Effects of antibiotics, hospitalisation and surgical complications on self-reported immunological vulnerability following paediatric open-heart surgery and thymectomy: a single-centre retrospective cohort study.

BACKGROUND: Partial or complete thymectomy is routinely performed in paediatric open-heart surgeries when treating congenital heart defects. Whether or not thymectomised children require systematic immunological monitoring later in life is unknown. The objective of this study was to investigate the effects of preoperatively and postoperatively used antibiotics, hospitalisation and surgical complications on self-reported immunological vulnerability in paediatric patients with early thymectomy to better recognise the patients who could benefit from immunological follow-up in the future. METHODS: We conducted a retrospective cohort study, including 98 children and adolescents aged 1-15 years, who had undergone an open-heart surgery and thymectomy in infancy and who had previously answered a survey regarding different immune-mediated symptoms and diagnoses. We performed a comprehensive chart review of preoperative and postoperative factors from 1 year preceding and 1 year following the open-heart surgery and compared the participants who had self-reported symptoms of immunological vulnerability to those who had not. RESULTS: The median age at primary open-heart surgery and thymectomy was 19.5 days in the overall study population (60% men, n=56) and thymectomies mainly partial (80%, n=78). Broad-spectrum antibiotics were more frequently used preoperatively in participants with self-reported immunological vulnerability (OR=3.05; 95% CI 1.01 to 9.23). This group also had greater overall use of antibiotics postoperatively (OR=3.21; 95% CI 1.33 to 7.76). These findings were more pronounced in the subgroup of neonatally operated children. There was no statistically significant difference in the duration of intensive care unit stay, hospitalisation time, prevalence of severe infections, surgical complications or glucocorticoid use between the main study groups. CONCLUSION: Antimicrobial agents were more frequently used both preoperatively and postoperatively in thymectomised children with self-reported immunological vulnerability after thymectomy. Substantial use of antimicrobial agents early in life should be considered a potential risk factor for increased immunological vulnerability when evaluating the significance of immune-mediated symptom occurrence in thymectomised paediatric patients.

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.

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.

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.

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.

Tonsillitis in children: unnecessary laboratory studies and antibiotic use.

BACKGROUND: The Finnish Current Care Guidelines on diagnostics and treatment of sore throat recommend the treatment of only group A streptococcus (GAS) positive cases with penicillin. The aim of the study was to evaluate how these guidelines are followed in the pediatric emergency unit. METHODS: We analyzed retrospectively the data on microbiological studies and blood tests done, and data on prescribing of antibiotics, of 200 children admitted for febrile exudative tonsillitis. RESULTS: After the clinical diagnosis of exudative tonsillitis, antigen test and/or culture for GAS identification was done in >95% of cases. All the 32 (16%) children with GAS infection, but also 52 (38%) of the 137 children without any evidence of bacterial infection received antibiotics. Additional laboratory studies were done in 96% of children. Serum C-reactive concentrations or white blood cell counts were not able to separate streptococcal from non-streptococcal tonsillitis. No serious bacterial infection was diagnosed. CONCLUSIONS: The Finnish Current Care Guidelines lead to over-treatment with antibiotics. None of the 200 children returned after discharge, suggesting that undertreatment did not happen.

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.).

Reactive oxygen species deficiency induces autoimmunity with type 1 interferon signature.

AIMS: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the phagocyte reactive oxygen species (ROS)-producing NOX2 enzyme complex and characterized by recurrent infections associated with hyperinflammatory and autoimmune manifestations. A translational, comparative analysis of CGD patients and the corresponding ROS-deficient Ncf1(m1J) mutated mouse model was performed to reveal the molecular pathways operating in NOX2 complex deficient inflammation. RESULTS: A prominent type I interferon (IFN) response signature that was accompanied by elevated autoantibody levels was identified in both mice and humans lacking functional NOX2 complex. To further underline the systemic lupus erythematosus (SLE)-related autoimmune process, we show that naïve Ncf1(m1J) mutated mice, similar to SLE patients, suffer from inflammatory kidney disease with IgG and C3 deposits in the glomeruli. Expression analysis of germ-free Ncf1(m1J) mutated mice reproduced the type I IFN signature, enabling us to conclude that the upregulated signaling pathway is of endogenous origin. INNOVATION: Our findings link the previously unexplained connection between ROS deficiency and increased susceptibility to autoimmunity by the discovery that activation of IFN signaling is a major pathway downstream of a deficient NOX2 complex in both mice and humans. CONCLUSION: We conclude that the lack of phagocyte-derived oxidative burst is associated with spontaneous autoimmunity and linked with type I IFN signature in both mice and humans.

Increased plasma levels of pro- and anti-inflammatory cytokines in patients with febrile seizures.

PURPOSE: Pro- and antiinflammatory cytokines regulate the febrile response during infection. Febrile seizures (FSs) conversely are associated with rapid onset of high fever. Activation of the cytokine network has been shown in previous studies of FSs and cytokines. In this study, the association between cytokines and FSs was further investigated. METHODS: Interleukin-1beta (IL-1beta), interleukin-1 receptor antagonist (IL-1RA), interleukin-6 (IL-6), interleukin-10, and tumor necrosis factor-alpha plasma levels were measured with enzyme-linked immunosorbent assay in 55 children with FSs and in 20 age-matched febrile controls immediately on arrival at the hospital. Cerebrospinal fluid cytokine levels also were measured in 16 FS children. RESULTS: The plasma IL-1RA/IL-1beta ratio (mean, 2,133 vs. 119; median, 790 vs. 105; p < 0.0001) and plasma IL-6 (mean, 41.7 pg/ml vs. 16.1 pg/ml; median, 19.6 pg/ml vs. 10.5 pg/ml; p = 0.005) were significantly higher in FS patients compared with control children. Logistic regression analysis was used to find the most significant predisposing factors for FSs. In this analysis, the high plasma IL-1RA/IL-1beta ratio was the most significant factor connected to FSs (OR, 41.5; 95% CI, 4.9-352.8), but high plasma IL-6 also was significantly associated with FSs (OR, 5.3; 95% CI, 1.4-20.3). CONCLUSIONS: Present results support the hypothesis that the cytokine network is activated and could have a role in the pathogenesis of FS.