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.

Tonsillotomy for Periodic Fever Syndrome: A Randomized and Controlled Trial.

OBJECTIVE: Tonsillectomy is an effective treatment for periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Tonsillotomy has a milder operative risk profile and postoperative morbidity in children than tonsillectomy. We aimed to compare the efficacy of tonsillotomy to observation-only in children with PFAPA syndrome at a 3-month follow-up. METHODS: This was a randomized multicenter trial with sequential design. Participants were randomized into a tonsillotomy group and a control group that was only observed. The trial started in 1/2017 and was accomplished in 12/2021 with 16 patients (10 boys, six girls, the mean age 4.2 years). The symptoms were monitored with daily symptom diaries. RESULTS: After the 3-month follow-up, 7/8 patients (87.5%) in the tonsillotomy group and 2/8 (25%) patients in the control group were free from PFAPA symptoms (95% CI 13% to 87%; p = 0.0021). The mean number of days with fever was 2.6 (SD 3.7) in the tonsillotomy group and 8.0 (SD 6.5) days in the control group (n = 8) (p = 0.06). Mean number of fever days compatible with PFAPA syndrome was 0.8 (SD 1.4) in the tonsillotomy group and 6.5 (SD 6.0) in the control group (95%CI -10% to -1%; p = 0.007). Rescue tonsillectomy was needed for all patients in the control group and none of the patients in the tonsillotomy group. CONCLUSIONS: Tonsillotomy might be an effective treatment option for children with PFAPA syndrome. Further studies are needed to clarify the long-term efficacy of tonsillotomy for treating PFAPA. LEVEL OF EVIDENCE: 2 Laryngoscope, 134:968-972, 2024.

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.

Risk factors for irreversible airway obstruction after infant bronchiolitis.

BACKGROUND: Increasing evidence shows that environmental factors in childhood play a role in development of irreversible airway obstruction. We evaluated early-life and preschool-age risk factors for irreversible airway obstruction in adolescence after bronchiolitis in infancy. METHODS: This study is a secondary analysis of data collected during prospective long-term follow-up of our post-bronchiolitis cohort. Risk factor data were collected during hospitalisation and on follow-up visits at 5-7 and 10-13 years of ages. Lung function was measured from 103 participants with impulse oscillometry at 5-7 years of age and from 89 participants with flow-volume spirometry at 10-13 years of age. RESULTS: Asthma diagnosis at <12 months of age showed a significant association with irreversible airway obstruction at 10-13 years of age independently from current asthma. Irreversible airway obstruction was less frequent in children with variant than wild genotype of the Toll-like receptor 4(TLR4) rs4986790, but the significance was lost in logistic regression adjusted for current asthma and weight status. Higher post-bronchodilator respiratory system resistance at 5 Hz and lower baseline and post-bronchodilator reactance at 5 Hz by impulse oscillometry at 5-7 years of age were associated with irreversible airway obstruction at 10-13 years of age. CONCLUSION: Asthma diagnosis during the first living year and worse lung function at preschool age increased the risk for irreversible airway obstruction at 10-13 years of age after bronchiolitis. TLR4 rs4986790 polymorphism may be protective for development of irreversible airway obstruction after bronchiolitis.

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.

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.

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.

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.

Polymorphisms in the promoter region of IL10 gene are associated with virus etiology of infant bronchiolitis.

BACKGROUND: Bronchiolitis is the most common infection leading to hospitalization in infancy. Interleukin-10 (IL-10) is an anti-inflammatory cytokine, and in our previous study, IL10 gene rs1800896 (- 1082A/G) polymorphism was associated with viral etiology of infant bronchiolitis. The objective of this study was to evaluate the associations between IL10 single nucleotide polymorphisms (SNPs) at rs1800890 (- 3575A/T), rs1800871 (- 819C/T) or rs1800872 (- 592C/A) either alone or combined with the SNP at rs1800896 (- 1082G/A), and the etiology and severity of infant bronchiolitis. METHODS: Data on four IL10 SNPs were available from 135 full-term infants, hospitalized for bronchiolitis at age less than 6 months, and from 378 to 400 controls. Viral etiology was studied, and oxygen support, feeding support and the length of stay in hospital were recorded during bronchiolitis hospitalization. RESULTS: Infants with rhinovirus bronchiolitis had the IL10 rs1800890 variant AT or TT genotype less often (18.2%) than controls (63.3%, P = 0.03), and likewise, had the IL10 rs1800896 variant AG or GG genotype less often (27.3%) than controls (65.5%, P = 0.009). Twenty-eight infants with bronchiolitis had the variant-variant Grs1800896Trs1800890 haplotype, and none of them had rhinovirus infection. The IL10 rs1800871 or rs1800872 genotypes showed no associations with viruses. No association was found between any genotypes and bronchiolitis severity measures. CONCLUSION: IL10 rs1800890 and rs1800896 polymorphisms differed between infants with rhinovirus bronchiolitis and controls, but not between infants with respiratory syncytial virus bronchiolitis and controls.

Impulse oscillometry at preschool age is a strong predictor of lung function by flow-volume spirometry in adolescence.

BACKGROUND: The transition from early childhood wheezing to persistent asthma is linked to lung function impairment over time. Little is known how the methods used to study lung function at different ages correlate longitudinally. METHODS: Sixty-four children with a history of hospitalization for bronchiolitis before 6 months of age were prospectively studied with impulse oscillometry (IOS) at the mean age of 6.3 years and these preschool IOS results were compared with flow-volume spirometry (FVS) measurements at mean age of 11.4 years. RESULTS: The baseline respiratory system resistance at 5 Hz (Rrs5) showed a modest statistically significant correlation with all baseline FVS parameters except FVC. The post-bronchodilator (post-BD) Rrs5 showed a modest statistically significant correlation with post-BD FEV1 and FEV1 /FVC. The bronchodilator-induced decrease in Rrs5 showed a modest statistically significant correlation with the percent increase in FEV1 . Baseline and post-BD respiratory reactance at 5 Hz (Xrs5) showed a modest statistically significant correlation with baseline and post-BD FVS parameters except post-BD FEV1 /FVC, respectively, and post-BD Xrs5 showed a strong correlation with post-BD FVC (ρ = 0.61) and post-BD FEV1 (ρ = 0.59). In adjusted linear regression, preschool Xrs5 remained as a statistically significant independent predictor of FVS parameters in adolescence; the one-unit decrease in the Z-score of preschool post-BD Xrs5 predicted 9.6% lower post-BD FEV1 , 9.3% lower post-BD FVC, and 9.7% lower post-BD MEF50 when expressed as %-predicted parameters. CONCLUSION: Persistent post-BD small airway impairment in children with a history of bronchiolitis detected with IOS at preschool age predicted FVS results measured in early adolescence.

TLR5 rs5744174 gene polymorphism is associated with the virus etiology of infant bronchiolitis but not with post-bronchiolitis asthma.

BACKGROUND AND AIM: Bronchiolitis is a leading cause of hospitalization in infants and is associated with a risk of subsequent asthma. The innate immunity genes, such as those encoding toll-like receptors (TLRs), are likely to play a role in bronchiolitis and post-bronchiolitis outcome. Thus far, only one study has considered TLR5 genes in respiratory syncytial virus (RSV) bronchiolitis. The aim of this study was to investigate the association of TLR5 gene polymorphism with virus etiology and severity of bronchiolitis, and with post-bronchiolitis asthma. METHODS: We recruited 164 infants (age < 6 months) hospitalized for bronchiolitis in this study and determined TLR5 rs5744174 (C > T) single nucleotide polymorphism, virus etiology and severity markers of bronchiolitis, and presence of post-bronchiolitis asthma until age 11 to 13 years. RESULTS: RSV was detected in 113 (68.9%), rhinovirus in 19 (11.6%), and some other virus in 20 (12.2%) cases. Non-RSV etiology was more common among infants with the variant CT or TT genotype in the TLR5 rs5744174 gene than in those with the CC genotype (89.7% vs 71.7%, P = 0.03). TLR5 rs5744174 polymorphism was not associated with the need of supplementary oxygen or feeding support, with the length of hospital stay, or with post-bronchiolitis asthma at any age. CONCLUSION: The TLR5 rs5744174 variant genotype may increase the susceptibility to bronchiolitis not caused by RSV.

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.

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.

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.

Polymorphism in the gene encoding toll-like receptor 10 may be associated with asthma after bronchiolitis.

Toll-like receptors (TLRs) recognise microbes that contribute to the severity of bronchiolitis and the subsequent risk of asthma. We evaluated whether post-bronchiolitis asthma was associated with polymorphisms in the TLR3 rs3775291, TLR4 rs4986790, TLR7 rs179008, TLR8 rs2407992, TLR9 rs187084, and TLR10 rs4129009 genes. The gene polymorphisms were studied at the age of 6.4 years (mean) in 135 children hospitalised for bronchiolitis in infancy. The outcome measure was current or previous asthma. Current asthma was more common (30%) in children with the variant AG or GG genotype in the TLR10 rs4129009 gene versus those who were homozygous for the major allele A (11%) (p = 0.03). The adjusted odds ratio (aOR) was 4.30 (95% CI 1.30-14.29). Asthma ever was more common (34.6%) in girls with the TLR7 variant AT or TT genotype versus those who were homozygous for the major allele A (12.5%) (p = 0.03). The adjusted OR was 3.93 (95% CI 1.06-14.58). Corresponding associations were not seen in boys. There were no significant associations between TLR3, TLR4, TLR8, or TLR9 polymorphisms and post-bronchiolitis asthma. Polymorphism in the TLR10 gene increases and in the TLR7 gene may increase the risk of asthma in preschool-aged children after infant bronchiolitis.