and current asthma, prolonged rhinitis and skin prick tests (SPT) to common inhaled allergens and lung function by impulse oscillometry (IOS) at five to seven years of age. Bronchial hyper-reactivity (BHR) was assessed using the exercise challenge test and bronchodilation test. RESULTS: Current asthma, but not previous transient asthma, was associated with prolonged rhinitis and a positive SPT. BHR, which reflected reactive airways, but not lung function, was associated with respiratory allergy, namely the combination of current asthma, prolonged rhinitis and a positive SPT. CONCLUSION: This post-bronchiolitis follow-up study suggested an association between respiratory allergy and reactive airways at five to seven years of age, which supported the UAD hypothesis. However, previous transient asthma and a reduction in lung function reduction did not support the hypothesis.